WO2019051213A1

WO2019051213A1 - Methods, systems and devices for creating therapeutic blood flow pathways

Info

Publication number: WO2019051213A1
Application number: PCT/US2018/049935
Authority: WO
Inventors: Paul Sobotka; Rodney Brenneman; J. Christopher Flaherty
Original assignee: Rox Medical, Inc.
Priority date: 2017-09-08
Filing date: 2018-09-07
Publication date: 2019-03-14

Abstract

Provided is a method of treating a patient by creating a flow pathway in the patient. The method comprises selecting a patient suffering from a disease and/or disorder, and subsequently creating a flow pathway between a first vascular location and a second vascular location. The first vascular location comprises a source of arterial blood and the second vascular location comprises a source of venous blood. A physiologic parameter of the patient is measured, and the flow pathway can be modified based on the measurement. The flow pathway treats the patient disease and/or disorder while avoiding significantly increasing heart rate of the patient. Systems and devices for creating a flow pathway are also provided.

Description

METHODS, SYSTEMS AND DEVICES FOR CREATING THERAPEUTIC BLOOD

FLOW PATHWAYS

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of U.S. Provisional Application Serial Number 62/556,200 (Attorney Docket No. 29919-715.101, Client Docket No. ROX-031-PR1), entitled "Methods, Systems and Devices for Creating Therapeutic Blood Flow Pathways", filed September 8, 2017, the content of which is incorporated herein by reference in its entirety for all purposes.

[002] This application is related to, but does not claim priority to, the following applications: United States Patent Application Serial Number 15/599,073 (Attorney Docket No. RXMD-N-Z002.13-US, Client Docket No. ROX-003-US-CIP10), entitled "Device and Method for Establishing an Artificial Arterio- Venous Fistula", filed May 18, 2017; U.S. Patent Number 8,641,747 (Attorney Docket No. 29919-704.202, Client Docket No. ROX- 014-US-Parent), entitled "Devices for Arterio- Venous Fistula Creation", filed June 13, 2005; U.S. Patent Number 8,016,782 (Attorney Docket No. 29919-704.203, Client Docket No. ROX-015-US-Parent), entitled "Methods for Providing Oxygenated blood to Venous

Circulation", filed June 13, 2005; United States Patent Application Serial Number 14/868,652 (Attorney Docket No. 29919-706.303, Client Docket No. ROX-006-US-CON2), entitled "Devices, Systems, and Methods for Creation of a Peripherally Located Fistula", filed September 29, 2015; United States Patent Application Serial Number 15/667,572 (Attorney Docket No. 29919-707.303, Client Docket No. ROX-012-US-CON2), entitled "Devices, Systems, and Methods for Peripheral Arteriovenous Fistula Creation", filed August 2, 2017; United States Patent Application Serial Number 14/587,314 (Attorney Docket No. RXMD-N- Z004.01-US, Client Docket No. ROX-023-US-CIP1), entitled "Device and Method for Establishing an Artificial Arteriovenous Fistula", filed December 31, 2014; United States Patent Application Serial Number 12/905,412 (Attorney Docket No. 29919-709.201, Client Docket No. ROX-022-US-Parent), entitled "Devices, Systems, and Methods for Enhanced Visualization of the Anatomy of a Patient", filed October 15, 2010; and United States Patent Application Serial Number 15/374,763 (Attorney Docket No. 29919-710.302, Client Docket No. ROX-024-US-CON1), entitled "Methods, Systems and Devices for Treating

Hypertension", filed December 9, 2016; United States Patent Application Serial Number 14/766,125 (Attorney Docket No. 29919-711.831, Client Docket No. ROX-025-US), entitled "Methods, Systems and Devices for Treating Cardiac Arrhythmias", filed August 5, 2015; United States Patent Application Serial Number 14/970,217 (Attorney Docket No. 29919- 712.301, Client Docket No. ROX-026-US), entitled "Methods, Systems and Devices for Treating Erectile Dysfunction", filed December 15, 2015; and United States Patent

Application Serial Number 15/173,505 (Attorney Docket No. 29919-713.301, Client Docket No. ROX-027-US), entitled "Methods, Systems and Devices for Treating Orthostatic

Intolerance", filed June 3, 2016; International PCT Application Serial Number

PCT/US2016/041783 (Attorney Docket No. 29919-714.601, Client Docket No. ROX-028- PCT-Parent), entitled "Methods, Systems and Devices for Creating a Blood Flow Pathway to Treat a Patient", filed July 11, 2016; the contents of each of which are incorporated herein by reference in their entirety for all purposes.

TECHNICAL FIELD

[003] The embodiments disclosed herein relate generally to systems, devices and methods for treating a patient disease or disorder. A flow pathway is created between a source of arterial blood and a source of venous blood to provide a therapeutic effect.

BACKGROUND

[004] Hypertension is a chronic medical condition in which the blood pressure in the arteries is elevated requiring the heart to work harder to circulate blood through the vessels. Blood pressure includes two measurements, systolic and diastolic, which depend on whether the heart muscle is contracting (systole) or relaxed between beats (diastole). Normal blood pressure at rest is within the range of 100-400mmHg systolic and 60-90mmHg diastolic. High blood pressure is typically present if it is persistently at or above 140/90mmHg.

[005] Hypertension is a major risk factor for stroke, myocardial infarction, heart failure, aneurysms of the arteries such as aortic aneurysms, peripheral arterial disease, and is a cause of chronic kidney disease. Even moderate elevation of arterial blood pressure is associated with a shortened life expectancy.

[006] Current treatment methods, such as the administration of pharmaceuticals and renal denervation therapy, are associated with incomplete or otherwise limited treatment; high cost; invasiveness; and numerous undesirable side effects. There is therefore a need for improved approaches, including both devices and methods, for treating patients suffering from hypertension. SUMMARY

[007] According to one aspect of the technology, a method of treating a patient comprises: selecting a patient exhibiting a disease and/or disorder; creating a flow pathway between a first vascular location and a second vascular location, the first vascular location comprising a source of arterial blood and the second vascular location comprising a source of venous blood; measuring at least one physiologic parameter of the patient; and modifying the flow pathway based on the measurement. The method can treat the patient disease and/or disorder while avoiding significantly increasing heart rate of the patient.

[008] In some embodiments, the method avoids a heart rate increase greater than 5%.

[009] In some embodiments, the method avoids a heart rate increase greater than 10%.

[010] In some embodiments, the method avoids a heart rate increase greater than 15%.

[011] In some embodiments, the at least one physiologic parameter measured comprises heart rate. The average heart rate of the patient can be measured. The modifying of the flow pathway can comprise reducing flow rate through the flow pathway if the measured heart rate is above a threshold. The heart rate threshold can be 5bpm. The heart rate threshold can be lObpm. The heart rate threshold can be 15bpm. The modifying of the flow pathway can comprise: reducing flow through the flow pathway; stopping flow through the flow pathway; and/or stopping flow through the flow pathway and creating a new flow pathway (e.g. at a different location). The modifying of the flow pathway can comprise placing a covered stent proximate the flow pathway. The first vascular location can comprise an artery, and the covered stent can be placed in the artery proximate the flow pathway. The second vascular location can comprise a vein, and the covered stent can be placed in the vein proximate the flow pathway. The creating the flow pathway can comprise placing an anastomotic clip between the first vascular location and the second vascular location, and the modifying of the flow pathway can comprise modifying the anastomotic clip. The modifying of the

anastomotic clip can comprise reducing the diameter of the anastomotic clip. The at least one physiologic parameter can further comprise blood pressure. The at least one physiologic parameter can further comprise systolic blood pressure or diastolic blood pressure. The at least one physiologic parameter can further comprise systolic blood pressure and diastolic blood pressure. The modifying of the flow pathway can comprise increasing flow through the flow pathway if the measured blood pressure is above a first threshold, and if the measured heart rate is below a second threshold. The modifying of the flow pathway can comprise dilating the flow pathway. The modifying of the flow pathway can comprise creating a second flow pathway. [012] In some embodiments, the at least one physiologic parameter measured comprises a physiologic parameter selected from the group consisting of: angina level; mitral

regurgitation type; mitral regurgitation severity; orthostatic intolerance level; dizziness level; lightheadedness level; a syncope event parameter; nausea level; fatigue level; tremor state; breathing state; swallowing ability; headache level; visual disturbance level; sweating level; pallor state; heart rate; cardiac output; blood pressure; systolic blood pressure; diastolic blood pressure; a respiration parameter; a blood gas parameter; blood flow; blood flow through a vein or artery within and/or proximate the right side of the heart; vascular resistance;

pulmonary resistance; average clotting time assessment; serum creatinine level assessment; level of B-type natriuretic peptide (B P); level of N-terminal pro B-type natriuretic peptide (NT-proB P); and combinations thereof.

[013] In some embodiments, the modifying the flow pathway comprises dilating the flow pathway with a balloon. The balloon can comprise a diameter between 2.5mm and 6.0mm. The balloon can comprise a diameter between 4.0mm and 5.0mm.

[014] In some embodiments, the flow pathway causes an increase in the patient's venous pressure. The patient's venous pressure can increase near-immediately after creation of the flow pathway.

[015] In some embodiments, the flow pathway causes an increase in the patient's venous pressure and/or a decrease in the patient's arterial blood pressure. The flow pathway can cause both an increase in the patient's venous pressure and a decrease in the patient's arterial blood pressure.

[016] In some embodiments, the flow pathway causes a decrease in the patient's systolic pressure. The patient's systolic pressure prior to the flow pathway creation can be at a level between 120mmHg and 220mmHg. The patient's systolic pressure prior to the flow pathway creation can be at a level between 140mmHg and 160mmHg. The patient's systolic pressure subsequent to the flow pathway creation can be at a level between 115mmHg and 180mmHg. The patient's systolic pressure subsequent to the flow pathway creation can be at a level between 120mmHg and 140mmHg. The patient's systolic pressure can be reduced between 5mmHg and 70mmHg subsequent to the creation of the flow pathway. The patient's systolic pressure can be reduced between lOmmHg and 40mmHg subsequent to the creation of the flow pathway. The patient's systolic pressure can be reduced 5% to 30% subsequent to the creation of the flow pathway. The patient's systolic pressure can be reduced 5% to 20% subsequent to the creation of the flow pathway. [017] In some embodiments, the flow pathway comprises a flow rate between 400ml/min and 1500ml/min. The flow pathway can comprise a flow rate between 600ml/min and 1200ml/min. The flow pathway can comprise a flow rate of at least 600ml/min. The flow pathway can comprise a flow rate of at least 800ml/min.

[018] In some embodiments, the flow pathway comprises a diameter between 2.5mm and 4mm.

[019] In some embodiments, the flow pathway comprises a diameter of approximately 4mm.

[020] In some embodiments, the method treats hypertension of the patient. The patient's systolic pressure prior to the flow pathway creation can be at a level above 140mmHg and/or above 160mmHg. The patient's systolic pressure can be reduced between 5mmHg and 70mmHg subsequent to the creation of the flow pathway. The patient's systolic pressure can be reduced between lOmmHg and 40mmHg subsequent to the creation of the flow pathway.

[021] In some embodiments, the method treats a disease and/or disorder selected from the group consisting of: angina; angina pectoris, mitral regurgitation; venous stenosis; deep vein thrombosis; hypertension; arterial hypertension; hypertension related to loss of capacitance artery elasticity; abnormalities of pulse and/or pressure generation related to structural hypertension; heart failure; congestive heart failure; atrial arrhythmia; ventricular arrhythmia; chronic obstructive pulmonary disease (COPD); lung fibrosis; adult respiratory distress syndrome; lymphangioleiomyomatosis; pulmonary hypertension; sleep apnea; sleep apnea due to hypoxemia or hypertension; orthostatic intolerance; orthostatic hypotension; chronic kidney disease; and combinations thereof.

[022] In some embodiments, the method reduces the likelihood of sudden cardiac death, syncope, and/or near syncope.

[023] In some embodiments, the method achieves a physiologic change selected from the group consisting of: reduced blood pressure; reduced angina; reduced mitral regurgitation; increased oxygen delivery by the arterial system; increased blood volume; increased proportion of blood flow to the descending aorta; increased blood flow to the kidneys;

increased blood flow outside the kidneys; increased cardiac output; and combinations thereof.

[024] In some embodiments, the method is constructed and arranged to increase cardiac output.

[025] In some embodiments, the method is constructed and arranged to cause one or more of: a decrease in systemic vascular resistance; a decrease in blood pressure; an increase in cardiac output; an increase in right atrial pressure; an atrial natriuretic peptide (A P) release; vasodilation; an increase in right atrial filling; a Bainbridge reflex; an increase in heart rate; peripheral sympatho-inhibition; activation of venous baroreceptors; activation of pulmonary arterial mechanoreceptors; an increase in venous oxygenation; an increase in pulmonary blood flow; an increase in arterial compliance; a decrease in a reflected pulse wave; a decrease in effective arterial volume; an increase in oxygen delivery to tissue; a decrease in chemoreceptor activity; a decrease in sympatho-excitation; a change in sodium and/or water retention; reduced renal ischemia; and combinations thereof.

[026] In some embodiments, the creating the flow pathway comprises a procedure selected from the group consisting of: dilating tissue proximate the flow pathway with a balloon; applying energy to tissue proximate the flow pathway such as RF energy applied to tissue; and combinations thereof.

[027] In some embodiments, the flow pathway comprises a fistula.

[028] In some embodiments, the first vascular location comprises an iliac artery. The second vascular location can comprise an iliac vein.

[029] In some embodiments, the first vascular location comprises an artery selected from the group consisting of: aorta; axillary; brachial; ulnar; radial; profundal; femoral; iliac; popliteal; and carotid. The second vascular location can comprise a vein.

[030] In some embodiments, the second vascular location comprises a vein selected from the group consisting of: inferior vena cava; saphenous; femoral; iliac; popliteal; brachial; basilic; cephalic; medial forearm; medial cubital; axillary; and jugular. The first vascular location can comprise an artery.

[031] In some embodiments, the first vascular location comprises a chamber of the heart. The first vascular location can comprise the left atrium and the second vascular location can comprise the right atrium. The first vascular location can comprise the left ventricle and the second vascular location can comprise the coronary sinus.

[032] In some embodiments, the first vascular location comprises the aorta and the second vascular location comprises a vein, and the flow pathway comprises a graft positioned between the aorta and the vein.

[033] In some embodiments, the flow pathway comprises a diameter of at least 2.5mm. The flow pathway can comprise a diameter of at least 3.0mm. The flow pathway can comprise a diameter of less than or equal to 6.0mm. The flow pathway can comprise a diameter of less than 5.0mm. The flow pathway can comprise a diameter of less than 4.0mm.

[034] In some embodiments, the flow pathway comprises a diameter based on a patient parameter. The patient parameter can comprise a parameter determined prior to the creation of the flow pathway. The patient parameter can comprise a parameter determined during the flow pathway creation procedure. The patient parameter can comprise a parameter measured after the creation of the flow pathway, and the method can further comprise modifying the flow pathway diameter based on the measured patient parameter. The patient parameter can comprise a parameter selected from the group consisting of: angina level; mitral regurgitation severity; mitral regurgitation type; cardiac output; blood pressure; flow rate; tilt table test result; ankle brachial index test result; venous insufficiency level; peripheral vascular resistance; shunt flow; pulmonary capillary wedge pressure; right atrial pressure; pulmonary pressure; left atrial pressure; arterial oxygenation; venous oxygenation; and combinations thereof.

[035] In some embodiments, the method further comprises creating a second flow pathway between a third vascular location and a fourth vascular location. The second flow pathway can comprise a fistula. The second flow pathway can be created at least twenty-four hours after the creation of the first flow pathway. The first vascular location can comprise an artery and the third vascular location can comprise the same artery. The second vascular location can comprise a vein and the fourth vascular location can comprise the same vein. The first vascular location can comprise the iliac artery in the right leg of the patient and the third vascular location can comprise the iliac artery in the left leg of the patient. The cumulative flow rate of the first flow pathway and the second flow pathway can comprise a flow rate of at least 400ml/min. The cumulative flow rate of the first flow pathway and the second flow pathway can comprise a flow rate of less than or equal to 1500ml/min. The method can further comprise creating multiple flow pathways comprising at least a third flow pathway. The cumulative flow rate of the multiple flow pathways can comprise a flow rate of at least 400ml/min. The cumulative flow rate of the multiple flow pathways can comprise a flow rate of less than or equal to 1500ml/min.

[036] In some embodiments, the method further comprises placing an implant proximate the flow pathway. The implant can comprise an anastomotic clip placed between the first vascular location and the second vascular location. The anastomotic clip can comprise at least a covered portion. The implant can comprise a component selected from the group consisting of: anastomotic clip; suture; staple; adhesive; and combinations thereof. The implant can comprise at least a biodegradable portion.

[037] In some embodiments, the method further comprises dilating the flow pathway. The dilating the flow pathway can comprise dilating the flow pathway by inflating a balloon in the flow pathway. [038] In some embodiments, the method further comprises modifying the flow pathway. The modifying the flow pathway can comprise dilating at least a portion of the flow pathway. The method can further comprise placing an anastomotic clip in the flow pathway, and the modifying the flow pathway can be performed after placement of the anastomotic clip. The modifying the flow pathway can comprise delivering energy to the flow pathway. The energy delivered can comprise radiofrequency energy. The modifying the flow pathway can be performed at least twenty-four hours after the creating of the flow pathway. The modifying the flow pathway can comprise modifying a flow pathway parameter selected from the group consisting of: flow pathway cross sectional diameter; flow pathway average cross sectional diameter; flow pathway flow rate; flow pathway average flow rate; diastolic pressure after flow pathway creation; diastolic pressure change after flow pathway creation; systolic pressure after flow pathway creation; systolic pressure change after flow pathway creation; ratio of diastolic to systolic pressure after flow pathway creation; difference between diastolic pressure and systolic pressure after flow pathway creation; and combinations thereof. The modifying the flow pathway can be constructed and arranged to perform a function selected from the group consisting of: increasing flow through the flow pathway; decreasing flow through the flow pathway; increasing the diameter of at least a segment of the flow pathway; decreasing the diameter of at least a segment of the flow pathway; removing tissue proximate the flow pathway; stenting a stenosis proximate the flow pathway; stenting a venous stenosis; delivering an agent to the flow pathway; delivering an agent to tissue proximate the flow pathway; delivering an agent to venous and/or arterial wall tissue proximate the flow pathway; blocking a sidebranch proximate the flow pathway; and combinations thereof.

[039] In some embodiments, the method further comprises performing a flow pathway assessment procedure. The flow pathway assessment procedure can comprise an anatomical measurement procedure. The anatomical measurement procedure can comprise measuring an anatomical feature selected from the group consisting of: a flow pathway diameter measurement; a flow pathway length measurement; a measurement of the distance between an artery and vein comprising the flow pathway; a measurement of the distance between the flow pathway and a vessel sidebranch; and combinations thereof. The flow pathway assessment procedure can comprise measuring flow at least one of within or proximate the flow pathway. The flow pathway assessment procedure can comprise measuring a flow selected from the group consisting of: flow through the flow pathway; flow in a vessel segment proximate the flow pathway; flow measured using Doppler Ultrasound; flow measured using angiographic techniques; and combinations thereof. The flow pathway assessment procedure can comprise an assessment of a patient physiologic condition. The patient physiologic condition can comprise a condition selected from the group consisting of: angina level; mitral regurgitation type; mitral regurgitation severity; orthostatic intolerance level; dizziness level; lightheadedness level; syncope events; nausea level; fatigue level; tremor state; breathing state; swallowing ability; headache level; visual disturbance level; sweating level; pallor state; cardiac output; blood pressure such as systolic and/or diastolic blood pressure; respiration; a blood gas parameter; blood flow such as blood flow through a vein or artery within and/or proximate the right side of the heart; vascular resistance;

pulmonary resistance; average clotting time assessment; serum creatinine level assessment; and combinations thereof.

[040] In some embodiments, the method further comprises applying an agent to a vein wall proximate the flow pathway. The agent can be applied to reduce venous stenosis formation. The agent can be applied in the vein downstream of the flow pathway. The agent can be applied at a time selected from the group consisting of: prior to creation of flow pathway; during creation of flow pathway; after creation of flow pathway; and combinations thereof. The agent can be applied to the vein wall at a location downstream from the flow pathway. The agent can comprise an agent selected from the group consisting of: antiproliferative agent; a chemotherapeutic agent; paclitaxel; an mTOR inhibitor; Sirolimus; Zotarolimus; Everolimus; and combinations thereof. The agent can comprise paclitaxel. A mass of at least 200μg of agent can be delivered to the venous wall. A mass of between 300μg and 600μg of agent can be delivered to the venous wall. The method can further comprise implanting an anastomotic clip in the flow pathway, and the agent can comprise a coating of the anastomotic clip. The agent can be applied to the vein wall by a delivery catheter. The agent can comprise a coating on a balloon of the delivery catheter. The delivery catheter can comprise a permeable balloon and the agent can be delivered through the permeable balloon.

[041] In some embodiments, the method further comprises implanting a venous stent in a vein proximate the flow pathway. The implanting a venous stent can comprise implanting multiple venous stents. The venous stent can be implanted to reduce future venous stenosis creation. The venous stent can comprise one or more venous stents comprising a diameter between 2mm and 16mm.

[042] In some embodiments, the method further comprises implanting a covered stent in a vein to at least partially occlude the flow pathway. The flow pathway can be at least partially occluded based on the measurement of the at least one physiologic parameter. The at least one physiologic parameter measured can comprise heart rate.

[043] According to another aspect of the invention, a system for treating angina in a patient comprises: a needle delivery device constructed and arranged to place a vessel-to- vessel guidewire from a starting vessel to a target vessel; and a flow creation device constructed and arranged to be advanced over the vessel-to-vessel guidewire and to create a flow pathway between the starting vessel and the target vessel. The system can be

constructed and arranged to treat a disease and/or disorder of the patient without significantly increasing heart rate of the patient.

[044] In some embodiments, the system further comprises a diagnostic device configured to measure at least one physiologic parameter of the patient, and the flow pathway is modified based on the measurement. The diagnostic device can be configured to measure at least heart rate. The diagnostic device can be configured to measure at least heart rate and blood pressure. The diagnostic device can be configured to measure blood pressure. The diagnostic device can be configured to measure one or more patient physiologic parameters selected from the group consisting of: angina level; mitral regurgitation type; mitral regurgitation severity; orthostatic intolerance level; dizziness level; lightheadedness level; a syncope event parameter; nausea level; fatigue level; tremor state; breathing state;

swallowing ability; headache level; visual disturbance level; sweating level; pallor state; heart rate; cardiac output; blood pressure; systolic blood pressure; diastolic blood pressure; a respiration parameter; a blood gas parameter; blood flow; blood flow through a vein or artery within and/or proximate the right side of the heart; vascular resistance; pulmonary resistance; average clotting time assessment; serum creatinine level assessment; level of B-type natriuretic peptide (B P); level of N-terminal pro B-type natriuretic peptide (NT-proB P); and combinations thereof.

[045] In some embodiments, the system further comprises a flow pathway maintaining implant. The flow pathway maintaining implant can comprise an anastomotic clip. The flow pathway maintaining implant can comprise a covered portion. The covered portion can be constructed and arranged to direct the flow of blood to and/or from the flow pathway.

[046] In some embodiments, the system further comprises a flow pathway modifying device. The flow pathway modifying device can comprise an expandable element. The flow pathway modifying device can comprise a covered stent configured to be implanted proximate the flow pathway to reduce flow through the flow pathway. The covered stent can be configured to reduce the patient's heart rate below a threshold. [047] In some embodiments, the system further comprises a patient imaging device.

[048] In some embodiments, the system further comprises a venous stent.

[049] In some embodiments, the system further comprises a covered stent. The covered stent can be constructed and arranged to be implanted to at least partially occlude the flow pathway. The system can further comprise a venous stent configured to treat a venous stenosis, the flow pathway can be created to elevate flow within the venous stent, and the covered stent can be constructed and arranged to occlude the flow pathway at least one week after the creation of the flow pathway. The covered stent can be configured to reduce the patient's heart rate below a threshold.

[050] In some embodiments, the system further comprises an agent configured to reduce a venous stenosis.

[051] In some embodiments, the system further comprises an agent delivery catheter configured to deliver an agent to a vessel wall. The system can further comprise an agent to be delivered to the vessel wall by the agent delivery catheter. The agent can comprise an agent selected from the group consisting of: anti-proliferative agent; a chemotherapeutic agent; paclitaxel; an mTOR inhibitor; Sirolimus; Zotarolimus; Everolimus; and combinations thereof. The agent can comprise paclitaxel.

BRIEF DESCRIPTION OF THE DRAWINGS

[052] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate various embodiments of the present inventive concepts, and, together with the description, serve to explain the principles of the invention. In the drawings:

[053] Fig. 1 is a flow chart of a method for treating a patient by creating a flow pathway between a first vascular location and a second vascular location, consistent with the present inventive concepts.

[054] Fig. 2 is a schematic view of a system for creating a flow pathway in a patient, consistent with the present inventive concepts.

[055] Figs. 3A through 3D are a set of steps for implanting an anastomotic clip, consistent with the present inventive concepts.

[056] Fig. 4 is a flow chart of a method for treating a patient with a flow pathway, consistent with the present inventive concepts.

[057] Fig. 5 is an angiographic view of a patient's vein and artery prior to advancement of a needle into the artery, consistent with the present inventive concepts. [058] Figs. 5A, 5B and 5C are anatomical views of three different needle trajectory paths, consistent with the present inventive concepts.

[059] Fig. 6 is a perspective view of an anastomotic clip, consistent with the present inventive concepts.

[060] Fig. 7 is a side and end view of a venous stent including a cutaway end, consistent with the present inventive concepts.

[061] Fig. 8 is a side and end view of a venous stent including an opening along its length, consistent with the present inventive concepts.

[062] Fig. 9 is a side and end view of a venous stent including a c-shaped profile, consistent with the present inventive concepts.

[063] Fig. 10 is a side and end view of a venous stent including a c-shaped end portion, consistent with the present inventive concepts.

[064] Fig. 11 is a side view of a venous stent being deployed from a delivery sheath, consistent with the present inventive concepts.

[065] Fig. 12 is a side sectional, anatomical view of an anastomotic clip and a venous stent positioned in and proximate to, respectively, a flow pathway, consistent with the present inventive concepts.

[066] Fig. 13 is a side sectional, anatomical view of an anastomotic clip, including a covered portion, positioned in a flow pathway, consistent with the present inventive concepts.

[067] Fig. 13A is a side sectional, anatomical view of the flow pathway of Fig. 13, showing only the covered portion of the anastomotic clip, consistent with the present inventive concepts.

DETAILED DESCRIPTION OF THE DRAWINGS

[068] Reference will now be made in detail to the present embodiments of the inventive concepts, examples of which are illustrated in the accompanying drawings. Wherever practical, the same reference numbers will be used throughout the drawings to refer to the same or like parts.

[069] The terminology used herein is for the purpose of describing particular

embodiments and is not intended to be limiting of the inventive concepts. As used herein, the singular forms "a," "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[070] It will be further understood that the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") when used herein, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

[071] It will be understood that, although the terms first, second, third etc. may be used herein to describe various limitations, elements, components, regions, layers and/or sections, these limitations, elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one limitation, element, component, region, layer or section from another limitation, element, component, region, layer or section. Thus, a first limitation, element, component, region, layer or section discussed below could be termed a second limitation, element, component, region, layer or section without departing from the teachings of the present application.

[072] It will be further understood that when an element is referred to as being "on" or "connected" or "coupled" to another element, it can be directly on or above, or connected or coupled to, the other element or intervening elements can be present. In contrast, when an element is referred to as being "directly on" or "directly connected" or "directly coupled" to another element, there are no intervening elements present. Other words used to describe the relationship between elements should be interpreted in a like fashion (e.g., "between" versus "directly between," "adjacent" versus "directly adjacent," etc.). When an element is referred to herein as being "over" another element, it can be over or under the other element, and either directly coupled to the other element, or intervening elements may be present, or the elements may be spaced apart by a void or gap.

[073] The term "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example "A and/or B" is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein.

[074] The term "diameter" where used herein to describe a non-circular geometry is to be taken as the diameter of a hypothetical circle approximating the geometry being described. For example, when describing a cross section, such as the cross section of a component, the term "diameter" shall be taken to represent the diameter of a hypothetical circle with the same cross sectional area as the cross section of the component being described.

[075] As used herein, the term "proximate" shall include locations relatively close to, on, in and/or within a referenced component, anatomical location, or other location. [076] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. For example, it will be appreciated that all features set out in any of the claims (whether independent or dependent) can be combined in any given way.

[077] It is to be understood that at least some of the figures and descriptions of the invention have been simplified to focus on elements that are relevant for a clear

understanding of the invention, while eliminating, for purposes of clarity, other elements that those of ordinary skill in the art will appreciate may also comprise a portion of the invention. However, because such elements are well known in the art, and because they do not necessarily facilitate a better understanding of the invention, a description of such elements is not provided herein.

[078] The systems, devices and methods of the present inventive concepts include creating a flow pathway between a first vascular location (e.g. a source of arterial blood) and a second vascular location (e.g. a source of venous blood). In some embodiments, multiple flow pathways are created. The one or more flow pathways can be configured to treat one or more diseases or disorders, such as hypertension. The flow pathway can be created while avoiding any significant changes in the patient's heart rate. The creation of the flow pathway can result in an increase (e.g. a near-immediate increase) in venous pressure, a decrease in arterial blood pressure (e.g. a decrease in systolic pressure), or both. In some embodiments, the one or more flow pathways are configured to treat a patient disease or disorder selected from the group consisting of: angina; angina pectoris, mitral regurgitation; venous stenosis; deep vein thrombosis; hypertension; arterial hypertension; hypertension related to loss of capacitance artery elasticity (referred to as "structural hypertension"); abnormalities of pulse and/or pressure generation related to structural hypertension; heart failure; congestive heart failure; atrial arrhythmia; ventricular arrhythmia; chronic obstructive pulmonary disease (COPD); lung fibrosis; adult respiratory distress syndrome; lymphangioleiomyomatosis; pulmonary hypertension; sleep apnea such as sleep apnea due to hypoxemia or hypertension; orthostatic intolerance; orthostatic hypotension; chronic kidney disease; and combinations of one or more of these. The one or more flow pathways of the present inventive concepts can be used to prevent or at least reduce the likelihood of sudden cardiac death, syncope, and/or near syncope. [079] The systems and devices of the present inventive concepts can include one or more anastomotic clips constructed and arranged to be placed in a flow pathway between a first vascular location (e.g. a source of arterial blood) and a second vascular location (e.g. a source of venous blood). In some embodiments, the anastomotic clip includes a covered portion. The covered portion can be constructed and arranged to direct the flow of blood to and/or from the flow pathway, such as to limit flow of blood from the flow pathway to a single direction within a receiving vessel (e.g. a vein) and/or to prevent or at least reduce

(hereinafter reduce) a current (already existing) or future vessel stenosis (e.g. a venous stenosis).

[080] The systems and devices of the present inventive concepts can include a venous stent configured to be positioned over, adjacent to and/or otherwise proximate a flow pathway between a first vascular location (e.g. a source of arterial blood) and a second vascular location (e.g. a source of venous blood). The venous stent can be constructed and arranged to reduce a current and/or future venous stenosis. The venous stent can include a cutaway portion or other opening configured to be positioned relatively aligned (axially and rotationally) with the opening in the vein wall at the venous wall end of the flow pathway (hereinafter "positioned over the flow pathway").

[081] The systems and devices of the present inventive concepts can include an agent and/or an agent-delivering device (e.g. an agent delivery catheter) configured to treat tissue within or proximate a flow pathway between a first vascular location (e.g. a source of arterial blood) and a second vascular location (e.g. a source of venous blood). The agent-delivering device can comprise an agent-delivering balloon that is configured to treat tissue to reduce a current and/or future vessel stenosis, such as a venous stenosis. The agent-delivering balloon can comprise a balloon coated with one or more stenosis reducing drugs or other agents and/or a permeable balloon configured to deliver the one or more agents.

[082] The systems and devices of the present inventive concepts can include a covered stent used to at least partially occlude a flow pathway, such as a flow pathway of the present inventive concepts. The covered stent can be placed in a vein or artery, such that a covered portion of the stent covers at least a portion of the flow pathway, such as to fully occlude the flow pathway at least twenty-four hours after the creation of the flow pathway.

[083] Referring now to Fig. 1, a flow chart for selecting and treating a patient by creating at least one fistula or other flow pathway between a first vascular location in the patient's arterial system and a second vascular location in the patient's venous system is illustrated, consistent with the present inventive concepts. In STEP 10, a patient assessment is performed, such as to diagnose the patient and determine whether one or more flow pathways (hereinafter "flow pathway" for either a single flow pathway or multiple flow pathways) should be created in the patient. A patient can be selected based on a disease or disorder which is diagnosed in STEP 10 or previously. In some embodiments, a patient diagnosed with hypertension and/or chronic obstructive pulmonary disease (COPD) is selected to receive a flow pathway. The flow pathway can be created to eliminate or at least decrease a symptom and/or adverse effect of hypertension and/or COPD of a patient. Alternatively or additionally, a patient can be selected to receive a flow pathway to treat a disease or disorder selected from the group consisting of: hypertension; arterial hypertension; chronic obstructive pulmonary disease (COPD); congestive heart failure; lung fibrosis; adult respiratory distress syndrome; lymphangioleiomyomatosis; pulmonary hypertension; sleep apnea such as sleep apnea due to hypoxemia or hypertension; arrhythmia; erectile dysfunction; orthostatic intolerance; angina; angina pectoris; mitral regurgitation; and combinations of these, or other disease or disorder as described herein. The flow pathway can be created to reduce arterial hypertension of the patient. The flow pathway can be created to increase cardiac output of the patient. The flow pathway can be created to increase the flow of blood to the right side of the heart, such as to increase cardiac output of the patient. The flow pathway can be created to cause a physiologic change in the patient selected from the group consisting of: increased oxygen delivery by the arterial system; increased blood volume; increased proportion of blood flow to the descending aorta; increased blood flow to the kidneys; increased blood flow outside the kidneys; increased cardiac output; and combinations of these.

[084] In STEP 20, a flow pathway creation procedure is performed on the patient. The flow pathway can be created while avoiding any significant changes in the patient's heart rate (e.g. avoiding a change in heart rate of 5% or more, or 10% or more, and/or 15% or more ), such as is described herebelow. The creation of the flow pathway can result in an increase (e.g. a near-immediate increase) in venous pressure, a decrease in arterial blood pressure (e.g. a decrease in systolic pressure), or both. In some embodiments, the flow pathway creation procedure is performed as described in reference to Fig. 4 herebelow. In some embodiments, the flow pathway creation procedure is performed using a system of devices and components similar to system 100 of Fig 2 described herebelow. The flow pathway is created between a first vascular location in the arterial system, such as an artery, and a second vascular location in the venous system, such as a vein. The flow pathway creation procedure can comprise a clinical procedure selected from the group consisting of: a surgical procedure such as a surgical procedure performed in an operating room; an interventional procedure such as an interventional procedure performed in a catheterization lab or radiology lab; and combinations of these. The flow pathway creation procedure can include the placement of a vessel-to-vessel guidewire between a starting vessel such as a vein (e.g. an iliac vein), and a target vessel such as an artery (e.g. an iliac artery). In these embodiments, the flow pathway can be created using one or more flow pathway creation devices that are advanced over the vessel-to-vessel guidewire. An anastomotic clip or other implant (e.g. one or more anastomotic clips 160 and/or 160' described herebelow) can be placed into the flow pathway via a clip placement device advanced over the vessel-to-vessel guidewire. Alternatively, a flow pathway can be created without an anastomotic clip, such as through placement of suture and/or staples (e.g. in an open surgery or via an over-the-wire suture and/or staple delivery device). One or more implants placed within and/or proximate the flow pathway can be biodegradable or comprise one or more biodegradable portions. In some embodiments, a tissue treatment procedure can be performed to create the flow pathway (e.g. with or without an implant) such as a procedure using energy (e.g. radiofrequency energy) or an adhesive (e.g. fibrin glue) coating applied to the tissue surrounding or otherwise proximate the flow pathway. One or more flow pathway treatment or modification procedures can be performed using flow pathway treatment or modification devices advanced over the vessel-to-vessel guidewire, such as the flow pathway modification procedure performed in STEP 40 herebelow (e.g. a flow pathway modification procedure performed in response to elevation of heart rate, and/or detection of another undesired patient condition). In some embodiments, the anastomotic clip comprises a covered portion, such as is described herebelow in reference to clip 160' of Fig. 13. The covered portion can be constructed and arranged to direct the flow of blood to and/or from the flow pathway, such as to limit the flow of blood from the flow pathway to a single direction within a receiving vessel (e.g. a vein) and/or to reduce an existing and/or future vessel stenosis (e.g. a venous stenosis).

[085] In some embodiments, at least one fistula or other flow pathway is created between an artery and a vein at a location distal to the renal arteries (i.e. at an infrarenal location such as a infrarenal flow pathway created between an iliac artery and an iliac vein). In some embodiments, a flow pathway is created proximate a kidney. Numerous locations for the fistula or other flow pathway can be selected, such as a flow pathway located between an artery and vein as described in reference to Fig. 4 herebelow. Alternatively or additionally, a flow pathway can be created between a chamber of the heart and a second vascular location, such as between the left atrium and the right atrium or between the left ventricle and the heart's coronary sinus. Alternatively or additionally, arterial blood can be diverted to the venous system by way of a flow pathway comprising a bypass graft, such as is described in applicant's U.S. Patent Number 8,016,782, entitled "Methods for Providing Oxygenated Blood to Venous Circulation", filed June 13, 2005, the contents of which are incorporated by reference herein in its entirety.

[086] During the flow pathway creation procedure of STEP 20 and/or in a subsequent flow pathway modification procedure (e.g. STEP 40), a flow pathway dilation procedure can be performed in which tissue surrounding, within and/or proximate the flow pathway is dilated with a balloon catheter. In some embodiments, an anastomotic clip is placed in the flow pathway and a balloon catheter is used to dilate the flow pathway and anastomotic clip simultaneously. In some embodiments, the dilating balloon comprises a diameter of approximately 2.5mm to 6mm, such as a diameter of approximately 4mm or a diameter of approximately 5mm. In some embodiments, a single flow pathway is created to treat the patient, and the flow pathway flow rate comprises a flow rate of at least 400ml/min and/or no more than 1500ml/min, such as a flow rate of at least 600ml/min, or at least 800ml/min, and/or no more than 1200ml/min. In other embodiments, multiple flow pathways are created to treat the patient (e.g. in one or more clinical procedures), and the cumulative flow rate through the multiple flow pathways comprises a flow rate of at least 400ml/min and/or no more than 1200ml/min or no more than 1500ml/min. In some embodiments, one or more flow pathways are created to treat a disease and/or disorder of the patient, such as one or more flow rates with a cumulative flow rate between 400ml/min and 1200ml/min, or between 800ml/min and 1200ml/min. Each flow pathway can comprise a diameter between 2.5mm and 5mm, or between 2.5mm and 4mm, or approximately 4mm. In each of these

embodiments, an avoidance of a significant heart rate increase (as described herein) can be achieved.

[087] In some embodiments, during the flow pathway creation procedure of STEP 20 and/or in a subsequent flow pathway modification procedure (e.g. STEP 40), one or more venous stents are placed in the vein, such as at a location over, adjacent and/or otherwise proximate the flow pathway. The one or more venous stents can be of similar construction and arrangement to venous stent 195, 195a, 195b, 195c or 195d described herebelow in reference to Figs. 2, 7, 8, 9 or 10, respectively. The one or more venous stents can be placed via a delivery catheter, such as delivery sheath 198 described herebelow in reference to Fig. 11.

[088] In some embodiments, during the flow pathway creation procedure of STEP 20 and/or in a subsequent flow pathway modification procedure (e.g. STEP 40), an agent- delivering device is positioned to deliver one or more agents to tissue, such as vessel wall tissue (e.g. venous wall tissue) to reduce a current and/or future vessel stenosis (e.g. venous stenosis). The agent-delivering device can be of similar construction and arrangement to balloon catheter 185 described herebelow in reference to Fig. 2.

[089] In STEP 30, a measurement of a patient physiologic parameter is performed, such as by using diagnostic device 200 described herebelow in reference to Fig. 2. STEP 30 can be performed in the same clinical procedure as STEP 20, and/or in a subsequent clinical procedure such as a procedure at least twenty -four hours after completion of STEP 20, or at least 1 week, at least 1 month, and/or at least 6 months after completion of STEP 20. In some embodiments, the measurement performed in STEP 30 comprises a measurement of heart rate (e.g. average heart rate), blood pressure (e.g. a measurement of systolic and/or diastolic pressure levels), or both. In some embodiments, the measurement performed in STEP 30 comprises a measurement of a patient physiologic parameter selected from the group consisting of: angina level; mitral regurgitation type; mitral regurgitation severity; orthostatic intolerance level; dizziness level; lightheadedness level; a syncope event parameter; nausea level; fatigue level; tremor state; breathing state; swallowing ability; headache level; visual disturbance level; sweating level; pallor state; heart rate; cardiac output; blood pressure such as systolic and/or diastolic blood pressure; a respiration parameter; a blood gas parameter; blood flow such as blood flow through a vein or artery within and/or proximate the right side of the heart; vascular resistance; pulmonary resistance; average clotting time assessment; serum creatinine level assessment; level of B-type natriuretic peptide (B P); level of N- terminal pro B-type natriuretic peptide (NT-proBNP); and combinations of these.

[090] In some embodiments, the assessment performed in STEP 30 further includes one or more anatomical measurements, such as a measurement selected from the group consisting of: a flow pathway diameter measurement; a flow pathway length measurement; a

measurement of the distance between an artery and vein comprising the flow pathway; a measurement of the distance between the flow pathway and a vessel sidebranch; and combinations of these. In some embodiments, the measurement performed in STEP 30 comprises an assessment of flow (e.g. flow within and/or proximate the flow pathway), such as a flow assessment selected from the group consisting of: flow through the flow pathway; flow in a vessel segment proximate the flow pathway; flow measured using Doppler

Ultrasound; flow measured using angiographic techniques; and combinations of these. [091] As described above, in some embodiments, the assessment performed in STEP 30 comprises an assessment of heart rate that can be compared to a heart rate level of the patient that was present prior to the creation of the flow pathway.

[092] In STEP 40, one or more flow pathway parameters can be modified, such as a modification based on one or measurements and/or assessments performed in STEP 30 as described hereabove. STEP 40 can be performed in the same clinical procedure as STEP 20, and/or in a subsequent clinical procedure such as a procedure at least twenty-four hours after completion of STEP 20, or at least 1 week, at least 1 month, and/or at least 6 months after completion of STEP 20. In some embodiments, STEP 30 and STEP 40 are performed in the same clinical procedure (e.g. both in the same clinical procedure as STEP 20 or both in a subsequent clinical procedure). In some embodiments, one or more patient or flow pathway parameters to be modified are selected from the group consisting of: flow pathway cross sectional diameter; flow pathway average cross sectional diameter; flow pathway flow rate; flow pathway average flow rate; diastolic pressure after flow pathway creation; diastolic pressure change after flow pathway creation (e.g. as compared to diastolic pressure prior to flow pathway creation); systolic pressure after flow pathway creation; systolic pressure change after flow pathway creation (e.g. as compared to systolic pressure prior to flow pathway creation); ratio of diastolic to systolic pressure after flow pathway creation;

difference between diastolic pressure and systolic pressure after flow pathway creation; and combinations of these.

[093] Flow pathway modification procedures can include but are not limited to: increasing flow through the flow pathway; decreasing flow through the flow pathway; increasing the diameter of at least a segment of the flow pathway; decreasing the diameter of at least a segment of the flow pathway; removing tissue proximate the flow pathway; stenting a stenosis proximate the flow pathway (e.g. stenting a venous stenosis); delivering an agent to the flow pathway; delivering an agent to tissue proximate the flow pathway (e.g. venous and/or arterial wall tissue proximate the flow pathway); blocking a sidebranch proximate the flow pathway; and combinations of one or more of these. A flow pathway modifying device can include one or more devices selected from the group consisting of: an over the wire device constructed and arranged to be delivered over a vessel-to-vessel guidewire as described herein; an expanding scaffold configured to increase or otherwise modify flow pathway geometry such as an expandable balloon; a stent configured to be placed in an artery or vein proximate the flow pathway; an energy delivery catheter such as a catheter configured to deliver energy to tissue proximate a flow pathway; an agent delivery catheter such as a catheter configured to deliver an agent such as a pharmaceutical agent (e.g. a venous stenosis treating agent as described herebelow) or an adhesive such as fibrin glue; and combinations of one or more of these.

[094] In some embodiments, the flow pathway comprises a diameter of at least 2.5mm, such as a diameter of at least 3.0mm. In some embodiments, the flow pathway comprises a diameter of no more than 6.0mm, such as a diameter of no more than 5.0mm or 4.0mm. In some embodiments, the flow pathway comprises a diameter and/or a target flow rate that is based on a patient parameter, such as a measured patient parameter. The patient parameter can be determined prior to the creation of the flow pathway, during creation of the flow pathway and/or after the creation of the flow pathway (e.g. when the flow pathway is modified based on the patient parameter). In these embodiments, the patient parameter on which the flow pathway diameter and/or target flow rate is based can comprise a parameter selected from the group consisting of: angina level; mitral regurgitation severity; mitral regurgitation type; cardiac output; blood pressure; flow rate; tilt table test result; ankle brachial index test result; venous insufficiency level; peripheral vascular resistance; shunt flow; pulmonary capillary wedge pressure; right atrial pressure; pulmonary pressure; left atrial pressure; arterial oxygenation; venous oxygenation; and combinations thereof.

[095] In some embodiments, a second fistula or second flow pathway is created, such as using the techniques of STEP 20 described hereabove. The second flow pathway can be created in the same clinical procedure as STEP 20 (in which the first flow pathway is created), or in a subsequent clinical procedure such as a procedure performed at least twenty- four hours after completion of STEP 20, or at least 1 week, at least 1 month, and/or at least 6 months after completion of STEP 20. A second flow pathway can be created due to inadequate therapy provided by the first flow pathway, and/or if the first flow pathway has insufficient flow (e.g. becomes non-patent). A second flow pathway can be created due to formation of a vascular (e.g. venous) stenosis proximate the first flow pathway. In these embodiments, the first flow pathway can be reversed (e.g. closed), such as through the placement of a covered stent (e.g. covered stent 199 described herebelow in reference to Fig. 2) in the vein or artery that covers the flow pathway, or other flow pathway-occlusive procedure. Alternatively or additionally, the venous stenosis can be stented, such as by implanting one or more venous stents 195 as described herein. In some embodiments, three or more flow pathways can be created. Multiple flow pathways can be created in similar or dissimilar arteries and/or veins. In some embodiments, single or multiple flow pathways are created that exhibit a cumulative flow rate of at least 400ml/min and/or no more than 1500ml/min, such as a flow rate of at least 600ml/min or at least 800ml/min and/or a flow rate of no more than 1200ml/min. In some embodiments, a first flow pathway is created between the iliac artery and iliac vein in the patient's right leg, and a second flow pathway is created between the iliac artery and iliac vein in the patient's left leg.

[096] In some embodiments, an undesired heart rate increase is determined in STEP 30 (e.g. an increase of more than 5%, more than 10%, and/or more than 15%), and the flow pathway is modified in STEP 40, such as a modification including: reducing the diameter of the flow pathway; occluding the flow pathway; and/or occluding the flow pathway and creating a new flow pathway at a different location.

[097] The method of Fig. 1 can be performed using real-time imaging, such as real-time imaging provided by a fluoroscope and/or an ultrasound imaging device.

[098] The method of Fig. 1 can be performed to decrease peripheral vascular resistance, such as to decrease infrarenal vascular resistance (e.g. below the kidneys or in a manner to include the great vessels of the aorta and/or the inferior vena cava). Alternatively or additionally, the method can be performed to achieve a physiologic change selected from the group consisting of: reduced blood pressure; reduced angina; reduced mitral regurgitation; increased oxygen delivery by the arterial system; increased blood volume; increased proportion of blood flow to the descending aorta; increased blood flow to the kidneys;

increased blood flow outside the kidneys; increased cardiac output; and combinations of these. The method can be constructed and arranged to prevent any significant chronic increase in heart rate. Alternatively or additionally, the method can be constructed and arranged to prevent a decrease in cardiac function. Alternatively or additionally, the method can be constructed and arranged to avoid undesired adverse effects to the kidneys, such as by avoiding the adverse effects that can be encountered in a renal denervation procedure, such as stenosis, lost autonomic control and/or vessel intima damage.

[099] In some embodiments, the method is performed to increase oxygenation and/or flow rates associated with the patient's chemo-receptors, such as to cause a therapeutic change to vascular resistance. In some embodiments, the method is performed to affect or otherwise modify the patient's central sympathetic tone. Modifications to central sympathetic tone can be performed to reduce systolic and/or diastolic blood pressure (e.g. mean systolic and/or mean diastolic blood pressure), and/or to treat other patient diseases and conditions such as angina, mitral regurgitation, diabetes, sleep apnea, or heart failure.

[100] In some embodiments, the method of Fig. 1 is constructed and arranged to cause a reduction in diastolic blood pressure that is equal to or greater than a concurrent reduction in systolic blood pressure. In some embodiments, the method is constructed and arranged to reduce the diastolic pressure more than the systolic pressure by an amount of at least 2mmHg, at least 4mmHg or approximately 5mmHg. In some embodiments, the method is constructed and arranged to reduce the diastolic pressure by at least 5mmHg, such as a reduction of at least lOmmHg, at least 15mmHg or approximately 18mmHg. In some embodiments, the method is constructed and arranged to reduce the systolic pressure by at least 5mmHg, such as a reduction of at least lOmmHg or approximately 13mmHg. In some embodiments, the method is constructed and arranged to cause a reduction in blood pressure to a level at or below 130/90 mmHg.

[101] In some embodiments, prior to the creation of the flow pathway of the present inventive concepts, the patient has a systolic pressure at a level between 120mmHg and 220mmHG, such as a level between 140mmHg and 160mmHg. In these embodiments, the flow pathway can be created to reduce the systolic blood pressure to a level between

115mmHg and 180mmHg, such as a reduction to a level between 120mmHg and 140mmHg. In some embodiments, the flow pathway is created to cause a systolic blood pressure reduction between 5mmHg and 70mmHg, such as a reduction between lOmmHg and

40mmHg. In some embodiments, the flow pathway is created to cause a reduction in systolic blood pressure between 5% and 30%, or between 5% and 20%. In each of these

embodiments, the flow pathway can be created while avoiding any significant changes in the patient's heart rate.

[102] In some embodiments, the method of Fig. 1 is constructed and arranged to cause one or more of: a decrease in systemic vascular resistance; a decrease in blood pressure; an increase in cardiac output; an increase in right atrial pressure; an atrial natriuretic peptide (A P) release; vasodilation; an increase in right atrial filling; a Bainbridge reflex; an increase in heart rate; peripheral sympatho-inhibition; activation of venous baroreceptors; activation of pulmonary arterial mechanoreceptors; an increase in venous oxygenation; an increase in pulmonary blood flow; an increase in arterial compliance; a decrease in a reflected pulse wave; a decrease in effective arterial volume; an increase in oxygen delivery to tissue; a decrease in chemoreceptor activity; a decrease in sympatho-excitation (e.g. due to cerebral and/or renal hypoperfusion); a change in sodium and/or water retention; reduced renal ischemia; and combinations of one or more of these.

[103] As described hereabove in reference to STEP 10, the method of Fig. 1 can be constructed and arranged to treat angina. The created flow pathway and/or an anastomotic clip positioned therein (e.g. anastomotic clip 160 or 160' described herebelow), can be configured to reduce cardiac work; reduce arterial pressure; reduce left ventricular pre-load; shift blood volume toward the venous system; increase systemic oxygenation; increase venous oxygenation; increase delivery of oxygen to tissue; and combinations of one or more of these. Creation of the flow pathway can be constructed and arranged to reduce the need for repetitive persistent medications, such as glyceryl trinitrate (also referred to as nitroglycerin or GTN), while allowing more patient activity.

[104] Applicant has performed significant research and clinical studies in the flow pathways of the present inventive concepts. Cardiovascular reflexes exert powerful effects upon the control of heart rate, cardiac contractility, systemic vascular resistance, as well as the maintenance of cardiac preload. Cardiovascular reflex effects are mediated primarily through two distinct sets of mechanoreceptors: arterial baroreflexes (ABR) and

cardiopulmonary baroreflexes (CPBR). Both sets of baroreflexes have afferent and efferent limbs with synapses in the central nervous system (CNS). The afferent limbs are activated via mechano-sensitive endings, whereas the efferent fibers are both sympathetic and parasympathetic (vagal). The sympathetic and parasympathetic outputs are reciprocal in nature. For example, the activation of the afferent fibers inhibits sympathetic outflow from the CNS, with concomitant activation of parasympathetic outflow. The result is that when pressure distends vessels or chambers sub-served by these baroreflexes, the resulting sympatho-inhibition can lead to decreases in blood pressure.

[105] There are important differences between ABR and CPBR. Afferent fibers of the ABR consist of pairs of nerves arising from the ascending aorta (the aortic depressor nerves) and the carotid bifurcations (carotid sinus nerve). Thus, with elevation of arterial blood pressure, the vessels (ascending aorta and carotids) become distended, resulting in inhibition of sympathetic outflow (to decrease blood pressure) and activation of parasympathetic outflow (to decrease heart rate). As opposed to the ABR, afferent fibers of the CPBR are located mainly in the atria and inferior wall of the left ventricle (LV). These fibers become activated with increases in filling pressure, leading to decreases in sympathetic outflow. In contrast to the ABR, little change occurs in parasympathetic outflow with activation of the CPBR afferent fibers, resulting in minimal changes in heart rate due to

activation/deactivation of the CPBR afferent fibers. However, powerful effects on sympathetic outflow are observed: small increases in filling pressure (e.g. 2-4 mmHg) result in marked inhibition in sympathetic outflow. Conversely, small reductions in filling pressure result in activation of sympathetic outflow. As an illustrative example, this phenomenon is observed in humans as they transition between an upright posture and a supine posture. Upon standing, filling pressure decreases, deactivating the CPBR afferent fibers, and sympathetic outflow increases to arterioles (to maintain blood pressure) and to the venous reservoir (to maintain filling pressure).

[106] The flow pathway of the present inventive concepts (e.g. a flow pathway created using anastomotic clip 160 described herebelow) is configured to divert blood from the arterial system into the venous space, such as at a minimum and/or maximum flow rate as described herein. The creation of the flow pathway can result in a near-immediate increase in venous pressure. This increase in venous pressure can inhibit sympathetic outflow through activation of the CBPR afferent fibers. This finding is evidenced by the absence of reflex increases in heart rate despite substantial and immediate reduction of blood pressure within beats of creating the anastomosis. Moreover, there is no long-term increase in heart rate with reduction of blood pressure indicating the sustained activation of the CBPR afferent fibers.

[107] Thus, the flow pathway of the present inventive concepts derives some arterial blood pressure reduction through the diversion of arterial blood into the venous system. In some embodiments, this reflex mediated inhibition of the CBPR afferent fibers can provide additional clinical benefits in the reduction of tachycardia mediated cardiac disorders, such as rapid ventricular rates of atrial fibrillation, persistent tachycardia, and paroxysmal tachycardia syndromes.

[108] In some embodiments, in STEP 30, heart rate is measured, and if an undesired condition is detected, the flow pathway is modified (e.g. flow through the flow pathway is decreased or stopped), such as is described hereabove. For example, an undesired condition can comprise: heart rate above a threshold; change in heart rate above a threshold (e.g.

change in heart rate after flow pathway creation compared to heart rate prior to flow pathway creation above a threshold); average heart rate over a time period above a threshold; and combinations of these. In some embodiments, an increase in heart rate or average heart rate (both referred to as "heart rate" herein) of at least 5 beats per minute (bpm), at least lObpm, or at least 15bpm is considered an undesired condition (e.g. a condition in which after detection the flow pathway is modified as described herein). In some embodiments, an increase in heart rate of at least 5%, at least 10%, or at least 15% is considered an undesired condition.

[109] A reduction of flow through the flow pathway performed in STEP 40 can be accomplished in a number of ways. In some embodiments, one, two or more covered stents (e.g. one or more covered stents 199 described herebelow in reference to Fig. 2) is placed in the artery and/or vein (e.g. a single covered stent placed in the artery or vein, or two covered stents with one covered stent placed in the artery and one covered stent placed in the vein). The one or more covered stents can be placed in the artery and/or vein proximate the flow pathway such that the flow pathway is partially occluded (e.g. to reduce flow) or fully occluded (e.g. to stop flow). The one or more covered stents can be implanted to cause a reduction in a patient's heart rate below a threshold (e.g. a threshold at a heart rate equivalent to a 10% increase in heart rate as compared to the patient's heart rate prior to flow pathway creation, as described herein). Alternatively or additionally, in embodiments in which one, two or more anastomotic clips is placed within the flow pathway (e.g. one or more clips 160 and/or 160' described herein), the flow modification can comprise modifying the implanted anastomotic clip(s), such as a reduction or other modification of the diameter of the opening of the anastomotic clip that is performed to reduce flow through the flow pathway.

[110] In some embodiments, in STEP 30, heart rate is measured, and blood pressure is measured (e.g. at least systolic blood pressure). If systolic pressure is above a desired level (e.g. above a threshold such as is described herein), and heart rate is at an acceptable level (e.g. not above a threshold such as not significantly increased from a pre-procedural level), an increase of flow through the flow pathway can be performed in STEP 40. The increase can be accomplished in a number of ways such as via dilation of the flow pathway (e.g. a flow pathway including an anastomotic clip that is dilated with a balloon catheter as described herein), or via the creation of a second flow pathway (also as described herein). The creation and/or modification of the flow pathway can result in an increase in venous pressure, a decrease in arterial blood pressure (e.g. systolic pressure), or both.

[I l l] Referring now to Fig. 2, a system for creating at least one fistula or other flow pathway between a first location in a patient's arterial system of a patient (e.g. an artery), and a second location in the patient's venous system (e.g. a vein), is illustrated. System 100 can comprise a vascular introducer, first introducer 110, configured to be placed into the patient to provide access to a starting vessel. System 100 can comprise another vascular introducer, second introducer 130, configured to provide access to a target vessel. In some

embodiments, the starting vessel is a vein, and the target vessel is an artery. In other embodiments, the starting vessel is an artery and the target vessel is a vein. System 100 can include target wire 120 which can comprise helical section 121 and can be configured to be placed through the second introducer 130 and into the target vessel. Target wire 120 can be placed through an elongate tube, catheter 122. System 100 can comprise needle deployment device 140 which can be configured to deploy crossing needle 145 (shown in an advanced position in Fig. 2), from the starting vessel and into the target vessel. System 100 can include a vessel-to-vessel guidewire 170, which can be placed from the starting vessel to the target vessel via needle deployment device 140. System 100 can also include clip deployment catheter 150, which can be configured to deploy anastomotic clip 160. System 100 can include one or more flow pathway modifying devices, such as one or more dilation devices 180 which can include one or more balloon catheters 185, each attachable to indeflator 181 (e.g. a standard angioplasty balloon indeflator). Catheter 185 can comprise at least one balloon 186. Balloon 186 can comprise an agent-coated balloon, including agent 187, such as is described in detail herebelow. Alternatively or additionally, balloon 186 can comprise at least a portion that is permeable and configured to deliver agent 187, also as described in detail herebelow. System 100 can further comprise imaging device 190, typically a fluoroscope and/or ultrasound imaging device used to image one or more device or components of system 100, as well as the patient's anatomy, during the creation of an arteriovenous flow pathway.

[112] First introducer 110 can be configured to be placed into the patient to provide access to a starting vessel (e.g. a vein of a patient). In some embodiments, introducer 110 comprises an 11 French vascular introducer. First introducer 110 can comprise beveled tip 111 with an angle ranging from 20° to 50°, such as at an angle of approximately 30°. Additionally, system 100 can include a kit comprising an additional introducer having a second angle providing the clinician or other user (hereinafter "clinician") with more options as may be appropriate for a particular patient's anatomical geometry. In some embodiments, beveled tip 111 comprises a marker, for example, a radiopaque or other visualizable marker, such that the luminal wall of the starting vessel can be imaged (e.g. when tip 111 is pressed against the vessel wall). The proximal portion of introducer 110 can comprise a contour or marker, such as to be correlated with or otherwise indicate the alignment of the bevel of tip 111.

[113] Introducer 110 can comprise shaft 117 which includes at least one thru lumen. Introducer 110 can also comprise port 116, typically a hemostasis valve, which can be fluidly connected to the lumen of shaft 117. A second port 118, typically a luer connector, can be connected to tubing 115 which in turn can be connected to port 116. Introducer 110 can further comprise a dilator, not shown but typically an 11 to 13 French dilator used to introduce and/or pre-dilate tissue receiving introducer 110. Introducer 110 can further comprise a radially expandable element, such as expandable element 119, such as a balloon or expandable cage located on the distal portion of introducer 110. In some embodiments, expandable element 119 can be configured to prevent or otherwise resist advancement of introducer 110 into the target vessel. In yet another embodiment, expandable element 119 can be configured to stabilize the starting vessel during insertion of introducer 110 or another device or component of system 100.

[114] System 100 can comprise second introducer 130 which can be configured to provide access to a target vessel, such as an artery of the patient when the starting vessel is a vein. In some embodiments, second introducer 130 comprises a 4 French vascular introducer. System 100 can comprise target wire 120 configured to be placed through second introducer 130 and into the target vessel. Target wire 120 can comprise helical section 121 configured to be deployed at the site where the flow pathway is to be created. Helical section 121 can be configured to provide structure and support to the site during a procedure. Additionally, target wire 120 can serve as a visual reference during insertion of vessel-to-vessel guidewire 170, as described herebelow.

[115] System 100 can comprise needle deployment device 140. Needle deployment device 140 can comprise shaft 141 which slidingly receives advanceable crossing needle 145, shown in an advanced state in Fig. 2. Shaft 141 can comprise shaft hub 142 mounted to its proximal end. Shaft 141 can comprise a curved distal portion as shown. Crossing needle 145 can comprise needle hub 146 mounted to its distal end. Movement of needle hub 146 relative to shaft hub 142 can cause crossing needle 145 to advance and retract within shaft 141.

Needle hub 146 can be fully advanced toward shaft hub 142 in the configuration of Fig. 2, such that the tip and distal portion of crossing needle 145 is fully advanced out of the distal end of shaft 141.

[116] Crossing needle 145 can comprise a 20 to 24 gauge needle, such as a 22 gauge needle. In some embodiments, the crossing needle comprises a curved distal portion (as shown). The curved distal portions of shaft 141 and/or crossing needle 145 can be aimed at the center of the target vessel prior to insertion into the target vessel. The radius of curvature can be reduced if the clinician has difficulty in aiming the needle tip at the center of the target vessel prior to insertion. Conversely, the radius of curvature can be increased to sufficiently aim the needle tip at the center of the target vessel. Additionally, the crossing needle 145 can comprise a marker, not shown but indicating the direction of curvature. Examples of markers include, but are not limited to: a flat surface; a textured surface; a visualizable marker such as a radiopaque marker; a magnetic marker; an ultrasonic marker or a visible marker; and combinations of these. In some embodiments, crossing needle 145 comprises a shaped memory alloy, for example, nickel titanium alloy. In some embodiments, shaft hub 142 and/or needle hub 146 comprise a marker or other visible demarcation (e.g. a flat portion) which correlates to the direction of curvature of shaft 141 and/or crossing needle 145, respectively.

[117] System 100 can comprise a guidewire to be placed from the starting vessel to the target vessel, vessel-to-vessel guidewire 170. Guidewire 170 can be configured to be placed via needle deployment device 140. In some embodiments, vessel-to-vessel guidewire 170 comprises a wire with an outer diameter of approximately 0.018". Vessel-to-vessel guidewire 170 can comprise a marker, not shown but configured to indicate the flow pathway location. In some embodiments, vessel-to-vessel guidewire 170 comprises a distal portion and a mid portion. Guidewire 170 mid portion can comprise a different construction than the distal portion. For example, the mid portion of guidewire 170 can be stiffer than the distal portion.

[118] System 100 can comprise clip deployment catheter 150 configured to house and deploy anastomotic clip 160. Clip 160 can comprise a plurality of distal arms 161 and a plurality of proximal arms 162, which can be deployed simultaneously or independently. Clip 160 can comprise at least two distal arms 161 and at least two proximal arms 162 configured to deploy and engage the starting vessel and the target vessel. In some embodiments, clip 160 comprises four deployable distal arms 161 and four deployable proximal arms 162. Clip 160 can comprise a shaped memory alloy, such as nickel titanium alloy. In some embodiments, clip 160 is constructed and arranged as described in applicant's U.S. Patent Number 8,273,095, entitled "Device and Method for Establishing an Artificial Arterio- Venous Fistula", filed July 13 2009, the contents of which are incorporated herein by reference in its entirety. Clip 160 can comprise one or more covered portions or otherwise be configured to direct and/or limit blood flow through clip 160, such as is described herebelow in reference to clip 160' of Fig. 13.

[119] In some embodiments, clip 160 is biodegradable or includes one or more biodegradable portions (e.g. one or more portions of clip are absorbed or otherwise degrade over time). In some embodiments, clip 160 comprises a biodegradable anastomotic device such as is described in applicant's co-pending U.S. Patent Number 8,926,545, entitled "Device and Method for Establishing an Artificial Arteriovenous Fistula", filed April 1, 2010, the contents of which are incorporated herein by reference in its entirety.

[120] Clip deployment catheter 150 can comprise shaft 151. Mounted to the proximal end of shaft 151 can be handle 153. On the proximal end of handle 153 can be port 155, which can be operably attached to shaft 151 such that a guidewire can travel from the distal end of shaft 151 to port 155, such as guidewire 170 after it has been previously placed between a starting vessel and a target vessel as has been described hereabove. Shaft 151 can comprise one or more tubular portions, such as an inner tubular segment that houses clip 160, and an outer tubular segment that covers clip 160 but can be retracted to deploy clip 160, such as is described in applicant's U.S. Patent Number 8,641,747, entitled "Devices for Arterio- Venous Fistula Creation", filed June 13, 2005, the contents of which is incorporated herein by reference in its entirety.

[121] Handle 153 can further include control 152 (e.g. a button, slide or lever), where control 152 can be operably configured to allow an operator to deploy distal arms 161 and/or proximal arms 162 of clip 160, such as via retraction of an outer tube or sheath portion of shaft 151 that can be covering one or more portions of clip 160. In some embodiments, a click or other tactile feedback is provided during retraction of a sheath portion of shaft 151. Control 152 can be moved via a stepped or otherwise segmented slot 156. Distal arms 161 can be deployed via moving control 152 from a "first ready to deploy" position to a "first deployed" position which can be achieved by moving control 152 relatively parallel to the longitudinal axis of handle 153. The at least two proximal arms 162 can be queued to be deployed via moving control 152 from the first deployed position to a "second ready to deploy" position. The second ready to deploy position can be achieved by moving control 152 in a direction perpendicular to the longitudinal axis of the handle. Subsequently, proximal arms 162 can be deployed via moving control 152 from the second ready to be deployed position to a "second deployed" position via a motion parallel to the longitudinal axis of the handle. In this embodiment, control 152 can include a safety position comprising a ready to deploy position which can be transitioned by moving control 152 in a direction that is perpendicular to the axis of handle 153. This control advancement arrangement can prevent inadvertent deployment of distal arms 161 and/or proximal arms 162.

[122] In some embodiments, prior to deployment of one or more arms of clip 160, introducer 110 is advanced such that beveled tip 111 applies a force to the wall of the starting vessel. Sufficient force can be applied by introducer 110 to enable an operator to "seat" the starting vessel against the target vessel to assist in proper deployment of clip 160.

[123] In some embodiments, clip deployment catheter 150 can be configured to recapture distal arms 161 and/or proximal arms 162. For example, clip deployment catheter 150 can deploy at least one distal arm 161 and subsequently recapture the at least one distal arm 161.

[124] Clip deployment catheter 150 and/or clip 160 can further comprise at least one marker, not shown but typically a radiopaque and/or ultrasonic marker configured to assist in the rotational positioning of clip 160 at the flow pathway location. For example, the marker can be oriented toward the target vessel prior to deployment of clip 160. In some embodiments, a marker is included on the distal portion of clip deployment catheter 150. In some embodiments, handle 153 comprises one or more markers that are circumferentially aligned with clip 160 prior to its deployment. In some embodiments, clip deployment catheter 150 and/or clip 160 comprise at least one marker configured to longitudinally position clip 160 at the flow pathway location. In these embodiments, the marker can indicate the distal and/or proximal end of clip 160.

[125] Clip deployment catheter 150 can further comprise a projection and/or recess, neither shown but configured to mechanically engage clip 160. The projection and/or pin can be used to stabilize clip 160 with shaft 151, such as when an outer tubular portion of shaft 151 is advanced or retracted.

[126] In some embodiments, clip deployment catheter 150 can be further constructed and arranged to deploy one or more other implants, such as venous stent 195 and/or covered stent 199 described herebelow. Alternatively or additionally, system 100 can comprise a second clip deployment catheter 150 constructed and arranged to deploy venous stent 195 and/or covered stent 199, such as delivery sheath 198 described herebelow in reference to Fig. 11.

[127] System 100 can comprise dilation device 180 configured to dilate clip 160 and/or the flow pathway. Dilation device 180 can include balloon catheter 185, such as a standard angioplasty balloon catheter comprising balloon 186. Attached to the proximal end of balloon catheter 185 can be indeflator 181, typically a standard balloon indeflator device. Alternatively, balloon 186 can comprise a non-balloon expandable component such as an expandable cage or radially deployable arms configured to dilate the flow pathway. Balloon catheter 185 can be configured to track over a vessel-to-vessel guidewire, such as guidewire 170 placed between a vein and an artery, such that balloon 186 can be positioned within the flow pathway (e.g. within clip 160). Typically, dilation device 180 can expand to a diameter of less than 5mm, and more typically to a diameter of approximately 4mm. In some embodiments, a second dilation device 180 is included, such as a device configured to expand to a different diameter than the first dilation device.

[128] System 100 can comprise an agent 187 configured to be delivered by an agent- delivering device, such as when balloon catheter 185 is configured to deliver agent 187. Alternatively or additionally, system 100 comprises a separate device configured to deliver agent 187. In some embodiments, balloon catheter 185 comprises a first catheter 185 (e.g. a balloon catheter or other radially deployable device) configured to dilate a flow pathway and/or clip 160 as described hereabove, and a second catheter 185 configured to deliver agent 187 to tissue. Catheter 185 can be configured to deliver one or more agents 187, such as one or more agents 187 configured to reduce a current or future stenosis, such as a current or future venous stenosis. An agent-delivering catheter 185 can comprise a balloon 186 comprising a distensible or non-distensible balloon. Catheter 185 can comprise an agent 187 configured as a coating on balloon 186. Alternatively, catheter 185 can be configured to deliver agent 187 from within balloon 186 (e.g. when catheter 185 comprises a porous or otherwise permeable balloon 186). Alternatively or additionally, clip 160 can be configured to deliver agent 187, such as when agent 187 is configured as an eluding coating on clip 160.

[129] Agent 187 of system 100 can comprise one or more agents selected from the group consisting of: an anti-proliferative agent; a chemotherapeutic agent such as paclitaxel; mTOR inhibitors (Mammalian target of rapamycin inhibitors), such as Sirolimus or its analogues Zotarolimus or Everolimus; and combinations of one or more of these. Agent 187 can be delivered prior to and/or during a flow pathway creation procedure or a flow pathway modification procedure (as described hereabove in reference to Fig. 2), and/or in one or more subsequent procedures. Agent 187 can be delivered to venous wall tissue, such as a full or partial circumferential segment of venous wall tissue proximate (e.g. within 10cm of) the flow pathway and/or proximate clip 160. In some embodiments, agent 187 is delivered to a 5mm to 60mm circumferential segment of venous wall tissue superior to; inferior to; medial to and/or lateral to the flow pathway and/or clip 160. In some embodiments, agent 187 is delivered to a venous wall location in between the flow pathway and the heart (i.e. at a vein location downstream of but within 10cm of the flow pathway). One or more agents 187 delivered by catheter 185 (and/or another component of system 100) can be configured to prevent or otherwise reduce a stenosis that might otherwise occur in a vein at a location proximate the flow pathway of the present inventive concepts. The delivered agent 187 can be configured to block cell proliferation and associated fibrosis and stenosis. The delivered agent 187 can be configured to be efficacious over an extended time period, such as at least 3months, at least 6 months, at least 12 months, at least 18 months or at least 24 months. Alternatively, delivered agent 187 can be delivered in multiple procedures, such as to be collectively efficacious for a time period of at least 3months, at least 6 months, at least 12 months, at least 18 months or at least 24 months. In some embodiments, agent 187 comprises paclitaxel or a similar agent, such as when agent 187 is delivered by anastomotic clip 160 (e.g. agent 187 comprises a coating of clip 160) and/or when agent 187 is delivered by catheter 185 (e.g. when agent 187 comprises a coating on balloon 186 and/or is delivered through a permeable balloon 186). In some embodiments, agent 187 comprises paclitaxel or a similar agent comprising a mass of at least 20C^g (e.g. a mass of at least 20C^g coated onto clip 160 or a mass of between 300μg and 600μg coated on and/or positioned within balloon 186 of catheter 185). In some embodiments, at least 80% (e.g. at least 90%) of the included amount of agent 187 is delivered to tissue by balloon 186 and/or clip 160 during a time period of approximately 20 seconds, between 20 seconds and 60 seconds, or approximately 60 seconds. In some embodiments, between 10% to 15% of the amount of agent 187 delivered, is still present in the vessel wall 40 minutes after delivery. In some embodiments, catheter 185 and/or balloon 186 are constructed and arranged to deliver agent 187 to tissue over a larger surface area than would correspondingly be delivered if agent 187 comprises a coating of clip 160.

[130] System 100 can include one or more venous stents 195. Stent 195 can comprise a kit of multiple stents with different diameters, such as a set of stents with diameters between 2mm and 16mm. One or more stents 195 can comprise a self-expanding stent, a balloon expandable stent, or stents with self-expanding portions and balloon expandable portions. System 100 can include a catheter device for implanting stent 195 into a vein, such as clip deployment catheter 150 and/or delivery sheath 198 described herebelow in reference to Fig. 11. In some embodiments, one or more venous stents 195 comprise an opening for positioning over a flow pathway, such as openings 196a, 196b, 196c or 196d described herebelow in reference to Figs. 7, 8, 9 or 10, respectively.

[131] System 100 can include one or more covered stents 199, such as one or more PTFE covered stents. Stent 199 can be configured to be positioned in a vein or an artery such as to fully or partially occlude a flow pathway of the present inventive concepts as described hereabove in reference to Fig. 1. Covered stent 199 can comprise a kit of multiple stents with different diameters, such as a set of stents with diameters between 2mm and 10mm. One or more covered stents 199 can comprise a self-expanding stent, a balloon expandable stent, or stents with self-expanding portions and balloon expandable portions. System 100 can include a catheter device for implanting covered stent 199 into a blood vessel (e.g. in a vein to partially or fully occlude a flow pathway), such as clip deployment catheter 150 and/or delivery sheath 198 described herebelow in reference to Fig. 11.

[132] System 100 can include patient imaging device 190. Non-limiting examples of an imaging device include: x-ray; fluoroscope; ultrasound imager; MRI; and combinations of these. The imaging device can allow the clinician to track the movement of all components comprising system 100 as well as view the position of the starting and target vessel relative to each other, as described in detail herein. [133] System 100 can comprise one or more diagnostic devices, diagnostic device 200 shown. Diagnostic device 200 can comprise one or more diagnostic devices configured to measure one or more physiologic parameters of the patient, such as heart rate (e.g. average heart rate), blood pressure (e.g. a measurement of systolic and/or diastolic pressure levels), or both. In some embodiments, diagnostic device 200 is configured to measure a patient physiologic parameter selected from the group consisting of: angina level; mitral

regurgitation type; mitral regurgitation severity; orthostatic intolerance level; dizziness level; lightheadedness level; a syncope event parameter; nausea level; fatigue level; tremor state; breathing state; swallowing ability; headache level; visual disturbance level; sweating level; pallor state; heart rate; cardiac output; blood pressure such as systolic and/or diastolic blood pressure; a respiration parameter; a blood gas parameter; blood flow such as blood flow through a vein or artery within and/or proximate the right side of the heart; vascular resistance; pulmonary resistance; average clotting time assessment; serum creatinine level assessment; level of B-type natriuretic peptide (B P); level of N-terminal pro B-type natriuretic peptide (NT-proB P); and combinations of these. The measurements performed by diagnostic device 200 can be used to modify the flow pathway of the present inventive concepts, such as to modify the flow through the flow pathway as described hereabove in reference to Fig. 1. In some embodiments, the flow through the flow pathway is modified (e.g. decreased), if heart rate measured by diagnostic device 200 is above a threshold (e.g. above a 10% increase in heart rate as compared to the heart rate of the patient prior to the flow pathway creation).

[134] In an exemplary procedure illustrated in Figs. 3A-D, an anastomotic clip can be deployed to create an iliac arteriovenous flow pathway (e.g. an arteriovenous fistula).

Vascular venous and arterial access can be obtained using standard interventional techniques (e.g. through a femoral vein and femoral artery). Figs. 3 A and 3B illustrate an anastomotic clip delivery device that can be used, including an anastomotic clip that can be implanted. In some embodiments, the anastomotic clip delivery device comprises clip deployment catheter 150, and the anastomotic clip comprises clip 160, each of Fig. 2 hereabove. In Fig. 3C, an angiogram of the flow pathway location AVF is illustrated, including artery A and vein V, prior to flow pathway creation. A radiopaque vessel targeting wire CW, such as target wire 120 of Fig. 2, can be inserted within artery A to provide a radiographic outline of the artery. A venogram can be performed to outline the vein and confirm proximity of the artery and vein at the target crossing location AVF for the creation of the arteriovenous flow pathway. A crossing needle device (e.g. a 22 gauge or 23 gauge crossing needle device), such as needle deployment device 140 of Fig. 2 hereabove, can be placed into vein V, such as a placement over a guidewire and through an introducer device (e.g. introducer 110 of Fig. 2). The crossing needle of the device can be advanced through the wall of vein V into artery A, and a guidewire can be advanced through a lumen of the crossing needle and into artery A. The crossing needle can be subsequently removed and the anastomotic clip delivery system can be tracked across the puncture site. The anastomotic clip can then be deployed so that the expanded arms of the anastomotic clip attach to the inner walls of artery A and vein V, and the retention arms maintain the anastomotic clip in the proper position (deployed position shown in Fig. 3D). After removal of the delivery system, a balloon catheter (e.g. a 2.5- 4.5mm balloon catheter) can be inserted into the center of the anastomotic clip and inflated to expand the anastomotic clip to a target diameter as described herein. The balloon can then be deflated and removed. An angiogram can confirm the patency of the flow pathway.

[135] Referring now to Fig. 4, a flow chart of a method of creating a flow pathway between a starting vessel and a target vessel at a flow pathway location, consistent with the present inventive concepts is illustrated. In Step 410, a procedural planning assessment of a patient is performed. Step 420 comprises placing a first introducer into a starting vessel, e.g. a vein, and placing a second introducer into a target vessel, e.g. an artery. In Step 430, an angiographic orientation is performed, and a flow pathway location is selected. Step 440 comprises placing a vessel-to-vessel guidewire between the vein and the artery. Step 450 comprises placing an anastomotic clip at the flow pathway location. In some embodiments, system 100 and/or one or more components of system 100 of Fig. 2 are used to perform the method of Fig. 4.

[136] The starting vessel can comprise a vein, such as a vein selected from the group consisting of: inferior vena cava (IVC); saphenous; femoral; iliac; popliteal; brachial; basilic; cephalic; medial forearm; medial cubital; axillary; and jugular. The target vessel can comprise an artery, such as an artery selected from the group consisting of: aorta; axillary; brachial; ulnar; radial; profundal; femoral; iliac; popliteal and carotid. In a preferred embodiment, the starting vessel and target vessel can comprise an external iliac. In an alternate embodiment, the starting vessel can comprise an artery and the target vessel can comprise a vein.

[137] Step 410, the first step in the illustrated method of the present inventive concepts comprises procedural planning. This step comprises properly orienting the vein and the artery, meaning a clinician becomes familiar with the anatomical orientation of the vein and artery relative to each other. Understanding the orientation of the vessels with respect to one another can be achieved through analysis of one or more images provided by an imaging device (e.g. a fluoroscope) such as imaging device 190 of Fig. 2. In some embodiments, at least one of the vein or artery has a diameter of at least 5mm proximate the flow pathway location. In another embodiment, both the vein and artery have a diameter of at least 5mm proximate the flow pathway location.

[138] In Step 420, the method comprises placing a first introducer into the vein.

Preferably, the first introducer comprises an 11 French introducer having a beveled tip, such as introducer 110 of Fig. 2 described hereabove. In some instances, the beveled tip of the first introducer can be rotated during insertion into the vein. Rotation of the introducer can be helpful during insertion into the starting vessel due to the tendency of the beveled tip to lift and pull back. Additionally or alternatively, the introducer can be vibrated while it is advanced into the vein. Step 420 can further comprise pre-dilating the vein with a dilator, preferably a 13 French dilator, prior to placing the introducer into the vein. Additionally, a second introducer can be placed into the artery. Preferably, the second introducer comprises a 4 French introducer, such as second introducer 130 described in Fig. 2 hereabove. The method further comprises placing a target wire into the second introducer and then into the artery such that the distal end of the target wire is positioned 5cm to 10cm past the flow pathway location, and the target wire can be configured to serve as a visual reference to a clinician. The target wire, typically including a helical section, is advanced. The

advancement can be combined with retracting the introducer such that the helical section of the wire is deployed at the targeted anastomotic site.

[139] In Step 430, the method comprises performing angiographic orientation and selecting a flow pathway location. Choosing the flow pathway location can be based upon a lack of thrombus or other soft tissue occlusive matter at the vascular location, as well as lack of plaque or calcified matter. Preferably, the flow pathway location is chosen at a location where the vein is less than or equal to 3mm apart from the artery. Techniques can be used to image the vein and artery in side-by-side configurations as well as overlapping (i.e. on top of each other in the image) orientations. Rotation of the imaging device 90° can modify the provided image from a side-by-side image to an overlapping image, and back again. In some embodiments, after a flow pathway location has been selected, a clinician can orient the fluoroscope such that the vein and artery are shown overlapping, such as with the vein on top of the artery. In some embodiments, the clinician can position a fluoroscope or other imaging device at an angle to the patient approximating 35° RAO. [140] In Step 440, the method comprises placing a vessel-to-vessel guidewire into the vein, such as while the vein and artery are imaged in an overlapping orientation, as described in Step 430 hereabove. A next step comprises placing a needle delivery device over the vessel-to-vessel guidewire and into the vein. The needle delivery device can comprise a marker, as described in Fig. 2 hereabove, such that a clinician can orient the marker toward the artery. The guidewire can be retracted and subsequently, the needle of the needle delivery device can be advanced toward the target wire and toward the artery. In some embodiments, the vessel-to-vessel guidewire can be placed through a dilator.

[141] Prior to inserting the crossing needle into the artery, a clinician can aim the needle tip at the center of the artery to ensure desired engagement of the artery with the needle, such as by rotating the proximal end of the needle or a device containing the needle. In some embodiments, the needle or needle delivery device includes a proximal hub with a

demarcation (e.g. a flat portion or a marker) positioned to indicate the orientation of a curved distal portion of the needle, such as is described in reference to needle deployment device 140 of Fig. 2 hereabove. In this operation, a clinician can torque or otherwise rotate the needle such that the direction of the needle curvature comes into view on the imaging device (e.g. fluoroscope). Confirming the direction of needle curvature ensures that the needle is to be advanced in the desired direction, such as into the center of the artery. In some embodiments, a target wire is placed in the target vessel, such as target wire 120 of Fig. 2 described hereabove. Preferably, the needle comprises a curved tip, and the radius of curvature can be reduced if a clinician has difficulty in aiming the needle at the center of the target vessel prior to insertion. Conversely, the radius of curvature can be increased to sufficiently aim the needle tip at the center of the target vessel. In some embodiments, the needle delivery catheter is oriented as described in reference to Fig. 5 herebelow.

[142] Additionally, a clinician can confirm that the distal portion of the vessel-to-vessel guidewire is located within the lumen of the artery. Also, the clinician can confirm the vessel-to-vessel guidewire is parallel with the target wire previously placed in the artery. A clinician can confirm that the needle is positioned within the target vessel by using a dye injection through the needle. Alternatively or additionally, a clinician can confirm that the needle is properly positioned in a target vessel by measuring the pressure in a distal portion of the needle, such as to confirm presence in an artery by confirming arterial pressure is recorded.

[143] In some embodiments, the needle deployment device is placed into the artery and the guidewire is advanced from the artery into the vein via the crossing needle. In these embodiments, the anastomotic clip delivery catheter can also be advanced from artery to vein.

[144] In Step 450, the method comprises placing an anastomotic clip at a flow pathway location. Prior to performing Step 450, placing an anastomotic clip at a flow pathway location, a user can retract the crossing needle while maintaining the position of the target wire. Next, the target wire can be removed from the second introducer. The target wire can also be removed after Step 450.

[145] In Step 450, a user can position the vein and artery such that the vein and artery are slightly apart from each other on the image (e.g. not overlapping). In one embodiment, this can be achieved by rotating a fluoroscopy unit 45° to 90° after an overlapping image is obtained (e.g. an image obtained during a dual contrast injection of both the artery and vein).

[146] Next, the tip of the clip deployment catheter (with a pre-loaded anastomotic clip) can be placed at the flow pathway site. In this step, a clinician can apply forward pressure and rotate the clip deployment catheter. The clip can comprise at least two distal arms and at least two proximal arms that can be deployed simultaneously or independently via a control located on the handle of the catheter.

[147] Step 450 further comprises deploying the anastomotic clip in the flow pathway, such as is described in detail in reference to clip deployment catheter 150 of Fig. 2 hereabove. The clip distal arms are deployed by moving a control on the clip deployment catheter from a ready to deploy position to a first deployed position, which can be achieved by moving the control relatively parallel to the longitudinal axis of the handle. Prior to deploying the proximal arms of the clip, a clinician can retract the first introducer to the flow pathway location and seat the vein against the artery. The clip deployment catheter can comprise a marker located on its distal end. Using this marker, a clinician can pull the clip deployment catheter back such that the marker is aligned with the distal end of the first introducer.

[148] In a next operation of STEP 450, the proximal arms can be queued to be deployed via moving the control from a first deployed position to a second ready to deploy position. The ready to deploy position can be achieved by moving the control in a direction

perpendicular to the longitudinal axis of the handle. Subsequently, the proximal arms can be deployed via moving the control from the second ready to be deployed position to the second deployed position via a motion parallel to the longitudinal axis of the handle. In this embodiment, the control includes a safety position comprising a ready to deploy position which can be transitioned by moving the control in a direction that is perpendicular to the axis of the handle. This control arrangement can prevent inadvertent deployment of the distal and/or proximal arms. After deployment of the proximal arms, a clinician can retract the first introducer from the anastomosis site, such as a retraction of approximately 2cm to 3cm, followed by retracting the clip deployment catheter.

[149] The method can further comprise dilating the flow pathway via a balloon or other expandable member. For example, a clinician can track a balloon catheter over the target wire and inflate the balloon. In a typical embodiment, the balloon catheter comprises a diameter of 4mm to 5mm and can be inflated via a 4mm by 1.5cm non-conforming balloon and indeflator device. The balloon then can be deflated and retracted out of the implant.

[150] The method can further comprise verifying clip patency. This can be achieved via a contrast/saline solution injected into the second introducer. A clinician can then remove all devices once it is confirmed that the clip is positioned as desired.

[151] The method can further comprise placing a second anastomotic clip, such as a second anastomotic clip 160 of Fig. 2 described hereabove. Alternatively or additionally, the method can further comprise creating a second flow pathway between, such as a second flow pathway created during the same clinical procedure or a subsequent clinical procedure. The second flow pathway can be between the same two vascular locations as the first flow pathway, or one or both of the second flow pathway vascular locations can be different (e.g. a different vein and/or artery).

[152] In some embodiments, the method of Fig. 4 further comprises measuring a physiologic parameter of the patient, such as heart rate, blood pressure, and/or another patient physiologic parameter (e.g. using diagnostic device 200 described hereabove in reference to Fig. 2). In these embodiments, the flow pathway can be modified based on the measurements of the one or more physiologic parameters, such as when flow through a flow pathway is decreased when a measured heart rate is above a threshold, as described herein.

[153] Referring now to Fig. 5, an angiographic view of a patient's vein and artery prior to advancement of a needle into the artery is illustrated, such as can be performed in Step 440 of the method of Fig. 4 described hereabove, consistent with the present inventive concepts. In the illustrated embodiment, a clinician has oriented an imaging device (e.g. a fluoroscope or other imaging device of Fig. 2), such that the segments of vein and artery at a proposed flow pathway location are overlapping (i.e. on top of each other in the image). The clinician has placed a target wire 120 into a patient's artery such that the helical section 121 can be positioned at the proposed flow pathway location. Additionally, needle deployment device 140 has been advanced intraluminally through the vein as shown such that its distal end is proximal to the proposed flow pathway location. A next step can comprise advancing needle 145 toward the helical section 121 at the proposed flow pathway location.

[154] Prior to insertion of needle 145 into the artery, a clinician can rotate needle deployment device 140 such that the direction of the needle deployment device 140 curvature can be viewed (i.e. a non-linear, curved segment can be visualized) on the imaging device. Confirming the direction of curvature ensures that needle 145 can be advanced in the desired direction, such as into the center of the artery. For example, if a clinician rotates needle deployment device 140 such that its tip is positioned as shown in Figs. 5A or 5C, a clinician will be aiming to an off-center location of the patient's artery. If a clinician rotates needle deployment device 140 such that its tip is positioned as shown in Fig. 5B, needle 145 will subsequently be advanced into the relative center of the patient's artery. The radius of curvature of a needle deployment device 140 can be reduced (e.g. by manual reshaping or by selected a different needle deployment device 140) if a clinician has difficulty in aiming needle 145 at the center of the artery prior to insertion. Conversely, the radius of curvature of needle deployment device 140 can be increased to create a more desirable needle 145 advancement trajectory.

[155] Referring now to Fig. 6, a perspective view of an anastomotic clip is illustrated, consistent with the present inventive concepts. Clip 160 can comprise at least two distal arms 161 and at least two proximal arms 162. In the illustrated embodiment, clip 160 comprises four distal arms 161 and four proximal arms 162. In some embodiments, clip 160 is constructed and arranged as described in applicant's U.S. Patent Number 8,273,095, entitled "Device and Method for Establishing an Artificial Arterio- Venous Fistula", filed July 13 2009, the contents of which are incorporated herein by reference in its entirety.

[156] Clip 160 can be formed from a single tube of resilient material, such as nickel titanium alloy, spring steel, glass or carbon composites or polymers, or pseudoelastic (at body temperature) material such as nickel titanium alloy or comparable alloys and polymers, by laser cutting several closed-ended slots along the length of the tube (leaving the extreme distal and proximal edges of the tube intact) and cutting open-ended slots from the longitudinal center of the tube through the distal and proximal edges of the tube. The open- ended slots are cut between each pair of closed-end slots to form a number of loops joined at the center section by waist segments. Many other fabrication techniques can be utilized, for example, clip 160 can be made of several loops of wire welded together at the waist section.

[157] After the tube is cut as described above, it can be formed into its eventual resiliently expanded configuration. In this configuration, the loops turn radially outwardly from the center section, and evert toward the center plane of the center section, thus forming clinch members, i.e. distal arms 161 and proximal arms 162, in the form of arcuate, everted, petaloid frames at either end of the loop, extending from the generally tubular center section formed by waist segments. For clarity, the term everted is used here to mean that the arc over which the petaloid frame runs is such that the inside surface of clip 160 faces radially outwardly from the cylinder established by the tube.

[158] Once clip 160 has resiliently expanded to the extent possible given its impingement upon the walls of the starting vessel and the target vessel, the center section can be further expanded by plastic deformation. This can be accomplished by inflating a balloon, not shown, within the center section and expanding the center section beyond its elastic or superelastic deformation range. By plastically deforming the center section of clip 160, the center section becomes more rigid and able to withstand the compressive force of the walls of the starting and target vessels.

[159] As illustrated, the construction provides several pairs of longitudinally opposed (that is, they bend to come into close proximity to each other, and perhaps but not necessarily, touch) and aligned (they are disposed along the same longitudinal line) distal arms 161 and proximal arms 162. Overall, the petaloid frames of distal arms 161 form a "corolla," analogous to the corolla of a flower, flange or rivet clinch, which impinges on the starting vessel wall and prevents expulsion into the target vessel, and the petaloid frames of proximal arms 162 form a corolla, flange or rivet clinch (this clinch would be analogous to a rivet head, but it is formed like the clinch after insertion of the rivet), which impinges on the target vessel wall and prevents the expulsion of clip 160 into the target vessel. Also, the central section forms a short length of rigid tubing to keep the flow pathway open. The resilient apposition of the at least two distal arms 161 and at least two proximal arms 162 will securely hold clip 160 in place by resiliently clamping the walls of the starting vessel and the target vessel, even over a considerable range of wall thickness or "grip range."

[160] The respective lengths of arms 161 and 162 can be variably sized to maximize or optimize the stability of clip 160 with respect to the vessels when deployed between adjacent vessels. Moreover, varying the lengths of the respective arms can further provide additional advantages. For instance, the arms which are shortened in length can facilitate the positioning and securement of clip 160 between the vessels by allowing for the relatively shorter member to swing into position within the vessel lumen during deployment, as described in further detail below. Additionally, a shorter member can provide for a minimized implant size when placed against the vessel interior wall for securement as well as a mitigating any physiologic reaction to the implant, e.g., a reduction in thrombosis, etc. Additionally, arms 161 and/or 162 which are lengthened relative to other arms can provide for increased clip stability by increasing the amount of force applied against the tissue walls.

[161] Moreover, arms having different lengths can additionally place the adjacent vessels in tension such that the vessel walls are drawn towards one another and arms 161 and/or 162 contact the vessel luminal walls to stabilize not only clip 160 within the vessels but also the vessels with respect to one another. Additionally, having one or more arms, such as distal arms 161, sized to have a length shorter than its respective apposed clinch member can also facilitate the deployment and/or positioning of distal arms 161 within the vessel since the shorter length clinch members can more easily "swing" through an arc within the vessel lumen without contacting the interior walls. Arms with differing lengths can further be configured to align along different planes when deployed to facilitate vessel separation, if so desired.

[162] Clip 160 can further comprise at least one marker, not shown, configured to rotationally position the clip at the flow pathway location. For example, a marker can be oriented toward the target vessel prior to deployment of clip 160. Alternatively or additionally, a marker can be oriented based upon a patient image, e.g. a real-time

fluoroscopy image. In yet another embodiment, clip 160 can comprise at least one marker configured to longitudinally position the clip at the flow pathway location. A marker can indicate the distal and/or proximal end of clip 160.

[163] Clip 160 can further comprise holes 164 configured to engage a clip delivery catheter projection such as to allow the shaft of the clip deployment catheter, not shown, to be retracted while clip 160 remains positioned in the distal portion of the shaft. In one embodiment, holes 164 are constructed and arranged about the clip asymmetrically such that clip 160 can be attached in the proper orientation.

[164] Figs. 7-10 illustrate various embodiments of a venous stent 195 for implanting in a vein proximate a flow pathway of the present inventive concepts. The venous stent can be constructed and arranged to treat and/or prevent a venous stenosis, such as a venous stenosis that might be present or otherwise (without the presence of venous stent 195) form at a location up to 3cm from an anastomotic clip (e.g. clip 160 described herein). Venous stent 195 of Figs. 7-10 can comprise a self-expanding and/or balloon expandable structure.

Venous stent 195 can comprise a cutaway section that is positioned over the venous entry portion of the flow pathway, such as to avoid venous stent 195 impeding blood flow. Venous stent 195 can be constructed and arranged to shield a segment of the vein proximate the flow pathway from the turbulent flow caused by blood entering from the connected artery. In some embodiments, venous stent 195 comprises at least one opening 196, such as an opening 196 constructed and arranged to be positioned over the flow pathway. Venous stent 195 can comprise one or more radiopaque markers, such as markers 197 described herebelow, such as a marker positioned to identify the cutaway portion of venous stent 195 or any opening along the length of stent 195 configured to accommodate blood flow through the flow pathway of the present inventive concepts. System 100 of Fig. 2 can comprise one or more venous stents 195, such as a kit of venous stents 195 with different parameters, such as one or more different parameters selected from the group consisting of: length; cutaway dimension;

cutaway location relative to an end of stent 195; diameter; pattern (e.g. pattern of stent mesh); number of radiopaque markers; position of a radiopaque marker; tensile strength; hoop strength; and combinations of one or more of these. In some embodiments, stent 195 comprises a first stent 195 with a cutaway portion, and a second stent 195 without a cutaway portion, such as when the first stent 195 comprises a C-shaped cutaway portion on one end, and the second stent 195 is configured to be positioned proximate the C-shaped cutaway portion. In some embodiments, clip 160 is configured to mechanically engage venous stent 195, such as to frictionally engage a portion of venous stent 195.

[165] Referring now to Fig. 7, a side and end view of a venous stent including a cutaway end is illustrated, consistent with the present inventive concepts. Stent 195a comprises a c- shaped opening 196a positioned on one end of stent 195a as shown. Stent 195a can comprise a self-expanding stent. Alternatively or additionally, stent 195a can comprise at least a balloon expandable portion. Opening 196a is configured to be positioned in a vein proximate (e.g. positioned over) a flow pathway of the present inventive concepts. Stent 195a comprises radiopaque marker 197 positioned along at least a portion of the periphery of opening 196a. Stent 195a can be constructed and arranged to be implanted by a delivery sheath, such as delivery sheath 198 described herebelow in reference to Fig. 11.

[166] Referring now to Fig. 8, a side and end view of a venous stent including an opening along its length is illustrated, consistent with the present inventive concepts. Stent 195b comprises a circle-shaped opening 196b positioned along a mid-portion of stent 195b as shown. Stent 195b can comprise a self-expanding stent. Alternatively or additionally, stent 195b can comprise at least a balloon expandable portion. Opening 196b is configured to be positioned in a vein proximate (e.g. positioned over) a flow pathway of the present inventive concepts. Stent 195b comprises radiopaque marker 197 positioned along at least a portion of the periphery of opening 196b. Stent 195b can be constructed and arranged to be implanted by a delivery sheath, such as delivery sheath 198 described herebelow in reference to Fig. 11.

[167] Referring now to Fig. 9, a side and end view of a venous stent including a C- shaped profile is illustrated, consistent with the present inventive concepts. Stent 195c comprises a rectangular-shaped opening 196c positioned along the entire length of stent 195c as shown. Stent 195c can comprise a self-expanding stent. Alternatively or additionally, stent 195c can comprise at least a balloon expandable portion. Opening 196c is configured to be positioned in a vein proximate (e.g. positioned over) a flow pathway of the present inventive concepts. Stent 195c comprises radiopaque marker 197 positioned along at least a portion of the periphery of opening 196c. Stent 195c can be constructed and arranged to be implanted by a delivery sheath, such as delivery sheath 198 described herebelow in reference to Fig. 11.

[168] Referring now to Fig. 10, a side and end view of a venous stent including a C- shaped end portion is illustrated, consistent with the present inventive concepts. Stent 195d comprises a rectangular-shaped opening 196d positioned along an end portion of stent 195d as shown. Stent 195d can comprise a self-expanding stent. Alternatively or additionally, stent 195d can comprise at least a balloon expandable portion. Opening 196d is configured to be positioned in a vein proximate (e.g. positioned over) a flow pathway of the present inventive concepts. Stent 195d comprises radiopaque marker 197 positioned along at least a portion of the periphery of opening 196d. Stent 195d can be constructed and arranged to be implanted by a delivery sheath, such as delivery sheath 198 described herebelow in reference to Fig. 11.

[169] Referring now to Fig. 11, a side view of a venous stent being deployed from a delivery sheath is illustrated, consistent with the present inventive concepts. Delivery sheath 198 comprises an elongate shaft comprising a lumen through which a venous stent, such as venous stent 195c shown and described hereabove in reference to Fig. 9, can be delivered (e.g. pushed out via a delivery rod or unsheathed by pulling back the elongate shaft surrounding venous stent 195c. In some embodiments, delivery sheath 198 is of similar construction and arrangement to clip deployment catheter 150.

[170] Referring now to Fig. 12, a side sectional, anatomical view of an anastomotic clip and venous stent positioned in and proximate to, respectively, a flow pathway is illustrated, consistent with the present inventive concepts. Anastomotic clip 160 has been implanted in a flow pathway as described hereabove (e.g. a flow pathway with an oval shaped cross section as shown). Venous stent 195 comprising rectangular shaped opening 196 along the length of stent 195 (e.g. rectangular shaped opening 196c shown in Fig. 9 or rectangular-shaped opening 196d shown in Fig. 10) has been implanted such that opening 196 is aligned with the flow pathway opening in the vein wall (e.g. such that stent 195 provides a stenting force to the vein without obstructing blood flow through the flow pathway. In some embodiments, venous stent 195 comprises an oval shaped opening.

[171] Referring now to Fig. 13 is a side sectional, anatomical view of an anastomotic clip including a covered portion and positioned in a flow pathway, consistent with the present inventive concepts. Anastomotic clip 160' has been implanted in a flow pathway as described hereabove. Anastomotic clip 160' comprises covered portion 165 which is positioned on a venous portion of clip 160' . Covered portion 165 can be constructed and arranged to direct the flow of blood in the vein in a single direction (e.g. to the right of the page as shown in Fig. 13). Covered portion 165 can be positioned to cause blood to flow in the vein in a retrograde direction (e.g. in a revascularization procedure) or in a normal venous return flow direction (e.g. when anastomotic clip 160' is implanted to reduce systemic vascular resistance and/or to enhance long term patency of a venous stent implanted to treat a venous stenosis. Covered portion 165 can comprise a material selected from the group consisting of: PTFE; nickel titanium alloy; polyurethane; one or more bioerodible polymers; a woven mesh of biocompatible polymers and/or nickel titanium fibers; and combinations of one or more of these.

[172] Referring now to Fig. 13A, a side sectional, anatomical view of the flow pathway of Fig. 13 is illustrated, showing only the covered portion of the anastomotic clip, consistent with the present inventive concepts. Covered portion 165 is oriented to direct blood passing through the flow pathway in a single direction (to the right of the page as shown).

[173] While the preferred embodiments of the devices and methods have been described in reference to the environment in which they were developed, they are merely illustrative of the principles of the inventions. Modification or combinations of the above-described assemblies, other embodiments, configurations, and methods for carrying out the invention, and variations of aspects of the invention that are obvious to those of skill in the art are intended to be within the scope of the claims. In addition, where this application has listed the steps of a method or procedure in a specific order, it may be possible, or even expedient in certain circumstances, to change the order in which some steps are performed, and it is intended that the particular steps of the method or procedure claim set forth herebelow not be construed as being order-specific unless such order specificity is expressly stated in the claim.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a patient, comprising:

selecting a patient exhibiting a disease and/or disorder; and

creating a flow pathway between a first vascular location and a second vascular location;

wherein the first vascular location comprises a source of arterial blood;

wherein the second vascular location comprises a source of venous blood; measuring at least one physiologic parameter of the patient; and modifying the flow pathway based on the measurement;

wherein the method treats the patient disease and/or disorder while avoiding significantly increasing heart rate of the patient.

2. The method according to any method claim herein, wherein the method avoids a heart rate increase greater than 5%, greater than 10%, and/or greater than 15%.

3. The method according to any method claim herein, wherein the at least one physiologic parameter measured comprises heart rate.

4. The method according to claim 3, wherein an average heart rate of the patient is measured.

5. The method according to claim 3, wherein the modifying of the flow pathway comprises reducing flow rate through the flow pathway if the measured heart rate is above a threshold.

6. The method according to claim 5, wherein the heart rate threshold is

5bpm.

The method according to claim 5, wherein the heart rate threshold is lObpm.

The method according to claim 5, wherein the heart rate threshold is

15bpm.

9. The method according to claim 5, wherein the modifying of the flow pathway comprises: reducing flow through the flow pathway; stopping flow through the flow pathway; and/or stopping flow through the flow pathway and creating a new flow pathway.

10. The method according to claim 5, wherein the modifying of the flow pathway comprises placing a covered stent proximate the flow pathway.

11. The method according to claim 10, wherein the first vascular location comprises an artery, and wherein the covered stent is placed in the artery proximate the flow pathway.

12. The method according to claim 10, wherein the second vascular location comprises a vein, and wherein the covered stent is placed in the vein proximate the flow pathway.

13. The method according to claim 5, wherein creating the flow pathway comprises placing an anastomotic clip between the first vascular location and the second vascular location, and wherein the modifying of the flow pathway comprises modifying the anastomotic clip.

14. The method according to claim 13, wherein the modifying of the anastomotic clip comprises reducing the diameter of the anastomotic clip.

15. The method according to claim 3, wherein the at least one physiologic parameter further comprises blood pressure.

16. The method according to claim 15, wherein the at least one physiologic parameter further comprises systolic blood pressure and/or diastolic blood pressure.

17. The method according to claim 16, wherein the at least one physiologic parameter further comprises systolic blood pressure and diastolic blood pressure.

18. The method according to claim 15, wherein the modifying of the flow pathway comprises increasing flow through the flow pathway if the measured blood pressure is above a first threshold, and if the measured heart rate is below a second threshold.

19. The method according to claim 18, wherein the modifying of the flow pathway comprises dilating the flow pathway.

20. The method according to claim 19, wherein the modifying of the flow pathway comprises creating a second flow pathway.

21. The method according to any method claim herein, wherein the at least one physiologic parameter measured comprises a physiologic parameter selected from the group consisting of: angina level; mitral regurgitation type; mitral regurgitation severity; orthostatic intolerance level; dizziness level; lightheadedness level; a syncope event parameter; nausea level; fatigue level; tremor state; breathing state; swallowing ability;

headache level; visual disturbance level; sweating level; pallor state; heart rate; cardiac output; blood pressure; systolic blood pressure; diastolic blood pressure; a respiration parameter; a blood gas parameter; blood flow; blood flow through a vein or artery within and/or proximate the right side of the heart; vascular resistance; pulmonary resistance; average clotting time assessment; serum creatinine level assessment; level of B-type natriuretic peptide (BNP); level of N-terminal pro B-type natriuretic peptide (NT-proBNP); and combinations thereof.

22. The method according to any method claim herein, wherein the modifying the flow pathway comprises dilating the flow pathway with a balloon.

23. The method according to claim 22, wherein the balloon comprises a diameter between 2.5mm and 6.0mm.

24. The method according to claim 23, wherein the balloon comprises a diameter between 4.0mm and 5.0mm.

25. The method according to any method claim herein, wherein the flow pathway causes an increase in the patient's venous pressure.

26. The method according to claim 25, wherein the patient's venous pressure increases near-immediately after creation of the flow pathway.

27. The method according to any method claim herein, wherein the flow pathway causes an increase in the patient's venous pressure and/or a decrease in the patient's arterial blood pressure.

28. The method according to claim 27 wherein the flow pathway causes both an increase in the patient's venous pressure and a decrease in the patient's arterial blood pressure.

29. The method according to any method claim herein, wherein the flow pathway causes a decrease in the patient's systolic pressure.

30. The method according to claim 29, wherein the patient's systolic pressure prior to the flow pathway creation is at a level between 120mmHg and 220mmHg.

31. The method according to claim 30, wherein the patient's systolic pressure prior to the flow pathway creation is at a level between 140mmHg and 160mmHg.

32. The method according to claim 29, wherein the patient's systolic pressure subsequent to the flow pathway creation is at a level between 115mmHg and 180mmHg.

33. The method according to claim 32, wherein the patient's systolic pressure subsequent to the flow pathway creation is at a level between 120mmHg and 140mmHg.

34. The method according to claim 29, wherein the patient's systolic pressure is reduced between 5mmHg and 70mmHg subsequent to the creation of the flow pathway.

35. The method according to claim 34, wherein the patient's systolic pressure is reduced between lOmmHg and 40mmHg subsequent to the creation of the flow pathway.

36. The method according to claim 29, wherein the patient's systolic pressure is reduced 5% to 30% subsequent to the creation of the flow pathway.

37. The method according to claim 36, wherein the patient's systolic pressure is reduced 5% to 20% subsequent to the creation of the flow pathway.

38. The method according to any method claim herein, wherein the flow pathway comprises a flow rate between 400ml/min and 1500ml/min.

39. The method according to claim 38, wherein the flow pathway comprises a flow rate between 600ml/min and 1200ml/min.

40. The method according to claim 38, wherein the flow pathway comprises a flow rate of at least 600ml/min.

41. The method according to claim 38, wherein the flow pathway comprises a flow rate of at least 800ml/min.

42. The method according to any method claim herein, wherein the flow pathway comprises a diameter between 2.5mm and 4mm.

43. The method according to any method claim herein, wherein the flow pathway comprises a diameter of approximately 4mm.

44. The method according to any method claim herein, wherein the method treats hypertension of the patient.

45. The method according to claim 44, wherein the patient's systolic pressure prior to the flow pathway creation is at a level above 140mmHg and/or above 160mmHg.

46. The method according to claim 45, wherein the patient's systolic pressure is reduced between 5mmHg and 70mmHg subsequent to the creation of the flow pathway.

47. The method according to claim 46, wherein the patient's systolic pressure is reduced between lOmmHg and 40mmHg subsequent to the creation of the flow pathway.

48. The method according to any method claim herein, wherein the method treats a disease and/or disorder selected from the group consisting of: angina; angina pectoris, mitral regurgitation; venous stenosis; deep vein thrombosis; hypertension; arterial hypertension; hypertension related to loss of capacitance artery elasticity; abnormalities of pulse and/or pressure generation related to structural hypertension; heart failure; congestive heart failure; atrial arrhythmia; ventricular arrhythmia; chronic obstructive pulmonary disease (COPD); lung fibrosis; adult respiratory distress syndrome; lymphangioleiomyomatosis; pulmonary hypertension; sleep apnea; sleep apnea due to hypoxemia or hypertension;

orthostatic intolerance; orthostatic hypotension; chronic kidney disease; and combinations thereof.

49. The method according to any method claim herein, wherein the method reduces the likelihood of sudden cardiac death, syncope, and/or near syncope.

50. The method according to any method claim herein, wherein the method achieves a physiologic change selected from the group consisting of: reduced blood pressure; reduced angina; reduced mitral regurgitation; increased oxygen delivery by the arterial system; increased blood volume; increased proportion of blood flow to the descending aorta; increased blood flow to the kidneys; increased blood flow outside the kidneys; increased cardiac output; and combinations thereof.

51. The method according to any method claim herein, wherein the method is constructed and arranged to increase cardiac output.

52. The method according to any method claim herein, wherein the method is constructed and arranged to cause one or more of: a decrease in systemic vascular resistance; a decrease in blood pressure; an increase in cardiac output; an increase in right atrial pressure; an atrial natriuretic peptide (A P) release; vasodilation; an increase in right atrial filling; a Bainbridge reflex; an increase in heart rate; peripheral sympatho-inhibition; activation of venous baroreceptors; activation of pulmonary arterial mechanoreceptors; an increase in venous oxygenation; an increase in pulmonary blood flow; an increase in arterial compliance; a decrease in a reflected pulse wave; a decrease in effective arterial volume; an increase in oxygen delivery to tissue; a decrease in chemoreceptor activity; a decrease in sympatho-excitation; a change in sodium and/or water retention; reduced renal ischemia; and combinations thereof.

53. The method according to any method claim herein, wherein creating the flow pathway comprises a procedure selected from the group consisting of: dilating tissue proximate the flow pathway with a balloon; applying energy to tissue proximate the flow pathway such as RF energy applied to tissue; and combinations thereof.

54. The method according to any method claim herein, wherein the flow pathway comprises a fistula.

55. The method according to any method claim herein, wherein the first vascular location comprises an iliac artery.

56. The method according to claim 55, wherein the second vascular location comprises an iliac vein.

57. The method according to any method claim herein, wherein the first vascular location comprises an artery selected from the group consisting of: aorta; axillary; brachial; ulnar; radial; profundal; femoral; iliac; popliteal; and carotid.

58. The method according to claim 57, wherein the second vascular location comprises a vein.

59. The method according to any method claim herein, wherein the second vascular location comprises a vein selected from the group consisting of: inferior vena cava; saphenous; femoral; iliac; popliteal; brachial; basilic; cephalic; medial forearm; medial cubital; axillary; and jugular.

60. The method according to claim 59, wherein the first vascular location comprises an artery.

61. The method according to any method claim herein, wherein the first vascular location comprises a chamber of the heart.

62. The method according to claim 61, wherein the first vascular location comprises the left atrium and the second vascular location comprises the right atrium.

63. The method according to claim 61, wherein the first vascular location comprises the left ventricle and the second vascular location comprises the coronary sinus.

64. The method according to any method claim herein, wherein the first vascular location comprises the aorta and the second vascular location comprises a vein, and wherein the flow pathway comprises a graft positioned between the aorta and the vein.

65. The method according to any method claim herein, wherein the flow pathway comprises a diameter of at least 2.5mm.

66. The method according to claim 65, wherein the flow pathway comprises a diameter of at least 3.0mm.

67. The method according to claim 65, wherein the flow pathway comprises a diameter of less than or equal to 6.0mm.

68. The method according to claim 67, wherein the flow pathway comprises a diameter of less than 5.0mm.

69. The method according to claim 68, wherein the flow pathway comprises a diameter of less than 4.0mm.

70. The method according to any method claim herein, wherein the flow pathway comprises a diameter based on a patient parameter.

71. The method according to claim 70, wherein the patient parameter comprises a parameter determined prior to the creation of the flow pathway.

72. The method according to claim 70, wherein the patient parameter comprises a parameter determined during the flow pathway creation procedure.

73. The method according to claim 70, wherein the patient parameter comprises a parameter measured after the creation of the flow pathway, the method further comprising modifying the flow pathway diameter based on the measured patient parameter.

74. The method according to claim 70, wherein the patient parameter comprises a parameter selected from the group consisting of: angina level; mitral

regurgitation severity; mitral regurgitation type; cardiac output; blood pressure; flow rate; tilt table test result; ankle brachial index test result; venous insufficiency level; peripheral vascular resistance; shunt flow; pulmonary capillary wedge pressure; right atrial pressure; pulmonary pressure; left atrial pressure; arterial oxygenation; venous oxygenation; and combinations thereof.

75. The method according to any method claim herein, further comprising creating a second flow pathway between a third vascular location and a fourth vascular location.

76. The method according to claim 75, wherein the second flow pathway comprises a fistula.

77. The method according to claim 75, wherein the second flow pathway is created at least twenty-four hours after the creation of the first flow pathway.

78. The method according to claim 75, wherein the first vascular location comprises an artery and the third vascular location comprises the same artery.

79. The method according to claim 78, wherein the second vascular location comprises a vein and the fourth vascular location comprises the same vein.

80. The method according to claim 75, wherein the first vascular location comprises the iliac artery in the right leg of the patient and the third vascular location comprises the iliac artery in the left leg of the patient.

81. The method according to claim 75, wherein the cumulative flow rate of the first flow pathway and the second flow pathway comprises a flow rate of at least

400ml/min.

82. The method according to claim 75, wherein the cumulative flow rate of the first flow pathway and the second flow pathway comprises a flow rate of less than or equal to 1500ml/min.

83. The method according to claim 75, further comprising creating multiple flow pathways comprising at least a third flow pathway.

84. The method according to claim 83, wherein the cumulative flow rate of the multiple flow pathways comprises a flow rate of at least 400ml/min.

85. The method according to claim 83, wherein the cumulative flow rate of the multiple flow pathways comprises a flow rate of less than or equal to 1500ml/min.

86. The method according to any method claim herein, further comprising placing an implant proximate the flow pathway.

87. The method according to claim 86, wherein the implant comprises an anastomotic clip placed between the first vascular location and the second vascular location.

88. The method according to claim 87, wherein the anastomotic clip comprises at least a covered portion.

89. The method according to claim 86, wherein the implant comprises a component selected from the group consisting of: anastomotic clip; suture; staple; adhesive; and combinations thereof.

90. The method according to claim 86, wherein the implant comprises at least a biodegradable portion.

91. The method according to any method claim herein, further comprising dilating the flow pathway.

92. The method according to claim 91, wherein the dilating the flow pathway comprises dilating the flow pathway by inflating a balloon in the flow pathway.

93. The method according to any method claim herein, further comprising modifying the flow pathway.

94. The method according to claim 93, wherein the modifying the flow pathway comprises dilating at least a portion of the flow pathway.

95. The method according to claim 93, further comprising placing an anastomotic clip in the flow pathway, wherein the modifying the flow pathway is performed after placement of the anastomotic clip.

96. The method according to claim 93, wherein the modifying the flow pathway comprises delivering energy to the flow pathway.

97. The method according to claim 96, wherein the energy delivered comprises radiofrequency energy.

98. The method according to claim 93, wherein the modifying the flow pathway is performed at least twenty-four hours after the creating of the flow pathway.

99. The method according to claim 93, wherein the modifying the flow pathway comprises modifying a flow pathway parameter selected from the group consisting of: flow pathway cross sectional diameter; flow pathway average cross sectional diameter; flow pathway flow rate; flow pathway average flow rate; diastolic pressure after flow pathway creation; diastolic pressure change after flow pathway creation; systolic pressure after flow pathway creation; systolic pressure change after flow pathway creation; ratio of diastolic to systolic pressure after flow pathway creation; difference between diastolic pressure and systolic pressure after flow pathway creation; and combinations thereof.

100. The method according to claim 93, wherein the modifying the flow pathway is constructed and arranged to perform a function selected from the group consisting of: increasing flow through the flow pathway; decreasing flow through the flow pathway; increasing the diameter of at least a segment of the flow pathway; decreasing the diameter of at least a segment of the flow pathway; removing tissue proximate the flow pathway; stenting a stenosis proximate the flow pathway; stenting a venous stenosis; delivering an agent to the flow pathway; delivering an agent to tissue proximate the flow pathway; delivering an agent to venous and/or arterial wall tissue proximate the flow pathway; blocking a sidebranch proximate the flow pathway; and combinations thereof.

101. The method according to any method claim herein, further comprising performing a flow pathway assessment procedure.

102. The method according to claim 101, wherein the flow pathway assessment procedure comprises an anatomical measurement procedure.

103. The method according to claim 102, wherein the anatomical measurement procedure comprises measuring an anatomical feature selected from the group consisting of: a flow pathway diameter measurement; a flow pathway length measurement; a measurement of the distance between an artery and vein comprising the flow pathway; a measurement of the distance between the flow pathway and a vessel sidebranch; and combinations thereof.

104. The method according to claim 101, wherein the flow pathway assessment procedure comprises measuring flow at least one of within or proximate the flow pathway.

105. The method according to claim 104, wherein the flow pathway assessment procedure comprises measuring a flow selected from the group consisting of: flow through the flow pathway; flow in a vessel segment proximate the flow pathway; flow measured using Doppler Ultrasound; flow measured using angiographic techniques; and combinations thereof.

106. The method according to claim 101, wherein the flow pathway assessment procedure comprises an assessment of a patient physiologic condition.

107. The method according to claim 106, wherein the patient physiologic condition comprises a condition selected from the group consisting of: angina level; mitral regurgitation type; mitral regurgitation severity; orthostatic intolerance level; dizziness level; lightheadedness level; syncope events; nausea level; fatigue level; tremor state; breathing state; swallowing ability; headache level; visual disturbance level; sweating level; pallor state; cardiac output; blood pressure such as systolic and/or diastolic blood pressure;

respiration; a blood gas parameter; blood flow such as blood flow through a vein or artery within and/or proximate the right side of the heart; vascular resistance; pulmonary resistance; average clotting time assessment; serum creatinine level assessment; and combinations thereof.

108. The method according to any method claim herein, further comprising applying an agent to a vein wall proximate the flow pathway.

109. The method according to claim 108, wherein the agent is applied to reduce venous stenosis formation.

110. The method according to claim 108, wherein the agent is applied in the vein downstream of the flow pathway.

111. The method according to claim 108, wherein the agent is applied at a time selected from the group consisting of: prior to creation of flow pathway; during creation of flow pathway; after creation of flow pathway; and combinations thereof.

112. The method according to claim 108, wherein the agent is applied to the vein wall at a location downstream from the flow pathway.

113. The method according to claim 108, wherein the agent comprises an agent selected from the group consisting of: anti-proliferative agent; a chemotherapeutic agent; paclitaxel; an mTOR inhibitor; Sirolimus; Zotarolimus; Everolimus; and combinations thereof.

114. The method according to claim 108, wherein the agent comprises paclitaxel.

115. The method according to claim 108, wherein a mass of at least 20C^g of agent is delivered to the venous wall.

116. The method according to claim 108, wherein a mass of between 300μg and 600 μg of agent is delivered to the venous wall.

117. The method according to claim 108, further comprising implanting an anastomotic clip in the flow pathway, wherein the agent comprises a coating of the anastomotic clip.

118. The method according to claim 108, wherein the agent is applied to the vein wall by a delivery catheter.

119. The method according to claim 118, wherein the agent comprises a coating on a balloon of the delivery catheter.

120. The method according to claim 118, wherein the delivery catheter comprises a permeable balloon and the agent is delivered through the permeable balloon.

121. The method according to any method claim herein, further comprising implanting a venous stent in a vein proximate the flow pathway.

122. The method according to claim 121, wherein the implanting a venous stent comprises implanting multiple venous stents.

123. The method according to claim 122, wherein the venous stent is implanted to reduce future venous stenosis creation.

124. The method according to claim 122, wherein the venous stent comprises one or more venous stents comprising a diameter between 2mm and 16mm.

125. The method according to any method claim herein, further comprising implanting a covered stent in a vein to at least partially occlude the flow pathway.

126. The method according to claim 125, wherein the flow pathway is at least partially occluded based on the measurement of the at least one physiologic parameter.

127. The method according to claim 126, wherein the at least one physiologic parameter measured comprises heart rate.

128. A system for treating angina in a patient, comprising: a needle delivery device constructed and arranged to place a vessel-to-vessel guidewire from a starting vessel to a target vessel; and

a flow creation device constructed and arranged to be advanced over the vessel-to-vessel guidewire and to create a flow pathway between the starting vessel and the target vessel; wherein the system is constructed and arranged to treat a disease and/or disorder of the patient without significantly increasing heart rate of the patient.

129. The system according to any system claim herein, further comprising a diagnostic device configured to measure at least one physiologic parameter of the patient, wherein the flow pathway is modified based on the measurement.

130. The system according to claim 129, wherein the diagnostic device is configured to measure at least heart rate.

131. The system according to claim 129, wherein the diagnostic device is configured to measure at least heart rate and blood pressure.

132. The system according to claim 129, wherein the diagnostic device is configured to measure blood pressure.

133. The system according to claim 129, wherein the diagnostic device is configured to measure one or more patient physiologic parameters selected from the group consisting of: angina level; mitral regurgitation type; mitral regurgitation severity; orthostatic intolerance level; dizziness level; lightheadedness level; a syncope event parameter; nausea level; fatigue level; tremor state; breathing state; swallowing ability; headache level; visual disturbance level; sweating level; pallor state; heart rate; cardiac output; blood pressure; systolic blood pressure; diastolic blood pressure; a respiration parameter; a blood gas parameter; blood flow; blood flow through a vein or artery within and/or proximate the right side of the heart; vascular resistance; pulmonary resistance; average clotting time assessment; serum creatinine level assessment; level of B-type natriuretic peptide (B P); level of N- terminal pro B-type natriuretic peptide (NT-proBNP); and combinations thereof.

134. The system according to any system claim herein, further comprising a flow pathway maintaining implant.

135. The system according to claim 134, wherein the flow pathway maintaining implant comprises an anastomotic clip.

136. The system according to claim 134, wherein the flow pathway maintaining implant comprises a covered portion.

137. The system according to claim 136, wherein the covered portion is constructed and arranged to direct the flow of blood to and/or from the flow pathway.

138. The system according to any system claim herein, further comprising a flow pathway modifying device.

139. The system according to claim 138, wherein the flow pathway modifying device comprises an expandable element.

140. The system according to claim 137, wherein the flow pathway modifying device comprises a covered stent configured to be implanted proximate the flow pathway to reduce flow through the flow pathway.

141. The system according to claim 140, wherein the covered stent is configured to reduce the patient's heart rate below a threshold.

142. The system according to any system claim herein, further comprising a patient imaging device.

143. The system according to any system claim herein, further comprising a venous stent.

144. The system according to any system claim herein, further comprising a covered stent.

145. The system according to claim 144, wherein the covered stent is constructed and arranged to be implanted to at least partially occlude the flow pathway.

146. The system according to claim 145, further comprising a venous stent configured to treat a venous stenosis, wherein the flow pathway is created to elevate flow within the venous stent, and wherein the covered stent is constructed and arranged to occlude the flow pathway at least one week after the creation of the flow pathway.

147. The system according to claim 144, wherein the covered stent is configured to reduce the patient's heart rate below a threshold.

148. The system according to any system claim herein, further comprising an agent configured to reduce a venous stenosis.

149. The system according to any system claim herein, further comprising an agent delivery catheter configured to deliver an agent to a vessel wall.

150. The system according to claim 149, further comprising an agent to be delivered to the vessel wall by the agent delivery catheter.

151. The system according to claim 150, wherein the agent comprises an agent selected from the group consisting of: anti-proliferative agent; a chemotherapeutic agent; paclitaxel; an mTOR inhibitor; Sirolimus; Zotarolimus; Everolimus; and combinations thereof.

152. The system according to claim 150, wherein the agent comprises paclitaxel.