WO2016168587A1 - Devices and methods for inhibiting stenosis, obstruction, or calcification of a native heart valve, stented heart valve or bioprosthesis - Google Patents
Devices and methods for inhibiting stenosis, obstruction, or calcification of a native heart valve, stented heart valve or bioprosthesis Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
- A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
- A61F2/2418—Scaffolds therefor, e.g. support stents
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
- A61L27/3625—Vascular tissue, e.g. heart valves
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- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
- A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
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- A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2430/00—Materials or treatment for tissue regeneration
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Definitions
- the invention relates to devices and methods for inhibiting stenosis, obstruction, or calcification of native heart valves and heart valve bioprostheses.
- the heart is a hollow, muscular organ that circulates blood throughout an organism's body by contracting rhythmically.
- the heart has four- chambers situated such that the right atrium and ventricle are completely separated from the left atrium and ventricle.
- blood flows from systemic veins to the right atrium, and then to the right ventricle from which it is driven to the lungs via the pulmonary artery.
- the blood Upon return from the lungs, the blood enters the left atrium, and then flows to the left ventricle from which it is driven into the systematic arteries.
- tricuspid separates the right atrium and right ventricle
- pulmonary valve separates the right atrium and pulmonary artery
- mitral valve separates the left atrium and left ventricle
- aortic valve separates the left ventricle and aorta.
- patients having an abnormality of a heart valve are characterized as having valvular heart disease.
- a heart valve can malfunction either by failing to open properly (stenosis) or by leaking (regurgitation).
- a patient with a malfunctioning aortic valve can be diagnosed with either aortic valve stenosis or aortic valve regurgitation.
- valve replacement by surgical means may be a possible treatment.
- Replacement valves can be autografts, allografts, or xenografts as well as mechanical valves or valves made partly from valves of other animals, such as pig or cow.
- the replacement valves themselves are susceptible to problems such as degeneration, thrombosis, calcification, and/or obstruction.
- the process of valve replacement may cause perforation in the surrounding tissue, leading also to stenosis, degeneration, thrombosis, calcification, and/or obstruction.
- the method slows the progression of bicuspid aortic valve(BAV) calcification, tricuspid aortic valve calcification (TAV), transcutaneous aortic valve replacement (TAVR), surgical bioprosthetic aortic valve replacement (SBAVR), mitral valve myxomatous degeneration (MVMD) via the activation of the Wnt pathway via the cleavage of Notch 1 protein and the phosphorylation of glycogen synthase kinase which in turn releases beta catenin to the nucleus to activate bone and cartilage formation the heart valve and or prosthesis.
- BAV bicuspid aortic valve
- TAV tricuspid aortic valve calcification
- TAVR transcutaneous aortic valve replacement
- SBAVR surgical bioprosthetic aortic valve replacement
- MVMD mitral valve myxomatous degeneration
- a method for inhibiting stenosis, obstruction, or calcification of a bioprosthetic valve implanted in a patient comprising: implanting a bioprosthetic valve in a patient to replace a natural heart valve; following implantation administering an effective amount of an anti- hyperlidemic agent in combination with a PCSK9 antibody; and causing the inhibition of stenosis, obstruction, or calcification of the bioprosthetic valve or natural valve or both.
- said effective amount of anti- hyperlidemic agents is selected from 10 mg to 80 mg of Atorvastatin, 10 mg to 40 mg of Simvastatin, 5 mg to 40 mg of Rosuvastatin, 20 mg to 80 mg of Pravastatin, 1 mg to 4 mg of Pitavastatin and combinations of the foregoing.
- bioprosthetic pulmonic valve 12. The method of clause 1, wherein the bioprosthetic valve is bioprosthetic tricuspid valve.
- bioprosthetic valve comprises one or more cusps of biological origin.
- Figure 1 is an illustration that depicts the signaling mechanisms of valve calcification in the presence of hyperlidemia.
- Figure 2 are images showing preliminary data of native valve atherosclerosis in the presence of a cholesterol diet, lithium chloride diet, and the attenuation of the valve leaflet with the treatment of atorvastatin in a mouse valve leaflet that has no LDL receptors.
- FIG. 3 Panel A depicts the in vitro data of the direct treatment of myofibroblast cells with the increasing dose of lithium chloride increasing cell proliferation.
- Panel B is the inhibition of DKK1 with atorvastatin and the direct inhibition of Lrp5.
- Figure 4 demonstrates the characterization of the eNOS phenotype as defined by histology, RTPCR and echocardiography.
- FIG 4 Panel A depicts the histology for BAV.
- FIG 4 Panel B depicts the semi-quantitative RTPCR from the BAV eNOS 7" mice, and echocardiographic data for the bicuspid vs. tricuspid aortic valves.
- Panel C is a table depicting the echocardiography from the eNOS null mouse on different diets.
- Figure 5 is a schematic view showing the cell layers which develop the disease process in the native valve leaflet via the signaling between the endothelial cell to the myofibroblast cell in the presence of hyperlipidemia to activate the secretion of Wnt to turn on the Lrp5 receptor which in turn activates bone formation in the native myofibroblast cell and the different inhibitors and oral agents to slow the progression of disease.
- FIG. 6 is a schematic view showing an aorta having the aortic valve with the cells therein the native valve or the bioprosthesis, in which the aorta surrounding the stent has been partially blocked by stenosis secondary to vascular smooth muscle cell proliferation and differentiation to bone forming cells after injury from the stent adjacent to the aorta, and c-kit stem cell or the in vivo myofibroblast cell proliferation and differentiation to bone formation cells secondary to inflammation and homing of c-kit stem cells to become bone forming cells and the effect of medications including statins, proprotein convertase subtilisin kexin type 9 antagonist antibody (“PCSK9 antibody”), and a farnesyltransferase (“FTI”) inhibitor.
- statins proprotein convertase subtilisin kexin type 9 antagonist antibody
- FTI farnesyltransferase
- Figure 7 depicts pannus formation and calcification in the explanted valves from human patients at the time of surgical valve replacement of a failed bioprosthetic heart valve secondary to proliferating mesenchymal stem cells attaching to the valve and stent which calcifies and causes valve leaflet and stent destruction.
- Figure 8 is a graph, which demonstrates the RNA expression of the ckit positive stem cell attachment to the calcified heart valve.
- Figure 9 depicts the results of testing the anti-inflammatory drug atorvastatin at 80 mg per day in a rabbit model of bioprosthetic valve calcification, with the control diet showing little atherosclerosis, the cholesterol diet demonstrating severe atherosclerosis and the Atorvastatin therapy with the cholesterol diet demonstrating attenuation of the atherosclerosis.
- the invention provides a method for inhibiting stenosis, obstruction, or calcification of a native valve, a stented aorta and valve leaflet or bioprosthesis with or without a sewing ring, following implantation of a valve prosthesis in a patient in need thereof, which may include treatment with a oral medical therapy for valvular heart disease that has evidence of early to late evidence disease, as soon as the deployment of the elastical stent, gortex covering, and the bioprosthesis wherein the oral therapy with one or more therapeutic agents alone or in combination to improve the efficacy of the inhibition of calcification and the improvement of the longevity of the prosthetic material including the stent, the valve, and the gortex covering specifically to slow the progression of bicuspid aortic valve(BAV) calcification, Tricuspid aortic valve calcification(TAV), transcutaneous aortic valve replacement(TAVR), Surgical Bioprosthetic aortic valve replacement(SBAVR), mitral valve myxomato
- the inventor has also developed a method for inhibiting stenosis, obstruction, or calcification of a native heart valve and bioprosthetic valve following surgical implantation of said bioprosthetic valve in a vessel having a wall is disclosed herein.
- a patient is provided with a series of medical treatments alone or in combination as the native valve develops valvular disease and at the moment of bioprosthetic valve for surgical replacement of a natural diseased valve.
- the bioprosthetic valve may include an elastical stent via the activation of osteogenic bone and cartilage formation in the native valve leaflets and or the bioprosthetic valve leaflet after the attachment of a mesenchymal stem cell with the potential for osteogenic bone formation (as best seen in Figure 2), the development of native valve atherosclerosis in the presence of a cholesterol diet, lithium chloride diet, and the attenuation of the valve leaflet with the treatment of atorvastatin in a mouse valve leaflet that has no LDL receptors.
- Figure 3 demonstrates the effect of the direct treatment of Lithium Chloride on myofibroblast cells in the activation of cell proliferation and the inactivation of D K1 in the presence of atorvastatin.
- a method to inhibit the splicing of the Notch 1 Receptor by treating the valve with lipid lowering agents statins in combination with PCSK9 antibody which will inhibit the LDL receptor to modulate the lipid levels is also provided herein.
- Farsnesyltransferase (“FTI") inhibitors inhibit the farsnesylation of Wnt to inhibit the binding of Wnt3a to LRP5 receptor which modulates the myofibroblast to differentiate via the osteogenic bone pathway in the presence of hyperlipidemia.
- FTI inhibitors are small molecules which reversibly bind to the farnesyltransferase CAAX binding site.
- An FTI inhibitor will inhibit the activation of Wnt3a in cell attachment to form disease in the prosthetic valve leaflet and or native valve cell proliferation and or bone formation by decreasing farnesylation of Wnt3a which is critical for the activation of the Wnt3a/LRP5/ Frizzled complex as demonstrated in Figure 5
- PCSK9 is a regulator of plasma lipoprotein cholesterol (LDL-C).
- the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein regulates the activity of low-density lipoprotein (LDL) receptors.
- Inhibition of PCSK9 with a monoclonal antibody results in increased cycling of LDL receptors and increased clearance of LDL cholesterol (LDL-C).
- PCSK9 is secreted after the autocatalytic cleavage of the prodomain, which remains non-covalently associated with the catalytic domain as indicated in Figure 5, which inhibits the LDLR receptor via the PCSK9 antibody in combination with a statin agent.
- These therapeutic agents inhibit cell proliferation and calcification in combination with an effective amount of a farsnesyltransferase inhibitor (FTI) which inhibits the activation of Wnt3a in cell attachment to form disease in the prosthetic valve leaflet and or native valve cell proliferation and or bone formation by decreasing farnesylation of Wnt3a which is critical for the activation of the Wnt3a/LRP5/ Frizzled complex as demonstrated in Figure 5.
- FTI farsnesyltransferase inhibitor
- stenosis may refer to the narrowing of a heart valve that could block or obstruct blood flow from the heart and cause a back-up of flow and pressure in the heart.
- Valve stenosis may result from various causes, including, but not limited to, scarring due to disease, such as rheumatic fever; progressive calcification via bone formation on the leaflet; progressive wear and tear; among others.
- valve may refer to any of the four main heart valves that prevent the backflow of blood during the rhythmic contractions.
- the four main heart valves are the tricuspid, pulmonary, mitral, and aortic valves.
- the tricuspid valve separates the right atrium and right ventricle
- the pulmonary valve separates the right atrium and pulmonary artery
- the mitral valve separates the left atrium and left ventricle
- the aortic valve separates the left ventricle and aorta.
- the bioprosthetic valve and the diseased valve may be an aortic valve, pulmonary valve, tricuspid valve, or mitral valve.
- valve prosthesis may refer to a device used to replace or supplement a heart valve that is defective, malfunctioning, or missing.
- valve prostheses include, but are not limited to, bioprostheses; mechanical prostheses, and the like including, ATS 3fs® Aortic Bioprosthesis, Carpentier-Edwards PERIMOUNT Magna Ease Aortic Heart Valve, Carpentier- Edwards PERIMOUNT Magna Aortic Heart Valve, Carpentier-Edwards PERIMOUNT Magna Mitral Heart Valve, Carpentier-Edwards PERIMOUNT Aortic Heart Valve, Carpentier-Edwards PERIMOUNT Plus Mitral Heart Valve, Carpentier-Edwards PERIMOUNT Theon Aortic Heart Valve, Carpentier- Edwards PERIMOUNT Theon Mitral Replacement System, Carpentier-Edwards Aortic Porcine Bioprosthesis, Carpentier-Edwards Duraflex
- Aortic Porcine Bioprosthesis Edwards Prima Plus Stentless Bioprosthesis, Edwards Sapien Transcatheter Heart Valve, Medtronic, Freestyle® Aortic Root Bioprosthesis, Hancock® II Stented Bioprosthesis, Hancock II Ultra® Bioprosthesis, Mosaic® Bioprosthesic, Mosaic Ultra® Bioprosthesis,St.
- bioprostheses comprise a valve having one or more cusps and the valve is mounted on a frame or stent, both of which are typically elastical.
- the term "elastical” means that the device is capable of flexing, collapsing, expanding, or a combination thereof.
- the cusps of the valve are generally made from tissue of mammals such as, without limitation, pigs (porcine), cows (bovine), horses, sheep, goats, monkeys, and humans.
- the valve may be a collapsible elastical valve having one or more cusps and the collapsible elastical valve may be mounted on an elastical stent.
- the collapsible elastical valve may comprise one or more cusps of biological origin.
- the one or more cusps are porcine, bovine, or human.
- bioprostheses may comprise a collapsible elastical valve having one or more cusps and the collapsible elastical valve is mounted on an elastical stent
- examples of bioprostheses include, but are not limited to, the SAPIEN transcatheter heart valve manufactured Edwards Lifesciences, and the CoreValve® transcatheter heart valve manufactured by Medtronic and Portico-Melody by Medtronic.
- the elastical stent portion of the valve prosthesis used in the present invention may be self-expandable or expandable by way of a balloon catheter.
- the elastical stent may comprise any biocompatible material known to those of ordinary skill in the art. Examples of biocompatible materials include, but are not limited to, ceramics; polymers; stainless steel; titanium; nickel-titanium alloy, such as Nitinol; tantalum; alloys containing cobalt, such as Elgiloy® and Phynox®; and the like.
- oral treatment of a patients with one or more therapeutic agents in combination to inhibit the development of valve calcification which develops in Figure 1 in the presence of hyperlidemia, there is a decrease in Nitric oxide and Wnt3a is farnesylated in order for the secretion of Wnt, which in turns binds to Lrp5, in addition Notch 1 is spliced and inactivated in order for the initiation of cell proliferation and the initiation of cell proliferation via activation of CBFA1 and the initiation of bone formation by activation of osteogenic bone program as listed in Table I .
- valve prosthesis may be any shape cylindrical (final shape is cylinder may be funnel shaped original all required to contact the valve or walls of the valve where, without being bound to theory, the therapeutic agents are released and absorbed by the valve or walls of the valve, or the aorta including aortic valve, mitral valve, tricuspid valve, vena cava valve.
- the elastical stent portion may be substantially cylindrical so as to be able to contact the valve or walls of the valve upon securing.
- the diameter of the elastical stent portion may be about 15 mm to about 42 mm.
- the method further may comprise introducing a nucleic acid encoding a nitric oxide synthase into the one or more cusps of the valve prosthesis. Methods for introducing a nucleic acid encoding a nitric oxide synthase into the one or more cusps are described in U.S. Patent No. 6,660,260, issued December 9, 2003, and is hereby incorporated by reference in its entirety.
- Panel B1-B5 is the microCT data from the corresponding diets in the valve leaflets defined in Figure 2, Panel A, Panel Bl control diet has no evidence of calcification, Figure 2, Panel B2 the cholesterol diet demonstrates increase in calcification, Figure 2, Panel B3 and B4 atorvastatin treatments has no evidence of calcification and Figure 2, Panel B5 with the lithium Chloride diet demonstrates micro calcification in the heart valve.
- Panel CI demonstrates the gene expression of the increase in the bone transcription factor CBFA1 in the cholesterol treatment and Lrp5 gene expression. The Lrp5 null mouse has no evidence of calcifications in the heart.
- Panel E is the confocal microscopy of the stain for beta catenin, which translocates to the nuclei to activate bone formation downstream of Lrp5.
- Panel El demonstrates the positive translocation of beta-catenin to the nuclei in the treatment of cholesterol diet.
- FIG. 3 Panel A depicts the in vitro data of the direct treatment of myofibroblast cells with the increasing dose of lithium chloride increasing cell proliferation.
- Panel B is the inhibition of D 1 with atorvastatin and the direct inhibition of Lrp5.
- Figure 4 demonstrates the characterization of the eNOS phenotype as defined by histology, RTPCR and echocardiography.
- Panel A is the histology for BAV
- Panel B is the semi-quantitative RTPCR from the BAV eNOS "7” mice, and echocardiographic data for the bicuspid vs. tricuspid aortic valves.
- Panel C to understand if eNOS "7" mice with the BAV phenotype, develops accelerated stenosis earlier than tricuspid aortic valves via the Lrp5 pathway activation, eNOS " " mice were given a cholesterol diet versus cholesterol and atorvastatin.
- Echocardiography hemodynamics was also performed to determine the timing of stenosis in bicuspid vs. tricuspid aortic valves eNOS "7' mice on different diets.
- Panel C is the echocardiography from the eNOS null mouse on the different diets.
- Notchl, Wnt3a and downstream markers of the canonical Wnt pathway were measured by protein and RNA expression. Notchl protein was diminished and the RNA expression demonstrates a similar spliced variant with lipid treatments, which was not present with the control and atorvastatin treatment. Cholesterol diets increased the members of the canonical Wnt pathway and Atorvastatin diminished these markers significantly (p ⁇ 0.05).
- FIG. 5 a schematic view showing the cell layers which develop the disease process in the native valve leaflet are depicted. Signaling between the endothelial cell to the myofibroblast cell in the presence of hyperlipidemia activates the secretion of Wnt to turn on the Lrp5 receptor, which in turn activates bone formation in the native myofibroblast cell. Different inhibitors and oral agents listed in Table I inhibit or slow the progression of disease.
- FIG. 5 further depicts the role of PCSK9 as a regulator of plasma lipoprotein cholesterol(LDL-C) and as an agent that is effective in risk reduction in coronary artery disease.
- the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein regulates the activity of low-density lipoprotein (LDL) receptors.
- Inhibition of PCSK9 with a monoclonal antibody results in increased cycling of LDL receptors and increased clearance of LDL cholesterol (LDL-C).
- Highly expressed in the liver, PCSK9 is secreted after the autocatalytic cleavage of the prodomain, which remains non-covalently associated with the catalytic domain.
- the catalytic domain of PCS 9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of low density lipoprotein receptor (LDLR). Both functionalities of PCS 9 are required for targeting the LDLR-PCSK9 complex for lysosomal degradation and lowering LDL-C, which is in agreement with mutations in both domains linked to loss-of- function and gain-of-function 1 .
- EGF-A epidermal growth factor-like repeat A domain of low density lipoprotein receptor
- the present invention provides for therapeutic regimens for prolonged reduction of LDL-C levels in blood by inhibiting PCS 9 activity and the corresponding effects of PCSK9 in combination with a statin agent as outlined in Table I below with a statin agent on LDL-C plasma levels in patients who have aortic valve disease, mitral valve prolapse and or bioprosthetic valves, including transcutaneous aortic valve replacements.
- Table I demonstrates the different oral therapies single and in combination to treat the slow the progression of bicuspid aortic valve(BAV) calcification, Tricuspid aortic valve calcification(TAV), transcutaneous aortic valve replacement(TAVR), Surgical Bioprosthetic aortic valve replacement(SBAVR), mitral valve myxomatous degeneration(MVMD) via the activation of the Wnt pathway via the cleavage of Notchl protein and the phosphorylation of glycogen synthase kinase which in turn releases beta catenin to the nucleus to activate bone and cartilage formation the heart valve and or prosthesis and this invention will include several therapeutic medical therapies to slow the progression of stenosis, obstruction, calcification and or regurgitation of the mitral valve.
- TAV Tricuspid aortic valve calcification
- TAVR transcutaneous aortic valve replacement
- SBAVR Surgical Bioprosthetic aortic valve replacement
- MVMD mitral valve myxomatous
- Anti-hyperlidemic agents including combination with an effective amount of Atorvastatin in the range of 10 mg to 80 mg, Simvastatin in the range of 10 mg to 40 mg, Rosuvastatin 5 mg to 40 mg, Pravastatin 20 mg to 80 mg, Pitavastatin 1 mg to 4 mg and a PCSK9 antibody
- the initial dose can be about 0.25 mg/kg, about 0.5 mg/kg, about 1 mg/kg or about 1.5 mg/kg
- the initial dose and the first subsequent dose and additional subsequent doses can be separated from each other in time by about one week and or in combination with an FTI inhibitor such as Lonafarnib at a 115 mg/m2 dose with a range from 1 15 mg/m to 150 mg/m , in combination with an effective amount of Zetia of 10 mg.
- FTI inhibitors include Chaetomellic acid A, FPT Inhibitor I, FPT Inhibitor II, FPT Inhibitor III, FTase Inhibitor I, FTase Inhibitor II, FTI-276 trifluoroacetate salt, FTI-277 trifluoroacetate salt, GGTI-297, Gingerol, Gliotoxin, L-744,832 Dihydrochloride, Manumycin A, Tipifarnib, a-hydroxy Farnesyl Phosphonic Acid.
- Figure 2 demonstrates the data to define the role of cholesterol in the activation of Lrp5 receptor and valve calcification experiments demonstrate atherosclerosis and calcification is developing in the aortic valves of the LDLR _ " mice. This data characterizes the hearts in these mice to determine if the lipids affected the bone formation in these tissues and if statins can improve the bone biology.
- Figure 2 is a composite of the Masson Trichrome light microscopy (40x) and MicroCT data from the aortic valves from the 5 different treatment groups.
- Figure 2 Panel Al shows that the control aortic valve does not develop any evidence of atherosclerosis.
- Figure 2, Panel A2 demonstrates that the hypercholesterolemic aortic valve develops an atherosclerotic lesion which is calcified. The lesion develops along the aortic surface of the aortic valve.
- Panel A3 is the aortic valve from the cholesterol plus atorvastatin treatment group which shows a marked improvement in the atherosclerotic lesion along the valve leaflet.
- FIG. 2 Panel A4, shows that the Group IV regression treatment aortic valves do not have any evidence of atherosclerosis along the aortic valve surface.
- Panel A5 demonstrates the effects of Lithium Chloride a direct inhibitor of Glycogen Synthase Kinase. Treatment with Lithium Chloride increases the beta catenin levels within the cells and therefore turns on bone formation via translocation of beta catenin to the nucleus and activation of the LEF/TCF transcription factors. This data demonstrates evidence of an atherosclerotic lesion in the lithium chloride aortic valves. Arrow in A5 points to the atherosclerotic lesion.
- the cholesterol (Group II) treated mice develop areas of early mineralization as shown by the two white areas of calcification present in the MicroCT scan shown in Figure 2, Panel B2.
- the atorvastatin (Group III) treated hearts did not develop any calcification as shown in Figure 2, Panel B3.
- Figure 2, Panel B4 shows that the regression treatment (Group IV) aortic valves which also did not develop any evidence of mineralization.
- Figure 2, Panel CI demonstrates the RTPCR data for the different treatment groups.
- the RTPCR shows an increase in cbfal and Lrp5 receptor gene expression with the cholesterol diet (Group II), and atorvastatin treatment decreased the Cbfal and Lrp5 expression in the aortic valves in both the 12 week treatment with Atorvastatin, (Group III), and further decreased the Cbfal and Lrp5 gene expression in the 6 week Atorvastatin Regression treatment, (Group IV). Finally, the lithium chloride treatment demonstrated an increase in the Cbfal without any Lrp5 expression.
- the control diet (Group I) showed no Lrp5 expression and no cbfal expression.
- Figure 2, Panel Dl is the control Lrp5 "A treated mice. There was no evidence of calcification in the Lrp5 " " mice ' .
- Panel E demonstrates the confocal microscopy of beta-catenin expression in three of the diet groups. Panel El, shows little cytoplasmic beta- catenin expression in the control valves. Panel E2, shows the increase in the beta- catenin expression located in the nucleus and Panel E3, demonstrates attenuation of the beta-catenin protein expression.
- Figure 6-9 depicts the pannus formation and calcification process in the explanted valves from human patients at the time of surgical valve replacement of a failed bioprosthetic heart valve.
- Panel (al) Ventricular surface of the control valve, (a2) ventricular surface of the diseased valve with the pannus and calcification process via a stem call attachment to the heart valve.
- Figure 7 is a graph which demonstrates the RNA expression of the ckit positive mesenchymal stem cell attachment to the calcified heart valve, causing the calcification process to occur on the valve as expressed by the well known bone transcription factor cbfal(core binding factor al) and opn(osteopontin) and extracellular matrix protein. The results are expressed as a percent of control with the control being 0 for all of these markers. GAPDH is a house keeping gene used as a control for the experiment.
- Figure 8 demonstrates the increase in the cKit gene expression in the diseased bioprosthetic valve as compared to the control.
- Figure 9 The implanted valve leaflets from the control animals appeared to have a mild amount of cellular infiltration along the surface of the leaflet as demonstrated by Masson Trichrome stain Figure 9, Panel Al .
- the high power magnification demonstrates the demarcation between the leaflet and cellular infiltrate that develops along the leaflet surface.
- Figure 9 depicts results from an experimental animal to test for the dosing of the atorvastatin to reduce the inflammation and also the pannus formation on the valve leaflet.
- the rabbits Prior to the initiation of the diet the rabbits underwent surgical implantation of bovine pericardial bioprosthetic valve tissue (Perimount, Edwards, Irvine CA) using intramuscular ketamine /xylazine (40/5 mg/kg). Following this 12-week period, the rabbits were anesthetized using intramuscular ketamine/xylazine (40/5 mg/kg) and then underwent euthanasia with intracardiac administration of 1 ml of Beuthanasia.
- Table 2 below depicts the results of testing the anti-inflammatory drug atorvastatin at 80 mg per day equivalent to human dosing and shows the percent reduction of stem cell RNA expression on the valves treated with Atorvastatin and the reduction of stem cell mediated pannus formation.
- Table 2 demonstrates the RNA gene expression for the control, cholesterol and cholesterol plus atorvastatin experimental assays.
- Sox9 Sox9
- osteoblast transcription factor Cyclin
- cKit a measure of the expression of the leaflets of the cholesterol-fed animals.
- Table I is the RTPCR data from the experimental model.
- the serum cholesterol levels were significantly higher in the cholesterol fed compared to control assays (1846.0 ⁇ 525.3mg/dL vs. 18.0 ⁇ 7mg/dL, p ⁇ 0.05).
- Atorvastatin treated experimental arm manifested lower cholesterol levels than the cholesterol diet alone (824.0 ⁇ 152.1mg/dl, p ⁇ 0.05).
- statin as anti-inflammatory agent and antiprolifearative and anticalcific agent in combination will mediate the inhibition of calcification and stem cell attachment.
- Atorvastatin reduces the ckit stem cell from adhering to the valve to reduce further destruction of the valve by activating endothelial nitric oxide synthase in the valves in combination with the antiproliferative agents.
- endothelial nitric oxide synthase in the valves in combination with the antiproliferative agents.
- treatment may include using the aforementioned anti- hyperlidemic agents and PCSK9 antibody in combination with antiplatelet therapy such as aspirin and/or a P2Y12 inhibitor including Clopidogrel, Prasugrel, Ticagrelor.
- P2Y12 inhibitor including Clopidogrel, Prasugrel, Ticagrelor.
- the P2Y12 protein is found mainly but not exclusively on the surface of blood platelets, and is an important regulator in blood clotting.
- P2Y12 belongs to the Gi class of a group of G protein-coupled (GPCR) purinergic receptors and is a chemoreceptor for adenosine diphosphate (ADP).
- GPCR G protein-coupled
- Doses that are effective to use in combination with treatment to prevent native and/or bioprosthetic heart valve calcification are Clopidogrel in a loading dose of 300 mg at the time of implantation and a maintenance dose of 75 mg/day thereafter; Prasugrel in a loading dose of 60 mg at the time of implantation and a maintenance dose of 10 mg/day thereafter; and Ticagrelor in a loading dose of 180 mg at the time of implantation and a maintenance dose of 90 mg two times per day thereafter.
- Treatment of patients in accordance with the invention further inhibits the low density lipoprotein receptor in the endothelial cells in one or more cusps; the LRP5 receptor in the myofibroblast cells in one or more cusps and or mesenchymal stem cells and WNT3a secretion in endothelial cells in one or more cusps.
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EP16780828.6A EP3283012A4 (en) | 2015-04-15 | 2016-04-15 | Devices and methods for inhibiting stenosis, obstruction, or calcification of a native heart valve, stented heart valve or bioprosthesis |
AU2016248997A AU2016248997B2 (en) | 2015-04-15 | 2016-04-15 | Devices and methods for inhibiting stenosis, obstruction, or calcification of a native heart valve, stented heart valve or bioprosthesis |
CN201680022277.1A CN107635512A (en) | 2015-04-15 | 2016-04-15 | For the cardiac valves that suppresses native heart valve, supported or the narrow of bioprosthesis, the apparatus and method of obstruction or calcification |
JP2017553407A JP2018516624A (en) | 2015-04-15 | 2016-04-15 | Devices and methods for inhibiting stenosis, occlusion or calcification of natural heart valves, stented heart valves or bioprostheses |
US15/564,341 US20180140747A1 (en) | 2015-04-15 | 2016-04-15 | Devices and methods for inhibiting stenosis, obstruction, or calcification of a native heart valve, stented heart valve or bioprosthesis |
HK18108322.2A HK1248515A1 (en) | 2015-04-15 | 2018-06-28 | Devices and methods for inhibiting stenosis, obstruction, or calcification of a native heart valve, stented heart valve or bioprosthesis |
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US14/687,479 US20150306281A1 (en) | 2014-04-28 | 2015-04-15 | Devices and methods for inhibiting stenosis, obstruction, or calcification of a native heart valve, stented heart valve or bioprosthesis |
US14/687,479 | 2015-04-15 |
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EP2703008A1 (en) * | 2012-08-31 | 2014-03-05 | Sanofi | Human antibodies to PCSK9 for use in methods of treating particular groups of subjects |
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