US20110240043A1 - Use of remote ischemic conditioning to improve outcome after myocardial infarction - Google Patents

Use of remote ischemic conditioning to improve outcome after myocardial infarction Download PDF

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US20110240043A1
US20110240043A1 US13/021,649 US201113021649A US2011240043A1 US 20110240043 A1 US20110240043 A1 US 20110240043A1 US 201113021649 A US201113021649 A US 201113021649A US 2011240043 A1 US2011240043 A1 US 2011240043A1
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regimens
conditioning
myocardial infarction
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Andrew Redington
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Hospital for Sick Children HSC
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Priority to US14/744,665 priority patent/US10136895B2/en
Priority to US16/160,995 priority patent/US20190269410A1/en
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    • A61B17/12009—Implements for ligaturing other than by clamps or clips, e.g. using a loop with a slip knot
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Definitions

  • MI myocardial infarction
  • This remodeling is associated with poor long-term prognosis, with patients with post-MI congestive heart failure reportedly at a 10-fold higher risk of death as shown in a 5 year follow up study.
  • Treatment of myocardial infarction has concentrated on reducing the period of ischemia and minimizing injury that occurs during post-ischemic reperfusion.
  • many therapies have aimed to reduce the size of the heart infarct as much as possible or to prevent its occurrence altogether.
  • Recently, deliberate and transient ischemic pre-conditioning has been proposed in order to reduce the effects of ischemic heart injury such as occurs with MI. It has been postulated that this pre-conditioning may essentially induce tolerance in the heart tissue to a later ischemic event such as MI, by reducing the infarct size and thus resulting in a better prognosis.
  • the invention relates generally to the use of remote ischemic conditioning (RIC) to reduce the occurrence and/or severity and/or delay the onset of heart dysfunction/failure associated with MI.
  • RIC remote ischemic conditioning
  • the invention contemplates the use of RIC on a subject that is experiencing or has experienced an MI.
  • RIC may be performed before and/or during and/or after and MI provided that at least one RIC (including the only RIC) is performed during or after the MI.
  • the invention further contemplates that, in some instances, the subject will undergo more than one RIC regimen.
  • the invention contemplates performing RIC on a subject during, or after, or during and after an MI.
  • the RIC is performed repeatedly, in some embodiments, including at least once during the MI and daily, every other day (i.e., every second day), every third day, or every fourth day thereafter for at least 10 days, at least 20 days, at least 28 days, at least 30 days, or longer.
  • the invention provides a method comprising performing a repeated RIC regimen on a subject during and/or after an MI.
  • the method may be a method for improving the overall outcome of a subject following MI, including but not limited to reducing the risk of heart dysfunction/failure following an MI, reducing the incidence, frequency and/or severity of the symptoms associated with heart dysfunction/failure following an MI, and/or delaying the onset of heart dysfunction/failure or its associated symptoms, including but not limited to exercise limitation, arrhythmia, and sudden unexpected death following MI.
  • These methods comprise, in another aspect, performing a repeated RIC regimen on a subject having an MI, wherein a first RIC regimen is performed during and/or after (including shortly after) the MI and one or more subsequent RIC regimens are performed at least every 7, every 6, every 5, every 4, every 3, or every 2 days, or every day after the first RIC regimen.
  • the invention provides a method comprising performing a repeated RIC regimen on a subject having an MI, wherein a first RIC regimen is performed during the MI and subsequent RIC regimens are performed daily after the first RIC regimen.
  • the invention provides a method comprising performing a repeated RIC regimen on a subject that has experienced an MI.
  • the subject has been given an RIC regimen during the MI or within 36 hours, within 24 hours, within 12 hours, within 6 hours, within 3 hours, within 2 hours, or within 1 hour of the MI, optionally locally or remotely.
  • the invention provides a method comprising performing repeated RIC regimens on a subject after an MI.
  • the repeated RIC regimens are commenced within 1 week or within 1 month of the MI.
  • the subject has not undergone prior ischemic conditioning during the MI.
  • the subject has not undergone ischemic conditioning prior to the MI. In some embodiments, the subject has undergone ischemic conditioning prior to the MI. In some embodiments, the ischemic conditioning prior to the MI was local or remote. In some embodiments, the ischemic conditioning during the MI was local or remote. It is to be understood that as used herein ischemic conditioning is a deliberate regimen performed on a subject and it does not embrace the ischemic and reperfusion phases that “naturally” occur during an MI.
  • the method does not impact (e.g., reduce) the size of the infarct that results from the MI (i.e., the infarct size remains relatively unchanged by the method).
  • the first RIC regimen is performed during ischemia associated with MI.
  • the first remote ischemic conditioning regimen is performed during reperfusion following ischemia associated with MI.
  • the first RIC regimen is performed during the ischemia associated with MI only, or during the ischemia performed during the ischemia associated with MI and then every day thereafter, every two days thereafter, every three days thereafter, every four days thereafter, every five days thereafter, every six days thereafter, or every seven days thereafter.
  • the subsequent RIC regimens are performed every three days, every two days, or every day after the first RIC regimen or after the MI.
  • the subsequent RIC regimens are performed for one or more months after the MI.
  • the repeated RIC regimens comprise more than one (e.g., 2, 3, 4, 5 or more) RIC regimens per day on one or more days.
  • the subject is human. In some embodiments, the subject is not at risk of restenosis, as described in greater detail herein. In some embodiments, the subject does not have a chronic medical condition such as hypertension.
  • the number of cycles per RIC regimen may be two, three, four, five, six or more cycles, with each cycle comprising supra-systolic pressure and reperfusion.
  • at least one RIC regimen of the repeated RIC regimen comprises at least four cycles.
  • at least one RIC regimen of the repeated RIC regimen comprises more than one cycle comprising 5 minutes of supra-systolic pressure and 5 minutes of reperfusion.
  • the supra-systolic pressure is a pressure that is at least an absolute number of mmHg above systolic pressure, or it is a percentage above of systolic pressure.
  • the supra-systolic pressure may be a pressure that is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or more mmHg above systolic pressure.
  • the supra-systolic pressure is a pressure that is at least 15 mmHg above systolic pressure, and may range to 20, 25, 30,35, 40, 45, 50 or more mmHg above systolic pressure.
  • the supra-systolic pressure is a pressure that is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or more than systolic pressure.
  • the supra-systolic pressure may also be referred to as being at a level that is 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110% (or more) of systolic pressure.
  • the supra-systolic pressure is at or about an absolute pressure such as for example at or about 170, 180, 190, 200, 210, 220, 230 or more mmHg.
  • the supra-systolic pressure is a pressure that is at or about 200 mmHg.
  • each of the RIC regimens in the repeated RIC regimen is performed at the same site.
  • the repeated RIC regimen is performed on an upper limb.
  • an individual RIC regimen or a repeated RIC regimen is performed using two or more devices such as two or more cuffs, positioned at different sites on the body (e.g., one cuff per arm, or one cuff per leg, or one cuff on an arm and one cuff on a leg, etc.).
  • the subject is further treated using a defibrillator.
  • the defibrillator may be an automated external defibrillator (AED).
  • AED automated external defibrillator
  • the method further comprises administering to the subject an angiotensin-converting enzyme (ACE) inhibitor.
  • ACE inhibitors suitable to the invention include but are not limited to captopril, enalapril, ramipril, lisinopril, quinapril, fosinopril, benazepril, and moexipril.
  • the method further comprises administering to the subject an angiotensin II receptor blocker.
  • angiotensin II receptor blocker examples include but are not limited to candesartan, irbesartin, losartin, telmisartin, and valsartan.
  • the method further comprises administering to the subject an anti-platelet agent.
  • an anti-platelet agent examples include aspirin and clopidogrel.
  • the method further comprises administering to the subject a statin.
  • the subject may be administered two or more of these aforementioned agents.
  • the invention provides a kit comprising a defibrillator and a device for performing remote ischemic conditioning, such as for example the automated device described herein.
  • the defibrillator may be an automated external defibrillator (AED).
  • FIG. 1 is a schematic figure illustrating the experimental protocol. Rats were randomly assigned to different groups: 1) Sham group, where rats underwent sham operation without any intervention; 2) MI group, rats underwent 45 minutes ischemia followed by reperfusion with no conditioning therapy given; 3) sPost group, a single conditioning event was delivered before the end of ischemia and continued during the initial reperfusion period; 4) dPost group, a single conditioning event was delivered on day 4 (72 hours after reperfusion); 5) rPost group, conditioning was given as in group 3 and then given every three days until day 28 and 6) iPost group, conditioning was given as in group 3 and then given every day until day 28. Vertical arrows indicate the dates (day 4 and day 28, respectively) for euthanization. All the abbreviations are the same as in the text.
  • Panel B Quantitative analysis of the number of infiltrating macrophages (positive ED-1 staining) and neutrophils (positive MPO staining) in infarcted area.
  • Panel B Quantification of myocardial MDA concentrations in each group on day 28.
  • Panel C Quantitative analysis of plasma TNF- ⁇ (Panel A) and IL-1 ⁇ (Panel B) levels in each group rats on day 28 after MI. Data are expressed as mean ⁇ SD, with the same abbreviations as above.
  • FIG. 4 Panel A: Representative western blot bands showing phospho-I ⁇ B ⁇ , I ⁇ B ⁇ and GAPDH (on the left side) and phospho-NF ⁇ B P65, NF ⁇ B P65 and GAPDH (on the right side) from each group rats.
  • Panel B Quantification of ratio of phospho-I ⁇ B ⁇ over I ⁇ B ⁇ protein expression and phospho-NF ⁇ B P65 over NF ⁇ B P65 protein expression were shown in bar graphs (GAPDH as loading control). Data are expressed as mean ⁇ SD, with the same abbreviations as above.
  • FIG. 5 shows representative Western blot bands for phospho-Smad2 and Smad2, ratio of phosphor Smad2 over total Smad2 protein expression was shown in bar graph (Panel A). TGF- ⁇ 1 from each group of rats was also shown in Panel B. GAPDH was for protein loading control. Data are expressed as mean ⁇ SD, with the same abbreviations as above.
  • FIG. 7 Panel A: Representative photomicrographs to show variations of cross section area of cardiomyocytes stained with hematoxylin and eosin (magnification ⁇ 400).
  • Panel B Quantitative morphometric analysis of cardiomyocyte cross sectional area (mm 2 )
  • Panel C, D and E showed the mRNA expression of ⁇ -MHC, ⁇ -MHC and ANP. Data are expressed as mean ⁇ SD, with the same abbreviations as above.
  • FIG. 8 is a schematic representation of one embodiment of a remote ischemic conditioning system, including a pneumatically inflatable cuff configured to contract about the limb of a subject.
  • FIG. 9 is a block diagram of one embodiment of an operating scheme of the RIC system.
  • FIG. 10 shows an alternate embodiment of a cuff configured to contract about the limb of a subject.
  • FIG. 11 A. Schematic for treatment groups.
  • Table 1 presents data obtained from each group of rats to assess cardiac geometry, function, infarct size and hemodynamic changes.
  • the invention is premised, in part, on the finding that heart dysfunction/failure post-MI can be reduced, delayed or prevented altogether by deliberately and, in some instances, repeatedly performing cycles of induced transient ischemia and reperfusion in subjects during and/or after an MI.
  • the invention is also premised in part on the finding that performing induced transient ischemia and reperfusion on subjects during an MI, including during the ischemia associated with an MI has similar benefits.
  • the use of induced transient ischemia and reperfusion according to the invention is also associated with increased survival in subjects post-MI.
  • the invention provides methods for reducing the risk, delaying the onset, and/or reducing the severity of heart dysfunction/failure following MI.
  • the invention aims to ameliorate or prevent heart dysfunction/failure that occurs as a result of MI.
  • the invention does so by subjecting the subject having or who has had an MI to one or more RIC regimens.
  • at least one of these regimens is performed during the MI.
  • per-conditioning regimens are referred to as “per-conditioning” regimens, and they can occur during the ischemic phase of an MI and/or the reperfusion phase that follows.
  • subjects receive an RIC regimen during the MI, including during the ischemic phase of the MI.
  • one or more regimens may be performed following the MI. These are referred to as “post-conditioning” regimens.
  • post-conditioning regimens Some methods of the invention involve performing RIC on a subject while such subject is experiencing an MI, and optionally after the MI. Other methods of the invention involve performing RIC on a subject following an MI, optionally if an RIC regimen has been performed on the subject during the prior MI.
  • RIC may be performed during an MI (e.g., during the ischemic phase of an MI, during the reperfusion phase of an MI, or during the ischemic and reperfusion phases of the MI), and/or immediately after the cessation of an MI (e.g., within hours, and preferably within an hour), and/or following the MI (as discussed below).
  • the subject has not received any pre-conditioning RIC regimens (i.e., an RIC regimen before the MI).
  • the subject has received one or more pre-conditioning RIC regimens.
  • the methods involve performing RIC during the MI and repeatedly after the MI.
  • the methods involve performing RIC repeatedly after an MI even if RIC was not performed during the MI.
  • Such RIC may be referred to herein as post-MI RIC.
  • post-MI RIC is performed days, weeks, or months after an MI.
  • the time in between the MI and the first RIC may be 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks, or 1, 2, 3, 4, 5, 6, or more months, or longer.
  • heart function is improved and/or heart dysfunction/failure is reduced, as described above, even if the infarct itself is not affected by the RIC that occurs post-MI. That is, the infarct size does not appear to be impacted by the post-MI RIC relative to the effect of a single RIC at the time of the MI.
  • survival time is increased.
  • post-conditioning regimens have been found to provide therapeutic benefit particularly since it had been thought heretofore that ischemic conditioning had to be performed prior to an ischemic event (i.e., “pre-conditioning”).
  • pre-conditioning ischemic conditioning had to be performed prior to an ischemic event.
  • the invention evidences that, regardless of whether a subject has undergone any form of ischemic pre-conditioning, it can still benefit from ischemic post-conditioning at least to the extent that such post-conditioning reduces or prevents heart dysfunction/failure associated with MI.
  • therapeutic post-MI benefit can be achieved by performing a single RIC regimen on a subject during an MI.
  • This regimen may occur during the ischemic phase of an MI and/or during the reperfusion phase of an MI.
  • the invention contemplates, in some instances, that once a subject is identified as one having an MI, as known in the art and as described below, then someone attending to that subject, including but not limited to medically trained personnel, will perform an RIC regimen on that subject.
  • This regimen involves performing one and preferably more than one ischemia-reperfusion cycle to a remote location on the subject. Such locations are preferably easily accessible and the regimen is preferably a non-invasive regimen.
  • the regimen is performed on one or more limbs through application of pressure at the skin (for example, through the use of a pressure cuff or a tourniquet).
  • an RIC regimen is performed within 30 days, or within 20 days, 10 days or within one 1 day, or within 12 hours, or within 6 hours, or within 3 hours, or within 2 hours, within 1 hour, within 30 minutes, within 10 minutes, or within 5 minutes of the myocardial infarction, and/or at the time of the myocardial infarction.
  • the Examples further show, again surprisingly, that even more benefit can be obtained when multiple RIC regimens are performed on the subject post-MI. More specifically, more protection against the adverse effects of remodeling and increased survival time were observed when multiple RIC regimens were performed following the MI. It was found that performing RIC once every three days after the MI provided greater protection than a single regimen at the time of the MI Importantly, infarct size was not significantly different between the two groups of animals, indicating that the beneficial effects provided by this early conditioning regimen were independent of effect on the infarct.
  • the invention in some instances provides methods that involve performing RIC on a subject at least once a week, at least once every 6 days, at least once every 5 days, or at least once every 4 days following an MI, preferably where RIC has also been performed during the MI.
  • the remote ischemic conditioning is performed on a subject at least once every 3 days, at least once every 2 days, or at least once every day (i.e., daily) following an MI, preferably where RIC has also been performed during the MI.
  • “at least once” as in for example “at least once every three days” means that in a three day period at least one RIC regimen is performed. As a result, this includes instances in which the RIC is performed every day, every two days, or every three days. Alternatively or additionally it includes instances in which on the first, second, and/or third day of the three day period, one or more RIC regimens are performed. In the simplest case, one RIC is performed every three days. However, it is to be understood that the invention contemplates more frequent performance on any given day. It is also to be understood that this same meaning applies for regimens that are performed at other frequencies, as recited above. Thus, for the sake of clarity, “at least daily” means that every day one or more RIC regimens is performed.
  • a single RIC regimen is performed on a single day. In other embodiments, more than one, including 2, 3, 4, 5 or more, RIC regimens are performed on a single day.
  • the RIC regimen may be performed at the same location or at different locations. These may alternate between two locations or they may cycle through more than two locations. The use of more than one location may be determined a priori or it may be random.
  • a single regimen may be performed using a single location or multiple locations. For example, a single regimen may be performed at a single location on an upper arm of a human subject or it may be performed using two upper arm locations (e.g., separate upper arms) simultaneously or in an alternating manner. When multiple locations are used, two or more devices may be used.
  • regimens are considered to be regular in nature to the extent that the frequency of the regimens is determined a priori and carried out in like manner. It will be clear that the time in between regimens may be uniform (or identical) or it may differ, provided that such timing is known ahead of time.
  • the invention contemplates protocols in which at least two sets of two contiguous regimens are separated by a first time period and at least two other sets of two contiguous regimens are separated by a second time period that is different from the first time period.
  • the invention however contemplates the performance of randomly spaced multiple regimens post-MI, provided however that even in such instances the regimens are performed at least as frequently as once every week.
  • the remote ischemic conditioning regimens may be performed over any time period including without limitation for up to 1 month, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or longer following an MI.
  • the regimens occur over years including up to 2, 3, 4, 5, or more years.
  • the regimens continue over the remaining lifespan of the subject or until it is determined that the subject is no longer at an elevated risk of heart dysfunction/failure.
  • an elevated risk of heart dysfunction/failure is a risk that is higher than the risk of the average population that has not experienced an MI.
  • the Examples show the effects of RIC regimens that are performed up to 30 days post-experimentally simulated MI, the invention contemplates both shorter and longer “treatment” times.
  • the subjects to be “treated” by the invention minimally are experiencing or have experienced an MI. They may or may not have been subjected to ischemic pre-conditioning (i.e., ischemic conditioning prior to the MI). They may or may not have a condition for which ischemic conditioning, including ischemic pre-conditioning, is indicated. They may or may not be at risk of restenosis, for example following a medical procedure or intervention that involves widening or dilation of a blood or other vessel in the body. Examples of such medical procedures or interventions include but are not limited to angioplasty or stent placement. Similarly, the subject may or may not be one who has undergone a medical intervention that induced or is likely to induce vessel damage. The subject may or may not present with or have a history of a chronic medical condition such as but not limited to hypertension.
  • the subjects of the invention will preferably be humans, although non-human subjects are also contemplated.
  • the term “treat” means to have a positive or therapeutic benefit on the likelihood, onset time, and/or severity of heart dysfunction/failure the subject may experience post-MI.
  • Such positive or therapeutically beneficial effects may be measured by comparing the subject to a population that has not been subjected to the methods of the invention. The subject and the population can be compared in terms of incidence of heart dysfunction/failure, time of onset of heart dysfunction/failure, and severity of heart dysfunction/failure. Heart dysfunction/failure indicia are described in greater detail below.
  • the invention contemplates performing RIC regimens on subjects who are having an MI as well as those who have already had an MI particularly if these latter subjects were administered an ischemic conditioning regimen at or near the time of the MI, whether locally or remotely.
  • MI Magnetic ink Characterization
  • Symptoms of MI particularly in men, include sudden chest pain (often times radiating to the left arm or left side of neck), shortness of breath, nausea, vomiting, palpitations, sweating, and anxiety.
  • Symptoms in women differ somewhat from those in men, and typically include shortness of breath, weakness, indigestion, and fatigue.
  • MI may be detected using, for example, electrocardiograms, blood marker tests (e.g., creatine-kinase, troponin T or I), and heart imaging such as chest X-rays.
  • blood marker tests e.g., creatine-kinase, troponin T or I
  • heart imaging such as chest X-rays.
  • WIIO criteria i.e., history of ischemic type chest pain lasting for more than 20 minutes, changes in serial ECG tracings, and rise/fall of serum cardiac markers such as creatine kinase MB and troponin
  • serum cardiac markers such as creatine kinase MB and troponin
  • RIC regimen refers to one or more ischemia-reperfusion cycles performed on a subject at a location on the body other than the heart (i.e., a “remote” location).
  • an RIC regimen or an individual RIC regimen means at least one cycle of an induced transient ischemic event followed by a reperfusion event.
  • An individual RIC regimen therefore may be comprised of 1, 2, 3, 4, 5, or more such cycles.
  • a repeated RIC regimen is two or more individual RIC regimens that occur on a single day and/or one or more RIC regimens that occur on a number of days.
  • the repeated RIC regimen may comprise performing multiple RIC regimens on a single day, or performing single RIC regimens on a number of days, or performing multiple RIC regimens on a number of days. If the repeated RIC regimen occurs on a single day, the time between individual regimens may be at least 10 minutes, at least 20 minutes, at least 40 minutes, at least 1 hour, at least 2 hours, or at least 6 hours, for example.
  • the time between individual regimens may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days or 7 days.
  • the totality of the repeated RIC regimens is referred to herein as an RIC protocol.
  • RIC regimens in a repeated RIC regimen be identical with respect to timing, number of cycles per regimen, supra-systolic pressure, location, and the like.
  • RIC is performed on a limb such as an upper or lower limb, although it is not so limited.
  • the repeated RIC regimen may be performed on a single site or on multiple sites in the body.
  • the repeated RIC regimen may comprise a first RIC regimen performed on the right upper arm, followed by a second RIC regimen performed on the left upper arm.
  • the repeated RIC regimen may comprise alternation between remote sites on the body.
  • an RIC regimen may be performed on a subject at two different sites at overlapping times including simultaneously. In such instances, two devices may be used, as described below.
  • Heart failure is defined as the inability of the heart to pump blood through the body or to prevent blood from backing up into the lungs. Heart failure is often times referred to as congestive heart failure and is associated with systolic or diastolic heart dysfunction. It typically develops over time and may be triggered or exacerbated by another condition that causes heart tissue damage (e.g., an MI) or that causes the heart tissue to work more (or harder) than normal.
  • heart tissue damage e.g., an MI
  • heart failure indicates heart dysfunction and the invention contemplates reducing the risk, delaying the onset, preventing and/or treating heart dysfunction in the presence or absence of heart failure.
  • the discussion of heart failure herein is therefore intended to capture heart dysfunction also, unless stated otherwise.
  • the invention provides, in some instances, methods for reducing the risk of heart dysfunction/failure in subjects who have had or are having an MI.
  • the method is intended to reduce the development and/or severity of heart dysfunction/failure and its associated symptoms which include but are not limited to, exercise intolerance, arrhythmia and sudden death, as a result of the MI.
  • Development and severity of heart dysfunction/failure can be measured by monitoring and measuring symptoms or other characteristics associated with heart dysfunction/failure. These are discussed below.
  • the methods may lead to the prevention of all or some such symptoms, the delayed onset of all or some such symptoms, and/or the reduction in the severity of all or some such symptoms.
  • a reduction in the risk of heart dysfunction/failure may be determined by monitoring the symptoms or other characteristics associated with heart dysfunction/failure in the treated subject and comparing the number, onset, and severity of such symptoms or characteristics in that subject with historical population data for heart dysfunction/failure. For example, it is known that subjects that survive MI are more likely to develop heart dysfunction/failure than the average population.
  • the methods of the invention aim to reduce this likelihood or risk of heart dysfunction/failure development.
  • Symptoms of heart dysfunction/failure include shortness of breath (dyspnea), swelling in the feet and legs (edema) typically as a result of abnormal fluid retention, fluid in the lungs, persistent coughing or wheezing, low exercise tolerance, general fatigue even in the absence of exercise, increased heart rate (or palpitations), loss of appetite, memory loss (or confusion), and nausea.
  • dyspnea shortness of breath
  • edema swelling in the feet and legs
  • Heart dysfunction/failure can be diagnosed based on presentation of one and typically more than one of the foregoing symptoms. Heart dysfunction/failure can also be diagnosed or a suspected diagnosis of heart dysfunction/failure can be confirmed with tests such as an electrocardiogram (ECG or EKG), an echocardiogram (“cardiac echo”), or cardiac catheterization. Echocardiograms, for example, are able to measure the volume or fraction of blood that is ejected from the left ventricle with each beat. This is referred to as the ejection fraction. In normal subjects, about 60% of the blood in the left ventricle is ejected.
  • Subjects may present with mildly depressed ejection fractions (e.g., 40-45%), moderately depressed ejection fractions (e.g., 30-40%), or severely depressed ejection fractions (e.g., 10-25%).
  • the methods aim to maintain the ejection fraction, particularly if the subject presents with normal or mildly depressed ejection fractions.
  • the methods of the invention aim to delay the onset of a depressed ejection fraction, regardless of the initial ejection fraction presentation. Stress tests may also be used to diagnose heart dysfunction/failure, and they may be combined with one or more of the imaging tests discussed above.
  • a stress test may be combined with an echocardiogram in order to monitor and measure heart dysfunction/failure before, during and/or following exercise periods.
  • an echocardiogram in order to monitor and measure heart dysfunction/failure before, during and/or following exercise periods.
  • the subjects intended to be treated according to the methods of the invention will also have a history of or evidence for, one or more MI.
  • the subject may or may not present or have a history of other risk factors or other conditions.
  • the subjects may not have a history and/or may not present with high blood pressure (hypertension).
  • the subjects may not have undergone a medical procedure or intervention that aims to dilate a tube such as an artery or vein in the subject. Examples of such interventions include angioplasty, stent placement, and the like.
  • one or more of the benefits provided by the methods of the invention occur independently of any effect on the myocardial infarct size or volume. That is, as described in the Examples, in some embodiments provided a first cycle of RIC is applied during an MI or shortly thereafter, the infarct size may not be significantly reduced through subsequent chronic RIC. However, surprisingly, even in the absence of any further reduction in the infarct size, it is still possible to reduce the risk, onset and/or severity of heart dysfunction/failure using the methods of the invention. Although not intending to be limited to any particular mechanism of action to explain this finding, chronic RIC may prevent or restrict the degree of left ventricular remodeling that occurs post-myocardial infarction. As discussed in the Examples, repeated post-MI RIC regimens may attenuate inflammatory responses, reduce oxidative stress, and/or modulate hypertrophic and fibrotic signals associated with MI.
  • Some methods of the invention therefore comprise performing an RIC regimen on a subject during and/or after (including shortly after) a myocardial infarction.
  • one RIC regimen is performed on the subject during the myocardial infarction.
  • it may be performed during the ischemic phase (or period), or during the reperfusion phase (or period), or it may overlap both phases to varying degrees.
  • the conditioning is referred to herein as perconditioning.
  • the RIC regimen is performed within 30 minutes, within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 18 hours, or 24 hours of the end of the ischemic period of the myocardial infarction. In still other embodiments, the RIC regimen is performed within 36 hours, 48 hours, or 60 hours of the myocardial infarction.
  • Subsequent RIC regimens may be performed on a daily basis, every other day, or every three days. These RIC regimens may be performed once a day, or more than once a day, including twice a day, 3 times a day, or more.
  • the RIC regimens of the invention may be used in combination with other therapies or procedures aimed at reducing the risk or severity of heart dysfunction/failure.
  • These therapies include without limitation antiplatelet drug therapy including fibrinolytic agents, anti-coagulation agents, and platelet function inhibitors, beta blocker therapy, ACE inhibitor therapy, statin therapy, aldosterone antagonist therapy (e.g., eplerenone), and omega-3-fatty acids therapy.
  • antiplatelet drug therapy including fibrinolytic agents, anti-coagulation agents, and platelet function inhibitors, beta blocker therapy, ACE inhibitor therapy, statin therapy, aldosterone antagonist therapy (e.g., eplerenone), and omega-3-fatty acids therapy.
  • these agents may be administered before, at the time of, or after MI, whether or not overlapping with the RIC regimens and/or protocol.
  • Fibrinolytic agents are agents that lyse a thrombus (e.g., a blood clot), usually through the dissolution of fibrin by enzymatic action.
  • thrombus e.g., a blood clot
  • examples include but are not limited to ancrod, anistreplase, bisobrin lactate, brinolase, Hageman factor (i.e. factor XII) fragments, molsidomine, plasminogen activators such as streptokinase, tissue plasminogen activators (TPA) and urokinase, and plasmin and plasminogen.
  • TPA tissue plasminogen activators
  • Anti-coagulant agents are agents that inhibit the coagulation pathway by impacting negatively upon the production, deposition, cleavage and/or activation of factors essential in the formation of a blood clot.
  • Anti-coagulant agents include but are not limited to vitamin K antagonists such as coumarin and coumarin derivatives (e.g., warfarin sodium); glycosoaminoglycans such as heparins both in unfractionated form and in low molecular weight form; ardeparin sodium, bivalirudin, bromindione, coumarin dalteparin sodium, desirudin, dicumarol, lyapolate sodium, nafamostat mesylate, phenprocoumon, sulfatide, tinzaparin sodium, inhibitors of factor Xa, factor TFPI, factor VIIa, factor IXc, factor Va, factor VIIIa as well as inhibitors of other coagulation factors.
  • vitamin K antagonists such as coumarin and coumarin derivatives (
  • Inhibitors of platelet function are agents that impair the ability of mature platelets to perform their normal physiological roles (i.e., their normal function). Examples include but are not limited to acadesine, anagrelide, anipamil, argatroban, aspirin, clopidogrel, cyclooxygenase inhibitors such as nonsteroidal anti-inflammatory drugs and the synthetic compound FR-122047, danaparoid sodium, dazoxiben hydrochloride, diadenosine 5′,5′′′-P1,P4-tetraphosphate (Ap4A) analogs, difibrotide, dilazep dihydrochloride, 1,2- and 1,3-glyceryl dinitrate, dipyridamole, dopamine and 3-methoxytyramine, efegatran sulfate, enoxaparin sodium, glucagon, glycoprotein IIb/IIIa antagonists such as Ro-43-8857 and L-700,462, ifetroban,
  • Pat. No. 5,440,020, and anti-serotonin drugs Clopridogrel; Sulfinpyrazone; Aspirin; Dipyridamole; Clofibrate; Pyridinol Carbamate; PGE; Glucagon; Antiserotonin drugs; Caffeine; Theophyllin Pentoxifyllin; Ticlopidine.
  • Anti-inflammatory agents include Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; Diflumidone Sodium;
  • Lipid reducing agents include gemfibrozil, cholystyramine, colestipol, nicotinic acid, probucol lovastatin, and statins such as fluvastatin, simvastatin, atorvastatin, pravastatin, and cirivastatin.
  • Direct thrombin inhibitors include hirudin, hirugen, hirulog, agatroban, PPACK, thrombin aptamers.
  • Glycoprotein IIb/IIIa receptor inhibitors are both antibodies and non-antibodies, and include but are not limited to ReoPro (abcixamab), lamifiban, tirofiban.
  • Calcium channel blockers are a chemically diverse class of compounds having important therapeutic value in the control of a variety of diseases including several cardiovascular disorders, such as hypertension, angina, and cardiac arrhythmias (Fleckenstein, Cir. Res. v. 52, (suppl. 1), p. 13-16 (1983); Fleckenstein, Experimental Facts and Therapeutic Prospects, John Wiley, New York (1983); McCall, D., Curr Pract Cardiol, v. 10, p. 1-11 (1985)). Calcium channel blockers are a heterogeneous group of drugs that prevent or slow the entry of calcium into cells by regulating cellular calcium channels. (Remington, The Science and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p. 963 (1995)).
  • the dihydropyridines such as nifedipine
  • the phenyl alkyl amines such as verapamil
  • benzothiazepines such as diltiazem.
  • calcium channel blockers useful according to the invention include, but are not limited to, amrinone, amlodipine, bencyclane, felodipine, fendiline, flunarizine, isradipine, nicardipine, nimodipine, perhexilene, gallopamil, tiapamil and tiapamil analogues (such as 1993RO-11-2933), phenytoin, barbiturates, and the peptides dynorphin, omega-conotoxin, and omega-agatoxin, and the like and/or pharmaceutically acceptable salts thereof.
  • Beta-adrenergic receptor blocking agents are a class of drugs that antagonize the cardiovascular effects of catecholamines in angina pectoris, hypertension, and cardiac arrhythmias.
  • Beta-adrenergic receptor blockers include, but are not limited to, atenolol, acebutolol, alprenolol, befunolol, betaxolol, bunitrolol, carteolol, celiprolol, hedroxalol, indenolol, labetalol, levobunolol, mepindolol, methypranol, metindol, metoprolol, metrizoranolol, oxprenolol, pindolol, propranolol, practolol, practolol, sotalolnadolol, tiprenolol, tomalolol,
  • COX-2 inhibitors include, but are not limited to, COX-2 inhibitors described in U.S. Pat. No. 5,474,995 “Phenyl heterocycles as cox-2 inhibitors”; U.S. Pat. No. 5,521,213 “Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2”; U.S. Pat. No. 5,536,752 “Phenyl heterocycles as COX-2 inhibitors”; U.S. Pat. No. 5,550,142 “Phenyl heterocycles as COX-2 inhibitors”; U.S. Pat. No. 5,552,422 “Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents”; U.S.
  • a number of the above-identified COX-2 inhibitors are prodrugs of selective COX-2 inhibitors, and exert their action by conversion in vivo to the active and selective COX-2 inhibitors.
  • the active and selective COX-2 inhibitors formed from the above-identified COX-2 inhibitor prodrugs are described in detail in WO 95/00501, published Jan. 5, 1995, WO 95/18799, published Jul. 13, 1995 and U.S. Pat. No. 5,474,995, issued Dec. 12, 1995. Given the teachings of U.S. Pat. No.
  • An angiotensin system inhibitor is an agent that interferes with the function, synthesis or catabolism of angiotensin II.
  • agents include, but are not limited to, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists, angiotensin II receptor antagonists, agents that activate the catabolism of angiotensin II, and agents that prevent the synthesis of angiotensin I from which angiotensin II is ultimately derived.
  • ACE angiotensin-converting enzyme
  • the renin-angiotensin system is involved in the regulation of hemodynamics and water and electrolyte balance. Factors that lower blood volume, renal perfusion pressure, or the concentration of Na + in plasma tend to activate the system, while factors that increase these parameters tend to suppress its function.
  • Angiotensin II antagonists are compounds which interfere with the activity of angiotensin II by binding to angiotensin II receptors and interfering with its activity.
  • Angiotensin II antagonists are well known and include peptide compounds and non-peptide compounds.
  • Most angiotensin II antagonists are slightly modified congeners in which agonist activity is attenuated by replacement of phenylalanine in position 8 with some other amino acid; stability can be enhanced by other replacements that slow degeneration in vivo.
  • angiotensin II antagonists include but are not limited to peptidic compounds (e.g., saralasin, [(San 1) (Val 5 )(Ala 8 )] angiotensin-(1-8) octapeptide and related analogs); N-substituted imidazole-2-one (U.S. Pat. No. 5,087,634); imidazole acetate derivatives including 2-N-butyl-4-chloro-1-(2-chlorobenzile)imidazole-5-acetic acid (see Long et al., J. Pharmacol. Exp. Ther.
  • peptidic compounds e.g., saralasin, [(San 1) (Val 5 )(Ala 8 )] angiotensin-(1-8) octapeptide and related analogs
  • N-substituted imidazole-2-one U.S. Pat. No. 5,087,634
  • ES8891 N-morpholinoacetyl-(-1-naphthyl)-L-alanyl-(4, thiazolyl)-L-alanyl(35,45)-4-amino-3-hydroxy-5-cyclo-hexapentanoyl-N-hexylamide, Sankyo Company, Ltd., Tokyo, Japan
  • SKF108566 E-alpha-2-[2-butyl-1-(carboxy phenyl)methyl]1H-imidazole-5-yl[methylane]-2-thiophenepropanoic acid, Smith Kline Beecham Pharmaceuticals, PA); Losartan (DUP753/MK954, DuPont Merck Pharmaceutical Company); Remikirin (RO42-5892, F. Hoffman LaRoche AG); A 2 agonists (Marion Merrill Dow) and certain non-peptide heterocycles (G.D.Searle and Company).
  • ACE inhibitors include amino acids and derivatives thereof, peptides, including di- and tri-peptides and antibodies to ACE which intervene in the renin-angiotensin system by inhibiting the activity of ACE thereby reducing or eliminating the formation of pressor substance angiotensin II.
  • ACE inhibitors have been used medically to treat hypertension, congestive heart dysfunction/failure, myocardial infarction and renal disease.
  • Classes of compounds known to be useful as ACE inhibitors include acylmercapto and mercaptoalkanoyl prolines such as captopril (U.S. Pat. No. 4,105,776) and zofenopril (U.S. Pat. No.
  • carboxyalkyl dipeptides such as enalapril (U.S. Pat. No. 4,374,829), lisinopril (U.S. Pat. No. 4,374,829), quinapril (U.S. Pat. No. 4,344,949), ramipril (U.S. Pat. No. 4,587,258), and perindopril (U.S. Pat. No. 4,508,729), carboxyalkyl dipeptide mimics such as cilazapril (U.S. Pat. No. 4,512,924) and benazapril (U.S. Pat. No. 4,410,520), phosphinylalkanoyl prolines such as fosinopril (U.S. Pat. No. 4,337,201) and trandolopril.
  • carboxyalkyl dipeptides such as enalapril (U.S. Pat. No. 4,374,829), lisinopri
  • Renin inhibitors are compounds which interfere with the activity of renin. Renin inhibitors include amino acids and derivatives thereof, peptides and derivatives thereof, and antibodies to renin. Examples of renin inhibitors that are the subject of United States patents are as follows: urea derivatives of peptides (U.S. Pat. No. 5,116,835); amino acids connected by nonpeptide bonds (U.S. Pat. No. 5,114,937); di- and tri-peptide derivatives (U.S. Pat. No. 5,106,835); amino acids and derivatives thereof (U.S. Pat. Nos. 5,104,869 and 5,095,119); diol sulfonamides and sulfinyls (U.S. Pat. No.
  • HMG-CoA reductase inhibitors include, but are not limited to, statins such as simvastatin (U.S. Pat. No. 4,444,784), lovastatin (U.S. Pat. No. 4,231,938), pravastatin sodium (U.S. Pat. No. 4,346,227), fluvastatin (U.S. Pat. No. 4,739,073), atorvastatin (U.S. Pat. No. 5,273,995), cerivastatin, and numerous others described in U.S. Pat. No. 5,622,985, U.S. Pat. No. 5,135,935, U.S. Pat. No. 5,356,896, U.S. Pat. No.
  • statins such as simvastatin (U.S. Pat. No. 4,444,784), lovastatin (U.S. Pat. No. 4,231,938), pravastatin sodium (U.S. Pat. No. 4,346,227), fluva
  • the invention contemplates the use of one or more of any of the foregoing agents in combination with the repeated RIC regimens of the invention.
  • an RIC regimen is at least one cycle of an induced transient ischemic event followed by a reperfusion event. Typically, these regimens are performed by restricting blood flow in a limb or a peripheral tissue of the subject and then removing the blood flow restriction and allowing blood to reperfuse the limb or tissue.
  • An RIC regimen is typically non-invasive.
  • a regimen may comprise a single cycle or multiple cycles, including 2, 3, 4, 5, or more cycles. In one important embodiment, a regimen comprises 4 cycles of ischemia and reperfusion.
  • the blood flow restriction typically takes the form of an applied pressure to the limb or tissue that is above systolic pressure (i.e., supra-systolic pressure). It may be about 5, about 10, about 15, about 20, or more mmHg above (or greater than) systolic pressure. Since systolic pressure will differ between subjects, the absolute pressure needed to induce ischemia will vary between subjects. In other embodiments the pressure may be preset at, for example, 200 mmHg
  • the blood flow restriction may be accomplished using any method as the invention is not limited in this regard. Typically, it may be accomplished with an inflatable cuff, although a tourniquet system is also suitable. Further examples of automated devices for performing RIC are described below.
  • the induced ischemic event is transient. That is, it may have a duration of about 1, about 2, about 3, about 4, about 5, or more minutes.
  • the reperfusion event may have a duration of about 1, about 2, about 3, about 4, about 5, or more minutes.
  • the Examples demonstrate the effect of 4 cycles of 5 minutes of ischemia followed by 5 minutes of reperfusion on physical performance.
  • the upper limb or lower limb may be used although in some instances the upper limb is preferred.
  • RIC is performed on two different sites on the body, in an overlapping or simultaneous manner.
  • RIC may be performed using any device provided it is capable of inducing transient ischemia and reperfusion, whether manually or automatically.
  • the method may be carried out using a sphygmomanometer (i.e., the instrument typically used to measure a subject's blood pressure).
  • a sphygmomanometer i.e., the instrument typically used to measure a subject's blood pressure.
  • the cuff of the sphygmomanometer is placed about a subject's limb (e.g., an arm or leg) and is inflated to a pressure great enough to occlude blood flow through the limb (i.e., a pressure greater than the subject's systolic blood pressure).
  • the cuff is maintained in the inflated state to prevent blood flow through the limb for a specified period of time, referred to herein as the ischemic duration.
  • the ischemic duration pressure is released from the cuff to allow reperfusion of blood through the limb for a period of time that is referred herein as the reperfusion duration.
  • the cuff is then re-inflated and the procedure is immediately repeated a number of times.
  • the method may similarly be carried out using a manual type tourniquet.
  • Devices such as those described in published PCT application WO 83/00995 and in published US application 20060058717 may also be used.
  • FIG. 8 illustrates a cuff 10 , an actuator 12 , a controller 14 and a user interface 16 .
  • the cuff is configured to be placed about the limb 15 of a subject, such as an arm or leg of the subject.
  • the actuator when actuated, causes the cuff to retract about the limb to occlude blood flow through the limb.
  • the controller executes a protocol that comprises repeating a cycle one or more times.
  • the cycle itself includes actuating the cuff to prevent blood flow, maintaining the cuff in an actuated state for an ischemic duration, releasing the cuff, and maintaining the cuff in a relaxed state to allow reperfusion.
  • FIG. 9 shows a block diagram that represents a scheme that may be used to perform RIC.
  • the scheme begins with placement of a cuff about a subject's limb.
  • the system is then activated and the protocol is initiated through the controller.
  • the system is activated by a medical professional.
  • the system may be activated by the subject.
  • the cuff contracts to apply an initial pressure, greater than systolic pressure, to the subject's limb.
  • the initial pressure may be a default value of the system or may be programmed into a particular protocol.
  • the cuff then deflates to identify the subject's systolic pressure. This may be accompanied by monitoring the subject for the onset of Korotkoff sounds or vibrations.
  • a distal remote sensor e.g., a device on the fingertip which is sensitive to the presence or absence of flow or maintenance of flow
  • systolic pressure may be identified as an initial portion of the protocol.
  • protocol and regimen are used interchangeably.
  • the cycle begins as the cuff contracts to apply a target pressure, greater than the subject's systolic pressure by an amount defined in the protocol, to the subject's limb. This occludes blood flow through the subject's limb.
  • the external pressure against the subject's limb is held for an ischemic duration defined in the protocol.
  • the system monitors the subject during the ischemic duration for pressure release criteria, which may include system power failure, system power spikes, and manual activation of quick release mechanism.
  • the system also monitors the subject during the ischemic duration for any signs of reperfusion through the subject's limb, and accordingly, increases the external pressure applied by the cuff to prevent such reperfusion. Signs of reperfusion can include the onset of Korotkoff sounds or vibrations.
  • the cuff releases pressure from about the subject's limb to allow reperfusion. Reperfusion is allowed for a reperfusion duration defined in the cycle.
  • the initial cycle typically concludes after the reperfusion duration.
  • a subsequent cycle may begin as the cuff is actuated to contract about the subject's limb to occlude blood flow through the limb for another ischemic duration.
  • the cuff illustrated in FIG. 8 is configured to be positioned about the limb of a subject and to contract about the limb when actuated.
  • the sleeve is wrapped about a subject's upper arm, calf, or thigh and is fastened snuggly in place.
  • Portions of the cuff may include hook and loop type material that can be used to fasten the sleeve in place about the subject's limb.
  • the actuator inflates the cuff such that the limb is constricted to the point of occluding blood flow through the subject's limb.
  • the illustrated cuff includes an inflatable bladder (not shown) that receives a fluid, such as air, to cause the cuff expand and retract about a subject's limb.
  • the bladder is constructed of an air impermeable material, such as flexible plastic or rubber.
  • a connection port 18 is present at one end of the bladder to allow air to enter the bladder during inflation, or to exit the bladder during deflation.
  • the port may include engagement features to facilitate a connection to the actuator, such as by an air hose. These features may include threads, clips, and the like.
  • the fabric sleeve may itself be air impermeable, such that no separate bladder is required.
  • multiple, separate inflatable bladders may be incorporated into a common sleeve, as aspects of the present invention are not limited in this respect.
  • the general size of subjects that undergo RIC may vary greatly, particularly given the range of species to which the methods may be applied. Given this variance, it may be desirable for some embodiments of cuffs to be adjustable over a wide range to accommodate the variety of subject limb girths that may be expected.
  • the cuff comprises an inflatable fabric sleeve having a length greater than three feet, such that a girth of up to three feet may be accommodated.
  • Embodiments of cuffs may include a width as small as two inches, one inch, or even smaller, so as to accommodate the upper arm or leg of a much smaller subject, including a neonatal infant. It is to be appreciated, however, that other embodiments may be configured to encircle a much smaller range of limb sizes, as aspects of the present invention are not limited in this regard.
  • the actuator includes a pneumatic pump to provide pressurized air to an inflatable cuff through an air hose.
  • the actuator also includes a release valve 20 that, when actuated, opens a passageway between the inflatable cuff and the external environment to allow pressurized air to escape from the cuff, so that the cuff loosens about the subject's limb.
  • the air pump can comprise any device capable of delivering compressed air.
  • the air pump includes a piston compressor, although other types of pumps, like centrifugal pumps and scroll compressor may also be used.
  • the pump may be configured to provide air flow at a rate of between 0.1 to 20 cubic feet per minute, with a head pressure of up to 50 psi, according to some embodiments.
  • other flow rates and/or pressures are possible, as aspects of the invention are not limited in this respect.
  • the actuator may also include a release mechanism to release a cuff from about the subject's limb.
  • the release comprises a release valve 20 that is positioned within the controller housing.
  • the release valve may be a solenoid that moves rapidly between fully closed and fully open positions to rapidly release air from the cuff and, in turn, to rapidly release the cuff from a subject.
  • the same release valve or another release valve may also be actuated to open slowly, such as to adjust the pressure of the cuff or to allow a more controlled release of pressure such as may be required when the subject's blood pressure is measured.
  • Embodiments of the system may include safety features to allow rapid release of the cuff from a subject's limb. Moreover, some of these embodiments may be readily activated by a subject, such as when the subject feels discomfort.
  • the safety release 22 includes a large button positioned on or near the cuff. In this regard, the safety release is within reach of the subject.
  • the safety release may comprise a separate actuator, such as one that may be held in the free hand of the subject. Activating the safety release may cause the release valve of a pneumatic cuff to open, thereby allowing rapid removal of air from the cuff.
  • the system may also include a continually operating, cuff release mechanism.
  • a slow release valve may be incorporated into a pneumatic cuff to provide for a continual, slow release of pressurized air from the cuff.
  • the continual slow release mechanism may provide for the safe release of a subject's limb, even in the face of power failures or other events that may prevent redundant safety features from operating properly.
  • Similar type mechanism may be incorporated into embodiments that do not utilize a pneumatically inflatable cuff, as continual slow release mechanisms are not limited to pneumatic cuffs.
  • the system may also comprise a pressure check valve as a safety feature. Such a valve may operate by releasing pressure above a maximum set point.
  • the maximum set point will be at or above the supra-systolic pressures used during remote ischemic conditioning, and may be but is not limited to 200 mmHg, 210 mmHg, 220 mmHg, 230 mmHg, 240 mmHg, or 250 mmHg
  • the system may also comprise software and/or hardware components that monitor pressure (e.g., the cuff pressure and/or the subject blood pressure) and preferably read out such pressure measurements whether in real-time or after the remote ischemic conditioning is complete. In this way, deviations in pressure can be identified.
  • Embodiments of the system include a controller that receives information from a protocol and any other sensors in the system to, in turn, control the actuator to perform RIC.
  • the controller and protocol combination may be implemented in any of numerous ways.
  • the controller and protocol combination may be implemented using hardware, software or a combination thereof.
  • the software code can be executed on any suitable processor or collection of processors, whether provided in a single computer or distributed among multiple computers. It should be appreciated that any component or collection of components that perform the functions described herein can be generically considered as one or more controllers that control the functions discussed herein.
  • the one or more controllers can be implemented in numerous ways, such as with dedicated hardware, or with general purpose hardware (e.g., one or more processors) that is programmed using microcode or software to perform the functions recited above.
  • the one or more controllers may be included in one or more host computers, one or more storage systems, or any other type of computer that may include one or more storage devices coupled to the one or more controllers.
  • the controller includes a communication link to communicate wirelessly, or via electrical or optical cable, to a remote location.
  • one implementation of the embodiments of the present invention comprises at least one computer-readable medium (e.g., a computer memory, a floppy disk, a compact disk, a tape, etc.) encoded with a protocol in the form of a computer program (i.e., a plurality of instructions), which, when executed by the controller, performs the herein-discussed functions of the embodiments of the present invention.
  • the computer-readable medium can be transportable such that the protocol stored thereon can be loaded onto any computer system resource to implement the aspects of the present invention discussed herein.
  • protocol is not limited to an application program running on a host computer. Rather, the term protocol is used herein in a generic sense to reference any type of computer code (e.g., software or microcode) that can be employed to program a processor to implement the herein-discussed aspects of the present invention.
  • the system may also comprise one or more sensors 26 that receive information from the subject and/or portions of the system itself. Such sensors may receive information regarding blood flow in any portion of the subject, including the limb that is being treated. These sensors may also receive information regarding other operating parameters of the system, such as air pressure within a pneumatic cuff, direct readings of pressure applied by cuff, or tension within portions of a tension band.
  • Pneumatic cuffs may include a sensor to measure pressure within the cuff.
  • Cuff pressure is often directly indicative of the pressure that exists within a blood vessel of the limb beneath the cuff.
  • the controller of a system is often programmed to target a particular cuff pressure that is to be maintained during the ischemic duration of a cycle, as is discussed herein.
  • the pressure sensor may be positioned anywhere within the pressurized space of the cuff, the air hose, or even within the actuator itself. Pressure sensors may also be positioned on an inner surface of the cuff to directly measure the pressure between the cuff and an outer surface of the subject's limb.
  • the cuff may be oriented such that the pressure sensor is positioned directly above the subject's artery, so as to provide a more direct measurement of pressure at a blood vessel of interest.
  • systems may also include one or more vibration and/or ultrasonic sensors 28 to identify Korotkoff sounds.
  • Korotkoff sounds are generally understood to be present when pressures between systolic and diastolic are externally applied to the artery of a subject.
  • Systolic pressure is associated with a pressure value that completely occludes blood flow through a subject's blood vessels, and in this regard, may be used by the system as feedback to identify when pressure in the system is low enough to allow blood flow, or high enough to occlude blood flow.
  • a pulse oximeter 30 may be positioned on a distal portion of the limb that receives the cuff, such as on a finger or toe of the limb.
  • the pulse oximeter can provide information regarding blood pulsing through the subject's blood vessels and the percentage of haemoglobin that is saturated with oxygen.
  • the pulse oximeter will detect an absence of pulses when blood flow though a limb is not occurring to confirm the occlusion of blood flow.
  • the pulse oximeter may also detect the percentage of haemoglobin saturated with oxygen, which will drop as blood flow through the limb ceases.
  • sensors may also be used to confirm the cessation of blood flow, such as a photoplethysmographic transducer, an ultrasonic flow transducer, a temperature transducer, an infrared detector, and a near infrared transducer, as aspects of the invention are not limited in this respect.
  • the system includes a protocol that, through the controller, directs the operation of the system.
  • Embodiments of the protocol include a cycle that comprises cuff actuation, an ischemic duration, cuff release, and a reperfusion duration.
  • the cycle may be repeated multiple times.
  • some embodiments of the protocol include systolic pressure identification.
  • the cuff actuation portion of the cycle comprises contracting the cuff about the limb of a subject to occlude blood flow through the limb. Contraction of the cuff is accomplished by the controller reading instructions from the protocol, such as a target set point for cuff pressure, and then by the initiating the controller to bring the cuff to the target set point. Attainment of the target set point may be sensed through any of the herein described sensors and techniques.
  • ischemic duration The length of the ischemic phase, termed the ischemic duration, is typically defined by a doctor, or other medical professional, and is programmed into the protocol. Ischemic duration may be as short as a few seconds, or as long as 20 minutes, or even longer, as aspects of the invention are not limited in this regard. In some embodiments, the ischemic duration varies from cycle to cycle during the same protocol, although in other embodiments, the ischemic duration remains constant.
  • the controller acts to maintain pressure, applied by the cuff, at a set point above the subject's systolic pressure.
  • Embodiments of the cuff may relax relative to the subject's limb over time, thereby reducing pressure and eventually allowing reperfusion. This may be caused by various factors, including relaxation of muscles in the subject's limb, stretching of the cuff about the limb, air leaks (intentional or unintentional), and the like.
  • a sensor may provide pressure readings as feedback to the controller. The controller can measure any difference between the set point and the actual pressure reading and can provide any necessary commands to the actuator to compensate for errors.
  • the set point is manually entered into the protocol by the doctor (or other medical professional). Alternately, the doctor may select a set point in terms of the subject's systolic blood pressure. In one embodiment, the set point may be selected as a fixed pressure amount over the subject's systolic blood pressure, such as 5 mmHg, 10 mmHg, 15 mmHg, 20 mmHg, 25 mmHg, 30 mmHg, 35 mmHg, or any other fixed amount above systolic pressure of the subject.
  • the set point may be defined as a percentage of the subject's systolic blood pressure, such as 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115% or systolic pressure and other percentages, as aspects of the invention are not limited in this respect.
  • the point above systolic pressure may be set by the medical professional and may be dependent upon several factors including, but not limited to the size of the subject, the size of the subject's limb, the subject's blood pressure, confirmation of blood flow cessation, and the like.
  • the protocol includes phases to identify the subject's systolic blood pressure.
  • the cuff may be allowed to loosen about the subject's limb, from a point believed to be above systolic pressure, in a systematic manner while sensors are monitoring the limb for the onset of Korotkoff sounds or vibrations. Once the systolic pressure is identified, the protocol may continue in the normal course.
  • Identification of systolic pressure may optionally occur at any time during a protocol, or not at all. According to some embodiments, each cycle begins with the identification of the subject's systolic blood pressure. In other embodiments, systolic pressure may be identified only once during an initial portion of the protocol. In still other embodiments, systolic pressure may be identified as the cuff is released during the cuff release portion of each cycle. Still, as discuss herein, systolic pressure may not be identified at all during a protocol, as aspects of the invention are not limited in this regard.
  • the system can be configured to adjust the pressure set point during the ischemic duration.
  • the system may include sensors that detect the onset of reperfusion. As an example, this may be accomplished by detecting the presence of Korotkoff sounds or vibrations.
  • the presence of Korotkoff sounds during an ischemic duration can indicate that either cuff pressure has fallen below systolic or that systolic pressure has risen above the set point that was previously above systolic pressure.
  • Other devices may additionally or alternatively be used including for example devices on digits that detect the presence or absence of flow.
  • the controller may adjust the set point based on the newly identified systolic pressure and/or other information and in this regard, can identify and prevent unwanted reperfusion that might otherwise occur.
  • the cuff release portion of a cycle occurs at the end of the ischemic duration and includes release of the cuff to a point below diastolic pressure.
  • cuff release comprises releasing the pressure or tension of the cuff. In embodiments that utilize a pneumatic cuff, this may simply be associated with moving an air release valve to the fully open position to allow a rapid reduction in cuff pressure and a corresponding rapid relaxation of the cuff about the subject's limb. However, it is to be appreciated, that in other embodiments, that cuff relaxation may occur in a slower, more controlled manner, as aspects of the invention are not limited in this respect. Additionally, as discussed herein, the cuff release may be accompanied by monitoring for the onset of Korotkoff sounds or vibrations to identify or confirm the systolic pressure of the subject.
  • reperfusion duration follows the cuff release in embodiments of the cycle.
  • Reperfusion through the limb is allowed for a period of time termed the reperfusion duration.
  • reperfusion duration Much like the ischemic duration, reperfusion may be allowed for varied lengths of time, as short as a five seconds, one minute or more, and as long as 20 minutes, or even longer.
  • the reperfusion duration may remain constant from cycle to cycle during a common protocol, or may vary between each cycle, as aspects of the invention are not limited in this respect.
  • the protocol may comprise any number of cycles. As discussed herein, a common cycle may simply be repeated a plurality of times, such as two, three, four, or more times, to complete a protocol. Alternately, the cycles of a protocol may be programmed with different parameters, such as different ischemic durations, reperfusion durations, pressure set points during the ischemic duration, and the like.
  • the system may include a data logging feature that records the system parameters, such as cuff pressure or tension, during all phases of a protocol. Date of time of operation may also be recorded. Other features, such as personal information to identify the subject, may also be recorded by the system.
  • Embodiments of the system may incorporate various features to inform the subject or medical professional about the progress of the protocol.
  • Audible or visual indicators may accompany any of the phases of the protocol.
  • a clock may show either the amount of time that has elapsed or that remains for a given portion of the protocol or the entire protocol.
  • Embodiments may also include other features to keep the subject and/or medical professional informed, as aspects of the invention are not limited in this regard.
  • the system includes features to prevent tampering or accidental reprogramming by a subject.
  • the reprogrammable features may only be accessed after entering a code. This can prevent a subject from mistakenly reprogramming the protocol or otherwise interfering with the operation of the system. It is to be appreciated that other devices may also be used to prevent accidental reprogramming, such as electronic keys, mechanical locks and the like.
  • the system may be configured for use is a variety of environments.
  • the system may be mounted on a portable stand with casters to facilitate easy movement.
  • the stand may position the controller, user interface, and connections to the cuff at a convenient height for the subject.
  • the system is configured for portable use.
  • the system may be configured for ready placement into a suitcase for easy transport.
  • cuffs may be configured to constrict a subject's limb through alternative mechanisms.
  • the cuff is configured as a band having a ratcheting mechanism positioned at one end.
  • the band is wrapped about the limb of a subject with the free end of the band passing through the ratcheting mechanism.
  • the actuator may comprise a mechanism that pulls the free end of the band further through the ratcheting mechanism to retract the cuff about the limb, or that frees the ratcheting mechanism to release the band to, in turn, release the band from the limb.
  • Still other mechanisms, such as tourniquet mechanisms are possible, as aspects of the invention are not limited in this respect.
  • some embodiments may have a cuff that comprises a band that does not inflate, but rather is tightened about a subject's limb by another mechanism.
  • the actuator may comprise a tensioning mechanism configured to move one end of the band relative to other portions of the band so as to place the band in tension.
  • the mechanism can include opposed rollers held in close proximity to one another within a housing.
  • the housing includes a slot for receiving a free end of the band and a fixation point for fixed attachment to the opposite end of the band.
  • the free end of the band is passed into the slot and between the rollers.
  • the rollers may be mechanically actuated to rotate relative to one another, such as by an electric motor, to pull the free end through the housing and thus tighten the band around a subject's limb.
  • the tensioning mechanism may include opposed rollers mounted on a ratcheting, free wheel mechanism.
  • the freewheel mechanism allows the band to be pulled through the slot in one direction with minimal resistance so that the band may be pulled rapidly to a snug position about a subject's limb.
  • the free wheel mechanism also prevents the band from moving through the slot in the loosening direction, unless the mechanism is released or the opposed rollers are actuated. It is to be appreciated that not all embodiments will include a free wheel mechanism, as aspects of the invention are not limited in this regard.
  • the opposed rollers rotate in either direction to tighten and loosen the band during use.
  • the rollers may rapidly rotate until the band achieves a particular tension.
  • the rollers may further be actuated to make minor adjustments to the tension in the band during use.
  • a ratcheting mechanism or clutch may be released such that the opposed rollers are allowed to move freely, thus rapidly releasing tension.
  • the system and/or device may comprise disposable components to prevent contamination between subjects and to avoid the need to sterilize the system or device between subjects.
  • the entire system or device may be disposable or one or more of its components may be disposable.
  • Disposable component include but are not limited to the cuff(s) of the system and/or sleeves or liners for the cuff(s).
  • the animals Prior to LAD occlusion, the animals were anticoagulated (150 U/Kg sodium heparin) and received an intravenous injection of lidocaine (4 mg/Kg). Cardiac ischemia was confirmed by a pale area below the suture or ST-T elevation shown in ECG, while reperfusion was characterized by rapid disappearance of cyanosis and vascular blush. At the end of the protocol, the snare was removed, the chest closed, and the animals allowed to recover, and they were given tamgesic (0.03 mg/kg) immediately before they gained consciousness.
  • MI group MI control
  • sPost Single remote ischemic post-conditioning (sPost) group (also referred to herein as rIPerC), during the ischemia reperfusion injury surgical procedure, while the animals were anesthetized remote ischemic post-conditioning was delivered starting 20 minutes before the end of index ischemic period by occluding hind limb blood flow with a torniquet tightened around the upper thigh for 4 cycles of 5 minutes occlusion followed by 5 minutes release. The limb ischemia was confirmed by pallor and cyanosis of the lower limb below the torniquet;
  • Delayed post-conditioning (dPost) group the delayed remote post-conditioning was delivered on day 4 (72 hours after reperfusion). Rats were anesthetized again with smaller dosage of sodium pentobarbital (30 mg/Kg). The remote post-conditioning was delivered the same way as described above. Tamgesic (0.03 mg/kg) was also given before they regained consciousness;
  • rPost Repetitive remote post-conditioning (rPost) group (also referred to herein as rPostC), after the initial remote post-conditioning (identical to group 2), post-conditioning was repeated every three days for 28 days, and therapy was delivered the same way as described in dPost group rats;
  • iPost Intensive remote post-conditioning group (also referred to herein as iPostC), after the initial remote post-conditioning (identical to group 2), the same remote post-conditioning therapy as described above was repeated every day for 28 days;
  • LV weight was recorded for hearts obtained from day 28 and the ratio of LV weight to body weight (LVMI) was calculated.
  • LV myocardial tissue was collected and fixed in 4% formalin followed by paraffin embedding for the histology examination. The remaining LV tissue was snap frozen in liquid nitrogen and stored at ⁇ 80° C. for later analysis.
  • Transthoracic echocardiography was performed only on day 28 after MI. using ultrasonic system equipped with a 15-MHz probe (Acuson Sequoia 512). Both two-dimensional and M-mode echocardiography was obtained after the induction of anesthesia.
  • LVEDD LV end diastolic diameter
  • LVESD LV end systolic diameter
  • FS fractional shortening
  • the right carotid artery was cannulated with a pre-heparinized fine polyetheylene tube connected to a fluid-filled pressure transducer (MPA-CFS, Alcott Biotech, Shanghai, China) and the tube was then advanced into the left ventricle.
  • Heart rate (HR), left ventricular peak systolic and end-diastolic pressure (LVEDP) and the maximal rates of rise and fall in LV pressure (dP/dt max and dP/dt min , respectively) were recorded.
  • IP percentage Infarct perimeter
  • Collagen deposition in the border area was quantified by Masson-staining and analyzed by using Image J software and expressed as the average percentage collagen staining of 10 randomized high power field.
  • CSA myocyte cross-sectional area
  • PCR quantification was performed starting with 12.5 ng cDNA and both sense and antisense primer at 900 nM concentration (Invitrogen) in final volume of 25 ⁇ l, using SYBR Green master mix (Applied Biosystem). Fluorescence was monitored and analyzed in a GeneAmp 7000 detection system instrument (Applied Biosystems). The PCR reactions were cycled 42 times by a three-step cycle procedure (denaturation 95° C., 15 s; annealing 60° C., 30 s; extension 72° C., 30 s) following the initial stage (95° C., 10 min). A ⁇ Ct value was obtained to quantify the mRNA levels and normalized with an endogenous control (b-tubulin mRNA) for each sample. A relative quantification ⁇ Ct method was used for comparison between groups. Oligonucleotide primers were designed using Primer Express software (Applied Biosystems).
  • the primers used were listed as follows:
  • MDA Malondialdehyde
  • Plasma levels of interleukin TNF- ⁇ and IL-1 ⁇ were evaluated by use of commercially available solid-phase sandwich ELISA kits (R&D Systems, Minneapolis, USA) according to the manufacturer's introduction. The detection limits of each assay were as follows: TNF- ⁇ ,16 pg/ml and IL-1 ⁇ , 10 pg/ml.
  • Late Phase Protection by Post-Conditioning There were fewer survivors on day 28 in the MI group and dPost group compared with sham group (P ⁇ 0.05, respectively), whereas sPost and repeated post-conditioning (rPost and iPost) treated groups rats showed no significant difference in comparison with sham group rats (See Table, P>0.05, respectively).
  • sPost was associated with less I ⁇ B ⁇ and NF- ⁇ B p65 phosphorylation.
  • rPost and iPost were associated with a further decrease in the degree of I ⁇ B ⁇ and NF- ⁇ B p65 phosphorylation (p ⁇ 0.001, respectively), with iPost group rats showing the lowest activation of NF- ⁇ B signaling (p ⁇ 0.01, respectively, FIG. 4 ).
  • FIGS. 7 A,B the average cross-sectional area (CSA) of cardiac myocytes decreased in dose-dependent fashion. Quantification of hypertrophy-related genes expression showed that increased gene expression of ANP and ⁇ -MHC was attenuated while the decrease in expression of ⁇ -MHC was recovered by rIPost, again in a dosage dependent fashion ( FIGS. 7C-E ). However, the effects were absent when the maneuver was delayed to 72 hours after reperfusion ( FIGS. 7A-E ).
  • MI rats demonstrated significant LV dilation, as evidenced by increases in LVEDD compared with sham rats (p ⁇ 0.05, table). This geometric change was accompanied by decrease in FS compared with sham rats (p ⁇ 0.05, table). While sPost significantly improved adverse LV remodeling, reflected by a decrease in LVEDD and an increase in FS compared with MI rats (p ⁇ 0.05, respectively. Table), rIPost therapy resulted in a further improvement in LV chamber size and function, with the greatest effects achieved by iPost in comparison with rPost (p ⁇ 0.05, respectively). Hemodynamic analysis demonstrated the same pattern of benefits from rIPost, in a dose-dependent manner compared with MI and dPost (Table).
  • ROS reactive oxygen species
  • ROS generation is of paramount importance in the protection afforded by these strategies.
  • continued ROS generation and inflammation is also pivotal in the process of post MI remodeling [29,30] .
  • Remote pre-, per- and post-conditioning induced by limb ischemia have all been demonstrated to provide potent acute protection against myocardial damage in experimental models [5,14,15] and in clinical trials [31] .
  • monocytes downregulating white cell proinflammatory pathways [21,32] and, when delivered daily for 10 days, reducing neutrophil adhesion phagocytosis and proinflammatory cytokine responses.
  • activated NF- ⁇ B pathways can also up-regulate the target gene expression of TNF- ⁇ and IL-1 ⁇ [29,30,33] .
  • This ‘anti-inflammatory’ effect is over and above infarct size reduction, as there was no additional benefit of repeated post-conditioning compared with perconditioning alone in our studies.
  • Clearly more focused experiments will be required to assess any causal relationship between rIPost, local oxidative stress and circulating cellular responses, but the overall effect of this stimulus, when repeated during the first 28 days after our experimental insult, to improve remodeling in the form of LV dilation and dysfunction in combination with myocyte hypertrophy has obvious clinical relevance to post-MI recovery in humans.

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US20190269410A1 (en) 2019-09-05
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SG10201908570RA (en) 2019-11-28
EP2552331A2 (fr) 2013-02-06
SG10201502031XA (en) 2015-05-28
KR20130040851A (ko) 2013-04-24
JP6326400B2 (ja) 2018-05-16
JP2016052600A (ja) 2016-04-14
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AU2011234189A1 (en) 2012-11-01
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US20160038147A1 (en) 2016-02-11
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SG184353A1 (en) 2012-11-29

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