Showing papers in "Journal of Cardiovascular Pharmacology and Therapeutics in 2011"
TL;DR: The central premise is that mitochondria are the key determinant of cardiomyocyte fate and the goal of cardioprotection is to prevent cell death during the acute injury as well as to modulate the detrimental processes that ensue during remodeling.
Abstract: The consequence of myocardial ischemia is energetic stress, while reperfusion is accompanied by abrupt ionic shifts and considerable oxidative stress. Cells die by apoptotic and necrotic pathways. After the acute injury, the healing myocardium is subject to biomechanical stress and inflammation, which can trigger a smaller but more sustained wave of cell death, as well as changes in the metabolic and functional characteristics of surviving cells. The goal of cardioprotection is to prevent cell death during the acute injury as well as to modulate the detrimental processes that ensue during remodeling. This review will focus on acute injury, and the central premise is that mitochondria are the key determinant of cardiomyocyte fate.
140 citations
TL;DR: Clinical evidence is now clinical evidence that no-reflow is a strong predictor of long-term mortality that is independent of and beyond that provided by infarct size.
Abstract: The no-reflow phenomenon relates to the inability to reperfuse regions of the myocardium after ischemia, despite removal of the large epicardial coronary artery occlusion. The mechanism involves microvascular obstruction. In experimental studies, using markers for flow (thioflavin S, carbon black, microspheres), perfusion defects associated with no-reflow demonstrated ultrastructural evidence of localized endothelial swelling and blebs that appeared to obstruct flow. In humans no-reflow is more complicated due to the microemboli of atherosclerotic debris and thrombi generated by percutaneous coronary intervention. The no-reflow zone expands during the first few hours of reperfusion suggesting an element of reperfusion injury. In animal models, extensive no-reflow was associated with worse infarct expansion. The phenomenon of no-reflow following reperfusion therapy for myocardial infarction in humans has been demonstrated by magnetic resonance imaging, echo contrast agents, thallium, technecium-99m-labeled albumin microspheres, Thrombolysis In Myocardial Infarction (TIMI) scores, and myocardial blush grade. Patients exhibiting no-reflow following reperfusion therapy for myocardial infarction have greater left ventricular dilation and remodeling, more congestive heart failure, shock, and reduced survival. Certain vasodilators (adenosine, nitroprusside, nicorandil, and calcium blockers) are used acutely in the catheterization laboratory and appear to improve no-reflow, but systematic studies on therapy for no-reflow are needed. There is now clinical evidence that no-reflow is a strong predictor of long-term mortality that is independent of and beyond that provided by infarct size. Identifying and treating no-reflow may have important benefits including enhancing delivery of nutrients and cells required for healing and reducing infarct expansion and ventricular remodeling, which ultimately may reduce congestive heart failure and mortality.
131 citations
TL;DR: Progress has been made in translating the concept of RIPC to patients undergoing planned ischemic events: evidence for attenuation of cardiac enzyme release with RIPC has been reported after elective abdominal aortic aneurysm repair, angioplasty, and coronary artery bypass graft surgery.
Abstract: Remote ischemic preconditioning (RIPC) is the phenomenon whereby brief episodes of ischemia-reperfusion applied in distant tissues or organs render the myocardium resistant to a subsequent sustained episode of ischemia. Reduction of infarct size with RIPC has been documented in response to (i) brief antecedent ischemia in a remote coronary vascular bed (intra-cardiac protection); (ii) collection and transfer of coronary effluent from perconditioning "donor" hearts to naive "receptor" hearts (inter-cardiac protection); (iii) brief ischemia applied in skeletal muscle, mesentery, and other organs (interorgan protection); and (iv) remote nociception ("remote PC of trauma"). Moreover, the paradigm has expanded to encompass temporal modifications in the application of the remote stimulus (remote perconditioning and remote postconditioning). Progress has also been made in translating the concept of RIPC to patients undergoing planned ischemic events: evidence for attenuation of cardiac enzyme release with RIPC has been reported after elective abdominal aortic aneurysm repair, angioplasty, and coronary artery bypass graft surgery. However, despite these advances in characterization and clinical application, the mechanisms of RIPC--most notably, the means by which the protective stimulus is communicated to the heart--remain poorly defined and, in all likelihood, are model dependent.
122 citations
TL;DR: Chronic treatment with losartan decreases cardiac and skeletal muscle fibrosis and improves cardiac systolic function in dystrophin-deficient mdx mice.
Abstract: Recent studies showed that chronic administration of losartan, an angiotensin II type I receptor antagonist, improved skeletal muscle function in dystrophin-deficient mdx mice. In this study, C57BL/10ScSn-Dmd(mdx)/J female mice were either untreated or treated with losartan (n = 15) in the drinking water at a dose of 600 mg/L over a 6-month period. Cardiac function was assessed via in vivo high frequency echocardiography and skeletal muscle function was assessed using grip strength testing, Digiscan monitoring, Rotarod timing, and in vitro force testing. Fibrosis was assessed using picrosirius red staining and Image J analysis. Gene expression was evaluated using real-time polymerized chain reaction (RT-PCR). Percentage shortening fraction was significantly decreased in untreated (26.9% ± 3.5%) mice compared to losartan-treated (32.2% ± 4.2%; P < .01) mice. Systolic blood pressure was significantly reduced in losartan-treated mice (56 ± 6 vs 69 ± 7 mm Hg; P < .0005). Percentage cardiac fibrosis was significantly reduced in losartan-treated hearts (P < .05) along with diaphragm (P < .01), extensor digitorum longus (P < .05), and gastrocnemius (P < .05) muscles compared to untreated mdx mice. There were no significant differences in skeletal muscle function between treated and untreated groups. Chronic treatment with losartan decreases cardiac and skeletal muscle fibrosis and improves cardiac systolic function in dystrophin-deficient mdx mice.
97 citations
TL;DR: The translational potential of per- and postconditioning will drive further experimental work and clinical trials, which will ask unprecedented cooperation and information sharing between basic and clinician scientists, and creative developments from industry.
Abstract: The broad definition of “conditioning” is the application of a series of alternating intervals of brief ischemia (hypoxia) and reperfusion (reoxygenation) applied in the setting of prolonged ischemia causing myocardial infarction. While the conditioning stimulus is applied before the major (index) ischemic event in ischemic preconditioning, it is applied during the event in perconditioning, and applied after the event (reperfusion) in postconditioning. Studies on perconditioning have only recently demonstrated a reduction in infarct size by remote ischemia applied during transport of heart attack victims to the hospital before percutaneous coronary interventions (PCIs). The “conditioning” paradigm has been extended to include remote perconditioning and remote postconditioning. However, the biology of perconditioning is virtually unknown. Postconditioning has enjoyed enthusiastic attention from scientists that have done much to demonstrate that the model of triggers, mediators, and effectors used in precon...
90 citations
TL;DR: There is a considerable lack of studies that comprehensively examine the time course, nature, and mechanisms of post-reperfusion myocyte death.
Abstract: While the majority of the cardiac myocyte death that makes up the final infarct occurs during ischemia and the first few minutes of reperfusion, cell death does not stop there. In fact necrosis and apoptosis, and potentially autophagy, can continue in the previously ischemic area for up to 3 days post-reperfusion. Several mechanisms can potentially contribute to this death continuum: (1) myocytes that have already passed the point of no return despite reperfusion; (2) continued dysfunction of the coronary microvasculature; and (3) infiltration of inflammatory cells. The latter in particular leads to elevated myocardial concentrations of reactive oxygen species (ROS), inflammatory cytokines, activation of toll-like receptors, secretion of toxic enzymes, and activation of the complement cascade--all of which can lead to myocyte death. However, there is a considerable lack of studies that comprehensively examine the time course, nature, and mechanisms of post-reperfusion myocyte death. Moreover, cell death types (apoptosis, necrosis, and autophagy) are inextricably linked to one another. Therefore, we do not know whether specific blockade of necrosis during the acute phase of myocyte death will instead enhance apoptosis during the late phase, that is, will we be simply delaying the inevitable? Consequently, the purpose of this article is to briefly review what we do, and more importantly what we do not, know about cardiac cell death in the reperfused heart and what is needed to advance our understanding of this phenomenon.
80 citations
TL;DR: The rationale, structure, and operation of the NHLBI CAESAR Consortium is summarized, which will enable rigorous preclinical evaluation of promising cardioprotective therapies and will serve the entire scientific community (both in the academia and in the biomedical industry), thereby constituting a public resource.
Abstract: An estimated 935 000 Americans suffer a myocardial infarction every year; because their prognosis is determined by the size of the infarct, reducing infarct size is of paramount importance to alleviate morbidity and mortality. For 40 years, the National Heart, Lung, and Blood Institute (NHLBI) has invested enormous resources (at least several hundred million dollars) in preclinical studies aimed at developing infarct-sparing therapies, and several hundred (if not thousands) therapies have been claimed to limit infarct size in preclinical models. Unfortunately, due largely to methodological problems, this enormous investment has not produced any notable clinical application, and no cardioprotective therapy is currently available for clinical use.Clearly, after 40 years of futile efforts, a new approach is needed to overcome the problems that have impeded the translation of cardioprotective therapies. The time has come to apply to preclinical research on cardioprotection, the same standards of scientific ri...
79 citations
TL;DR: There is hope that applying some of the body’s own conditioning mechanisms may provide protection against ischemic damage and there are several reports in the cardiothoracic literature, suggesting that remote preconditioning protects hearts during surgery.
Abstract: The National Heart, Lung, and Blood Institute convened a Workshop on September 20-21, 2010, "New Horizons in Cardioprotection," to identify future research directions for cardioprotection against ischemia and reperfusion injury. Since the early 1970s, there has been evidence that the size of a myocardial infarction could be altered by various interventions. Early coronary artery reperfusion has been an intervention that consistently reduces myocardial infarct size in animal models as well as humans. Most cardiologists agree that the best way to treat acute ST-segment elevation myocardial infarction is to reperfuse the infarct artery as soon as possible and to keep the infarct artery patent. In general, stenting is superior to angioplasty, which is superior to thrombolysis. There is no accepted adjunctive therapy to acutely limit myocardial infarct size along with reperfusion that is routinely used in clinical practice. In the Kloner experimental laboratory, some adjunctive therapies have reproducibly limited infarct size (regional hypothermia, preconditioning, cariporide, combinations of the above, remote preconditioning, certain adenosine agonists, and late sodium current blockade). In clinical trials, a host of pharmacologic adjunctive therapies have failed to either reduce infarct size or improve clinical outcome. Potential reasons for the failure of these trials are discussed. However, some adjunctive therapies have shown promise in data subanalyses or subpopulations of clinical trials (adenosine, therapeutic hypothermia, and hyperoxemic reperfusion) or in small clinical trials (atrial natriuretic peptide, ischemic postconditioning, and cyclosporine, the mitochondrial permeability transition pore inhibitor). A recent clinical trial with remote conditioning induced by repetitive inflation of a brachial artery cuff begun prior to hospitalization showed promise in improving myocardial salvage and there are several reports in the cardiothoracic literature, suggesting that remote preconditioning protects hearts during surgery. Thus, in 2011, there is hope that applying some of the body's own conditioning mechanisms may provide protection against ischemic damage.
56 citations
TL;DR: Global left ventricular function, as assessed by the myocardial performance index, was significantly improved on drug therapy, due to improvement in both diastolic and systolic parameters.
Abstract: Purpose: Ranolazine is a novel antianginal medication that acts by ameliorating disturbed sodium and calcium homeostasis. By preventing myocyte sodium and calcium overload, ranolazine also have potential beneficial effects on myocardial function. Experimental models support this concept, as do 2 small studies in human participants receiving ranolazine intravenously. We evaluated changes in parameters of left ventricular function in stable angina patients treated with oral ranolazine. Methods: Twenty-two participants were enrolled with Doppler echocardiography performed at baseline and a mean of 2 months after initiation of treatment. Results: Global left ventricular function, as assessed by the myocardial performance index, was significantly improved on drug therapy (P < .0001). This was due to improvement in both diastolic and systolic parameters. Of 21 patients, 17 reported less angina and 8 patients reported an increase in activity level. Conclusions: We report improved parameters of left ventricular f...
51 citations
TL;DR: It has been shown in experimental and clinical studies that for therapeutic hypothermia to be effective it must be initiated as early as possible after the onset of ischemia and initiated before reperfusion.
Abstract: In many animal models, mild therapeutic hypothermia is a powerful intervention, reducing myocardial infarct size, reducing the no-reflow phenomenon, and improving healing after infarction. Cooling in these models has been produced by various means including whole-body hypothermia, synchronized hypothermic coronary venous retro-perfusion, heat exchangers, and regional hypothermia targeting the heart alone. However, in humans, the most widely used techniques are surface cooling and cooling by endovascular heat-exchange catheters. The reduction in temperature necessary to produce cardioprotection is mild (32-34°C), appears to have no detrimental effects on left ventricular function or regional myocardial blood flow, and may improve microvascular reflow to previously ischemic heart tissue. It has been shown in experimental and clinical studies that for therapeutic hypothermia to be effective it must be (1) initiated as early as possible after the onset of ischemia and (2) initiated before reperfusion. This ma...
51 citations
TL;DR: Findings indicate Mfn2 is a critical protein in modulating myocyte hypertrophy and inhibition of Akt activation seems to play a significant role in this process.
Abstract: Background and Objectives: Myocardial hypertrophy is a common clinical finding leading to heart failure and sudden death. Mitofusin 2 (Mfn2), a hyperplasia suppressor protein, is downregulated in h...
TL;DR: Several recently published proof-of-concept clinical studies have reported encouraging results with RIC, and large multicenter randomized clinical trials are now underway to investigate whether this simple noninvasive and virtually cost-free intervention has the potential to improve clinical outcomes in patients with CAD.
Abstract: Coronary artery disease (CAD) is the leading cause of death and disability worldwide, and early and successful restoration of myocardial reperfusion following an ischemic event is the most effective strategy to reduce final infarct size and improve clinical outcome. This process can, however, induce further myocardial damage, namely acute myocardial ischemia-reperfusion injury (IRI) and worsen clinical outcome. Therefore, novel therapeutic strategies are required to protect the myocardium against IRI in patients with CAD. In this regard, the endogenous cardioprotective phenomenon of "ischemic conditioning," in which the heart is put into a protected state by subjecting it to one or more brief nonlethal episodes of ischemia and reperfusion, has the potential to attenuate myocardial injury during acute IRI. Intriguingly, the heart can be protected in this manner by applying the "ischemic conditioning" stimulus to an organ or tissue remote from the heart (termed remote ischemic conditioning or RIC). Furthermore, the discovery that RIC can be noninvasively applied using a blood pressure cuff on the upper arm to induce brief episodes of nonlethal ischemia and reperfusion in the forearm has greatly facilitated the translation of RIC into the clinical arena. Several recently published proof-of-concept clinical studies have reported encouraging results with RIC, and large multicenter randomized clinical trials are now underway to investigate whether this simple noninvasive and virtually cost-free intervention has the potential to improve clinical outcomes in patients with CAD. In this review article, we provide an update of recently published and ongoing clinical trials in the field of RIC.
TL;DR: It is indicated that the hydroalcoholic extract of N oleander Linn flowers aid in cardioprotection probably by improving the antioxidant defense system during experimental myocardial necrosis.
Abstract: Nerium oleander Linn (NOL) an evergreen shrub belonging to the Apocynaceae family has been reported to have a wide spectrum of bioactivities. In in vitro study, the free radical scavenging potential of the hydroethanolic extract of N oleander Linn (ENO) flower and its fractions (glycosidic and nonglycosidic) were studied using 2, 2'-azino-di [3-ethylbenzthiazoline sulphonate] (ABTS*+ ) and 1, 1-diphenyl-2-picrylhydrazyl (DPPH*) scavenging assay. ENO exhibited better radical scavenging activities than its fractions. Furthermore, the cardioprotective role of ENO (10, 30, 100 mg/kg, per oral [po]) was tested against isoproterenol-induced myocardial toxicity (ISO, 120 mg/kg per day, subcutaneously [sc], for 2 days at 48 hours interval) in experimental rats when compared to propranolol (5 mg/kg, po) which was the standard. Pretreatment with ENO (10, 30, and 100 mg/kg) and propranolol for 2 weeks followed by ISO challenge in rats prevented the elevation of marker enzymes such as lactate dehydrogenase (LDH), γ-g...
TL;DR: The purpose of this review is to define the scope of the clinical problem, summarize the outcomes of selected phases II and III clinical trials, and identify the gap that needs to be closed in order to address the unmet clinical need.
Abstract: One of the unmet clinical needs in heart surgery is the prevention of myocardial stunning and necrosis that occurs as a result of ischemia-reperfusion. Myocardial stunning, a frequent consequence after heart surgery, is characterized by a requirement for postoperative inotropic support despite a technically satisfactory heart operation. In high-risk patients with marginal cardiac reserve, stunning is a major cause of prolonged critical care and may be associated with as much as a 5-fold increase in mortality. In contrast, the frequency of myocardial necrosis (myocardial infarction [MI]) after cardiac surgery is less appreciated and its consequences are much more subtle. The consequences may not be apparent for months to years. While we now have a much better understanding of the molecular mechanisms underlying myocardial stunning and MI, we still have no effective way to prevent these complications, nor a consistently effective means to engage the well-studied endogenous mechanisms of cardioprotection. The failure to develop clinically effective interventions is multifactorial and can be attributed to reliance on findings obtained from subcellular and cellular studies, to drawing conclusions from preclinical large animal studies that have been conducted in a disease-free state, and to accepting less than robust surrogate markers of injury in phase II clinical trials. These factors also explain the disappointing failure to identify effective adjuvant therapy in the setting of percutaneous coronary revascularization for acute MI (AMI) and reperfusion injury. These issues have contributed to the disappointing outcomes of large and costly phase III trials, resulting in a lack of enthusiasm on the part of the pharmaceutical industry to engage in further drug development for this indication. The purpose of this review is to (1) define the scope of the clinical problem; (2) summarize the outcomes of selected phases II and III clinical trials; and (3) identify the gap that needs to be closed in order to address the unmet clinical need.
TL;DR: A recent review of the physiological preclinical data on both ischemic and pharmacological postconditioning that are relevant to their translation to clinical therapeutics can be found in this article.
Abstract: Infarct size is determined not only by the severity of ischemia but also by pathological processes initiated at reperfusion. Accumulating experimental evidence indicates that lethal reperfusion injury might account for up to half of the final size of the myocardial infarct. Ischemic postconditioning (brief repeated periods of ischemia-reperfusion applied at the onset of coronary reflow) has been recently described as a powerful cardioprotection mechanism that prevents lethal reperfusion injury. This is the first method proven to reduce the final infarct size by about 50% in several in vivo models and to be confirmed in recent preliminary human studies. The molecular pathways are incompletely mapped but they probably converge to a mitochondrial key target: the mitochondrial permeability transition pore (PTP) which opening during early reperfusion is an event that promotes myocardial cell death. In different animal models and experimental settings, pharmacological PTP inhibition at the onset of reperfusion reproduces all the cardioprotective effects of ischemic postconditioning. In a recent proof-of-concept trial, the administration (just before percutaneous coronary intervention) of cyclosporine A, a potent PTP inhibitor, was associated with smaller infarct size. This review will focus on the physiological preclinical data on both ischemic and pharmacological postconditioning that are relevant to their translation to clinical therapeutics.
TL;DR: The purpose of this review is to provide an overview of how MRI can determine the area at risk, infarct size, and thus measure myocardial salvage.
Abstract: Almost all published preclinical studies of cardioprotective agents include a measurement of area at risk, infarct size, and thus allow determination of myocardial salvage as an indicator of therapeutic benefit. Until recently, single-photon emission tomography (SPECT) imaging with injection of sestamibi prior to intervention was the only clinical method suitable for making similar assessments in patients. Over the past 5 years, a large number of articles have documented that magnetic resonance imaging (MRI) can noninvasively determine area at risk, infarct size, and myocardial salvage. While T2-weighted imaging has been the method used most commonly, precontrast T1-weighted images and early gadolinium enhancement (EGE) images can also determine the size of the area at risk. All 3 of these MRI methods detect the area at risk based on myocardial edema resulting from ischemia. Late gadolinium enhancement (LGE) images provide a well-accepted reference standard for infarct size in all of those methods. Finally, LGE images can also provide a single modality measure of myocardial salvage based on the "wave front" of myocardial injury associated with the progressively more severe damage associated with acute myocardial infarction (MI). Essentially, the LGE images can provide an endocardial-based snap shot of infarct size and salvaged myocardium is estimated as the viable myocardium within the circumferential extent of the infarct. Thus, the purpose of this review is to provide an overview of how MRI can determine the area at risk, infarct size, and thus measure myocardial salvage.
TL;DR: In rat models, successful correction of deficiency was associated with reductions in ventricular hypertrophy, however, echocardiographic dimensions did not change significantly, bringing into questions whether vitamin D is a risk factor for HF, a marker of HF disease severity, or has a true pathologic role.
Abstract: An estimated 1 billion people worldwide have deficient or insufficient levels of vitamin D. Even more alarming is the association of vitamin D deficiency with many types of diseases, particularly heart failure (HF). Hypovitaminosis D has been observed to be highly prevalent in the HF community with rates varying from approximately 80% to 95%. Higher rates of deficiency have been linked to winter months, in patients with protracted decompensated HF, darker skin pigmentation, and higher New York Heart Association (NYHA) classes. In fact, some data suggest vitamin D deficiency may even be an independent predictor of mortality in patients with HF. Traditionally obtained through UV exposure and activated in the liver and then the kidneys, vitamin D is classified as a vitamin but functions as a steroid hormone. The hormone acts through the vitamin D receptor (VDR), which is expressed in vascular smooth muscle cells, renal juxtaglomerular cells, and most interestingly, cardiac myocytes. Studies have shown that the association between vitamin D deficiency and HF often manifests in the structural components of cardiac myocytes and/or through alterations of the neurohormonal cascade. In addition, vitamin D may also act rapidly through intracellular nongenomic receptors that alter cardiac contractility. Unfortunately, prospective vitamin D supplementation trials show mixed results. In rat models, successful correction of deficiency was associated with reductions in ventricular hypertrophy. In humans, however, echocardiographic dimensions did not change significantly. These results bring into questions whether vitamin D is a risk factor for HF, a marker of HF disease severity, or has a true pathologic role. This article provides a thorough review of vitamin D deficiency etiology, prevalence, and possible pathophysiologic role in HF. Furthermore, we carefully review prospective trials on vitamin D therapy in HF. We believe more trials on vitamin D therapy in HF need to be conducted before any conclusions can be drawn.
TL;DR: The case is made that ischemic preconditioning (IPC), still the most potent anti-infarct intervention ever described, is ready for serious clinical testing now and the time has come for large-scale clinical trials.
Abstract: After three decades of intense research on cardioprotection, we still do not have an approved intervention for limiting infarct size in the patient with acute myocardial infarction (AMI) aside from reperfusion therapy. Yet approximately 25% of patients with AMI that are reperfused are still at risk for heart failure because of excessive muscle necrosis. This article will try to make the case that ischemic preconditioning (IPC), still the most potent anti-infarct intervention ever described, is ready for serious clinical testing now. Over the past 25 years, IPC’s mechanism has been largely elucidated and targets a reperfusion injury. Ischemic preconditioning was never considered an intervention for AMI because of its need for pretreatment. However, knowledge of IPC’s mechanism has revealed a large number of drugs and interventions that will activate IPC’s signaling pathway at the time of reperfusion. Several small clinical trials suggest that they can be quite effective, but so far industry seems to have l...
TL;DR: The effects of sex and diseases need to be considered in design of cardioprotective interventions in animal studies and clinical trials.
Abstract: Cardioprotective strategies such as pre- and postconditioning result in a robust reduction in infarct size in young, healthy male animals. However, there are data suggesting that the protection is diminished in animals with comorbidities such as hypertension, hypercholesterolemia, and diabetes. It is important to understand at a mechanistic level the reasons for these differences. The effects of sex and diseases need to be considered in design of cardioprotective interventions in animal studies and clinical trials.
TL;DR: In this paper, the roles of protein kinase C (PKC) isozymes in platelets, leukocytes, endothelial cells and smooth muscle cells are discussed.
Abstract: Vascular restenosis, an overreaction of biological response to injury, is initialized by thrombosis and inflammation. This response is characterized by increased smooth muscle cell migration and proliferation. Available pharmacological treatments include anticoagulants, antiplatelet agents, immunosuppressants and antiproliferation agents. Protein kinase C (PKC), a large family of serine/threonine kinases, has been shown to participate in various pathological stages of restenosis. Consequently, PKC inhibitors are expected to exert a wide range of pharmacological activities therapeutically beneficial for restenosis. In this review, the roles of PKC isozymes in platelets, leukocytes, endothelial cells and smooth muscle cells are discussed, with emphasis given to smooth muscle cells. We will describe cellular and animal studies assessing prevention of restenosis with PKC inhibitors, particularly targeting -alpha, -beta, -delta and -zeta isozymes. The delivery strategy, efficacy and safety of such PKC regulators will also be discussed.
TL;DR: Compared with placebo, ACE inhibition or ARB significantly lowered risks of hospitalization for HF and the combined endpoint of cardiovascular mortality and hospitalization at 1 year, in patients with HF and preserved LVEF, but they have no significant effect on mortality during more prolonged follow-up.
Abstract: Background: Heart failure (HF) with a preserved left ventricular (LV) ejection fraction (EF) is the leading cause of hospitalization after 65 years of age. Individual randomized trials have not shown benefits conferred by angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor blockers (ARB) in these patients. To overcome this limitation, we performed a meta-analysis of the randomized trials of ACE inhibitors or ARB in patients with HF and preserved LVEF. Methods: Our search identified 4 randomized trials, comprising a total of 8152 patients, that investigated the effects of ACE inhibitors (n = 1), ARB (n = 2), or both treatments (n = 1). Risk ratios (RR) and 95% confidence intervals (CI) were calculated using a fixed-effect estimate method in the randomised trials. Results: Compared with placebo or no treatment, treatment with ACE inhibition or ARB was associated with lower rates of hospitalization for HF (RR 0.90; 95% CI 0.81-0.99, P = .032), though not cardiovascular mortality (RR 1.0...
TL;DR: In this first head-to-head comparison of R vs other antiarrhythmic agents at therapeutic doses in an ischemia/reperfusion model, ranolazine was as effective as either sotalol or lidocaine to reduce reperfusion-induced ventricular arrhythmias.
Abstract: Introduction: There are few safe antiarrhythmics for ischemic heart disease. Whereas ranolazine is a promising late INa blocker with antiarrhythmic effects, and devoid of pro-arrhythmic properties, there are no direct comparisons between ranolazine and other antiarrhythmic agents in an ischemia/reperfusion setting. Hypothesis and methods: To determine whether ranolazine was as effective as sotalol and lidocaine to reduce ischemia/reperfusion-induced arrhythmias, anesthetized rats were subjected to 5 minutes of proximal left coronary artery occlusion plus 5 minutes of reperfusion, which causes severe ventricular arrhythmias. At 21 minutes prior to coronary occlusion, rats (n = 20 per group) were randomized to receive either sotalol (intravenous [IV] bolus 5 mg/kg, 10 mg/kg per hour infusion), lidocaine (IV bolus 2.5 mg/kg, 2.5 mg/kg/hr infusion), ranolazine (IV bolus 3.3 mg/kg, 3.2 mg/kg per hour infusion), or saline (control). Results: The incidence of ventricular arrhythmias in the sotalol (S), lidocaine...
TL;DR: This review summarizes the available evidence validating the use of technetium-99m sestamibi single-photon emission computed tomography (SPECT) for this purpose and concludes that SPECT sESTamibi infarct size is a well-validated measurement with a long track record of performance in multicenter, randomized clinical trials.
Abstract: There are a variety of approaches to assess the efficacy of reperfusion therapy, and myocardial protection, in acute myocardial infarction. This review summarizes the available evidence validating the use of technetium-99m sestamibi single-photon emission computed tomography (SPECT) for this purpose. Multiple lines of evidence have validated its clinical utility. SPECT sestamibi infarct size has been used as an endpoint in multiple randomized clinical trials. A smaller number of clinical trials have used both early and later imaging with SPECT sestamibi to assess myocardium at risk and myocardial salvage. SPECT sestamibi has a number of limitations which must be recognized. Nevertheless, SPECT sestamibi infarct size is a well-validated measurement with a long track record of performance as an endpoint in multicenter, randomized clinical trials.
TL;DR: Although none of these newer agents have the data required to make blanket recommendations for use at this point, given the safety profile and low costs of some, many continue to be evaluated in randomized-controlled trials.
Abstract: Postoperative atrial fibrillation (POAF), a common complication of cardiac surgery, can increase the morbidity and mortality, as well as the costs of the surgery being preformed. Guidelines recommend the use of β-blockers, amiodarone, or sotalol to decrease the risk of experiencing POAF. However, none of these agents fully protect the patient from POAF, thus newer agents are needed to be used in combination with them. Many different agents have been studied to fit this role and may be grouped into 2 categories: agents with antiarrhythmic activity such as magnesium and polyunsaturated fatty acids and agents with anti-inflammatory activity such as statins and free radical scavengers. Most of these novel agents have been studied in a wide variety of trials; however, some clearly have more effect than others. Although none of these newer agents have the data required to make blanket recommendations for use at this point, given the safety profile and low costs of some, many continue to be evaluated in randomiz...
TL;DR: Patients on pravastatin had a significantly lower incidence of CIN compared to patients on simvastatin, and the difference between statins remained an independent predictor for the development of Cin.
Abstract: Contrast-induced nephropathy (CIN) is associated with long-term morbidity, mortality, and increased health care costs. It has been suggested that statins have pleiotropic effects countering inflammatory and oxidative stress involved in CIN. Several studies support this theory; however, previously published studies have not evaluated the potential differences between statins in reducing the incidence of CIN. The purpose of this retrospective, single-center trial was to compare the incidence of CIN in patients receiving simvastatin or pravastatin therapy undergoing percutaneous coronary intervention (PCI). A total of 261 patients were included (145 received simvastatin and 116 received pravastatin) with the majority undergoing elective PCI. The population was predominantly male (65%), Hispanic (65%), and diabetic (62%), with a mean age of 59 years and a low-density lipoprotein (LDL) of 85 mg/dL. No significant differences were found between groups for risk factors or prophylactic strategies (eg, hydration). Contrast-induced nephropathy occurred in 26 patients (17.9%) in the simvastatin group versus 10 (8.6%) in the pravastatin group (P < .05). No patients required dialysis as a result of contrast administration. Acute kidney injury (AKI) occurred in 21 patients (14.5%) in the simvastatin group compared to 8 (6.9%) in the pravastatin group (P < .05). In multivariate analysis, the difference between statins remained an independent predictor for the development of CIN. In conclusion, patients on pravastatin had a significantly lower incidence of CIN compared to patients on simvastatin.
TL;DR: In this meta-analysis of RCTs not designed a priori to test the hypothesis, ACEs and ARBs were associated with a significant reduction in recurrent AF.
Abstract: Background: Controversy persists regarding the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in the prevention of recurrent atrial fibrillati...
TL;DR: Fucoidan, a nonselective selectin blocker, attenuates the progression of EAM and is accompanied by inhibition of both macrophage and CD4-positive T-cell infiltration into the myocardium.
Abstract: Homing of cardiac myosin-specific CD4-positive T cells into the myocardium is the initial pathologic event of experimental autoimmune myocarditis (EAM). Subsequently, various bystander inflammatory cells are recruited into the myocardium crossing vascular endothelial cell walls. Sulfated polysaccharide fucoidan binds selectin nonselectively and blocks its function. Therefore, this study was designed to evaluate whether in vivo fucoidan treatment can improve EAM. A 21-day infusion of physiological saline or fucoidan was administrated intraperitoneally to the rats with sham operation (sham-saline, n = 5; sham-fucoidan, n = 6) or those with cardiac myosin injection (EAM-saline, n = 10; EAM-fucoidan, n = 10). After 3 weeks, fucoidan treatment improved left ventricular ejection fraction (79.04 ± 2.81 vs 65.94% ± 3.22%; P < .01 vs EAM-saline) with a reduced ratio of heart weight to body weight (4.016 ± 0.239 vs 4.975 ± 0.252 mg/g; P < .05 vs EAM-saline) in EAM. Furthermore, fucoidan treatment decreased serum levels of BNP (292.0 ± 53.4 vs 507.4 ± 89.2 ng/mL; P < .05 vs EAM-saline) and the myocarditis area (31.66 ± 1.53 vs 42.51% ± 3.24%; P < .01 vs EAM-saline) in EAM. These beneficial effects of fucoidan were accompanied by inhibition of both macrophage and CD4-positive T-cell infiltration into the myocardium. Fucoidan, a nonselective selectin blocker, attenuates the progression of EAM. This observation may be explained, at least in part, by blocking the extravasation of inflammatory cells into the myocardium.
TL;DR: Three interventions appear to be promising: myocardial conditioning, which consists of repetitive occlusions of coronary or other arteries prior to or at the time of myocardian reperfusion; the administration of cyclosporine A; and theadministration of adenosine.
Abstract: Prompt myocardial reperfusion reduces infarct size in patients experiencing coronary occlusion. However, its clinical value is limited because reperfusion also causes ischemic myocardial reperfusion injury (IMRI). Considerable research to reduce IMRI has been conducted. Three interventions appear to be promising: 1) myocardial conditioning, which consists of repetitive occlusions of coronary or other arteries prior to or at the time of myocardial reperfusion; 2) the administration of cyclosporine A; and 3) the administration of adenosine. A plan for the testing of these interventions in patients with acute myocardial infarction is described.
TL;DR: To move preconditioning into a broader clinical arena will require resolution of important fundamental yet stubborn problems involving both basic and clinical science.
Abstract: Ischemic preconditioning (IP) is the most effective, reproducible form of protection against myocardial cell death yet described. The mechanism of classic IP has not been identified, but recent investigations have focused on the mitochondrial permeability transition pore (mPTP). Similarly, the mechanism of the “second window of protection” (SWOP) is not known but thought to involve increased expression of important gene products. Currently, IP in the clinical arena is limited to cardiac surgery, planned angioplasty, and organ preservation protocols. To move preconditioning into a broader clinical arena will require resolution of important fundamental yet stubborn problems involving both basic and clinical science. Important unresolved issues include the mechanisms involved in the transition from reversible to irreversible injury, the amount of potential salvageable myocardium present at the onset of reperfusion, the identity and signaling of the mPTP, the optimization of protocols, the identity of end eff...
TL;DR: Higher diuretic doses associated strongly and independently with adverse long-term outcome in chronic HF and possibly, in euvolemic patients, efforts should be made to reduce diuretics dose.
Abstract: Background: Prognostic implications of diuretics dose are not completely understood. We aim to study the association between diuretic doses and long-term prognosis in patients with chronic stable heart failure (HF). Methods and Results: We conducted a retrospective cohort study of 244 patients followed at an outpatient HF clinic. Admission criteria were clinical stability in the previous 3 months and optimized medical therapy. Demographic characteristics, clinical, and laboratory parameters were recorded. Patients were followed for 2 years and the outcome was defined as all-cause death or hospital admission due to HF worsening. Patients on ≤80 mg furosemide were compared with those on higher doses. Patients were grouped according to furosemide dose (≤80 mg and >80 mg/d) and according to volemia as assessed by the sodium retention score: 80 mg furosemide had ...