Search PubMed⌕ Search

Biomedical subjects

Robert A Kloner

Publications and source records attributed to Robert A Kloner.

At least 19 recordsLinked to original sources
PubMed2006

Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial.

AIMS: The purpose of this analysis was to determine whether the efficacy of adenosine vs. placebo was dependent on the timing of reperfusion therapy in the second Acute Myocardial Infarction Study of Adenosine (AMISTAD-II). METHODS AND RESULTS: Patients presenting with ST-segment elevation anterior AMI were randomized to receive placebo vs. adenosine (50 or 70 microg/kg/min) for 3 h starting within 15 min of reperfusion therapy. In the present post hoc hypothesis generating study, the results were stratified according to the timing of reperfusion, i.e. > or = or < the median 3.17 h, and by reperfusion modality. In patients receiving reperfusion < 3.17 h, adenosine compared with placebo significantly reduced 1-month mortality (5.2 vs. 9.2%, respectively, P = 0.014), 6-month mortality (7.3 vs. 11.2%, P = 0.033), and the occurrence of the primary 6-month composite clinical endpoint of death, in-hospital CHF, or rehospitalization for CHF at 6 months (12.0 vs. 17.2%, P = 0.022). Patients reperfused beyond 3 h did not benefit from adenosine. CONCLUSION: In this post hoc analysis, 3 h adenosine infusion administered as an adjunct to reperfusion therapy within the first 3.17 h onset of evolving anterior ST-segment elevation AMI enhanced early and late survival, and reduced the composite clinical endpoint of death or CHF at 6 months.

Adenosine↗
PubMed2006

Cardiovascular safety update of Tadalafil: retrospective analysis of data from placebo-controlled and open-label clinical trials of Tadalafil with as needed, three times-per-week or once-a-day dosing.

Because most men with erectile dysfunction have underlying vascular disease, it is important to update the cardiovascular safety profile of medications used in the treatment of erectile dysfunction. This retrospective analysis evaluated serious cardiovascular treatment-emergent adverse events (CVTEAEs) reported in 36 clinical trials of tadalafil, a phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. A serious CVTEAE was defined as myocardial infarction, cardiovascular death, or cerebrovascular death. In the 36 trials, 12,487 men (mean age 55 years) with erectile dysfunction received tadalafil, with 5,771 patient-years (PYs) of exposure, and 2,047 men (mean age 56 years) received placebo, with 460 PYs of exposure. Tadalafil 2 to 50 mg was taken as needed, 3 times/week, or once a day. Co-morbidities at baseline included hypertension (31%), diabetes (21%), hyperlipidemia (17%), and coronary artery disease (5%). Across all trials, the incidence rate of serious CVTEAEs was 0.40/100 PYs in tadalafil-treated patients and 0.43/100 PYs in placebo-treated patients. In patients taking tadalafil as needed, 3 times/week, or once a day, the incidence rates of serious CVTEAEs ranged from 0.17 to 0.54/100 PYs across placebo-controlled and open-label trials. In conclusion, the incidence rates of serious CVTEAEs were comparable among men with erectile dysfunction taking tadalafil as needed, 3 times/week, or once a day, and these rates were also comparable with those in placebo-treated patients. In this clinical trial population of men with erectile dysfunction, tadalafil was not associated with an increased risk for serious cardiovascular adverse events.

Aged↗
PubMed2006

Improved left ventricular function and reduced necrosis after myocardial ischemia/reperfusion in rabbits treated with ranolazine, an inhibitor of the late sodium channel.

Ranolazine is an inhibitor of the late sodium current and, via this mechanism, decreases sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces angina, but there is little information on its effects in acute myocardial infarction. The aim of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial infarct size after ischemia/reperfusion in rabbits. Ten minutes before coronary artery occlusion (CAO), anesthetized rabbits were assigned to vehicle (n=15) or ranolazine (2 mg/kg i.v. bolus plus 60 microg/kg/min i.v. infusion; n=15). Hearts received 60 min of CAO and 3 h of reperfusion. CAO caused LV dysfunction associated with necrosis. However, at the end of reperfusion, rabbits treated with ranolazine had better global LV ejection fraction (0.42+/-0.02 versus 0.33+/-0.02; p<0.007) and stroke volume (1.05+/-0.08 versus 0.78+/-0.07 ml; p<0.01) compared with vehicle. The fraction of the LV wall that was akinetic or dyskinetic was significantly less in the ranolazine group at 0.23+/-0.03 versus 0.34+/-0.03 in vehicle-treated group; p<0.02. The ischemic risk region was similar in both groups; however, infarct size was significantly smaller in the treated group (44+/-5 versus 57+/-4% vehicle; p<0.04). There were no significant differences among groups in heart rate, arterial pressure, LV end-diastolic pressure, or maximum-positive or -negative first time derivative of LV pressure (dP/dt). In conclusion, the results of this study show that ranolazine provides protection during acute myocardial infarction in this rabbit model of ischemia/reperfusion. Ranolazine treatment led to better ejection fraction, stroke volume and less wall motion abnormality after reperfusion, and less myocardial necrosis.

Acetanilides↗
PubMed2006

Preconditioning, postconditioning and their application to clinical cardiology.

Ischemic preconditioning is a well-established phenomenon first described in experimental preparations in which brief episodes of ischemia/reperfusion applied prior to a longer coronary artery occlusion reduce myocardial infarct size. There are ample correlates of ischemic preconditioning in the clinical realm. Preconditioning mimetic agents that stimulate the biochemical pathways of ischemic preconditioning and protect the heart without inducing ischemia have been examined in numerous experimental studies. However, despite the effectiveness of ischemic preconditioning and preconditioning mimetics for protecting ischemic myocardium, there are no preconditioning-based therapies that are routinely used in clinical medicine at the current time. Part of the problem is the need to administer therapy prior to the known ischemic event. Other issues are that percutaneous coronary intervention technology has advanced so far (with the development of stents and drug-eluting stents) that ischemic preconditioning or preconditioning mimetics have not been needed in most interventional cases. Recent clinical trials such as AMISTAD I and II (Acute Myocardial Infarction STudy of ADenosine) suggest that some preconditioning mimetics may reduce myocardial infarct size when given along with reperfusion or, as in the IONA trial, have benefit on clinical events when administered chronically in patients with known coronary artery disease. It is possible that some of the benefit described for adenosine in the AMISTAD 1 and 2 trials represents a manifestation of the recently described postconditioning phenomenon. It is probable that postconditioning--in which reperfusion is interrupted with brief coronary occlusions and reperfusion sequences--is more likely than preconditioning to be feasible as a clinical application to patients undergoing percutaneous coronary intervention for acute myocardial infarction.

Adenosine↗
PubMed2006

The no-reflow phenomenon: A basic mechanism of myocardial ischemia and reperfusion.

Both animal models of experimental myocardial infarction and clinical studies on reperfusion therapy for acute myocardial infarction have provided evidence of impaired tissue perfusion at the microvascular level after initiation of reperfusion despite adequate restoration of epicardial vessel patency. Characteristics of this "no-reflow" phenomenon found in basic science investigations, such as distinct perfusion defects, progressive decrease of resting myocardial flow with ongoing reperfusion and functional vascular alterations are paralleled by clinical observations demonstrating similar features during the course of reperfusion. In experimental animal investigations of coronary occlusion and reperfusion, this no-reflow phenomenon could be characterized as a fundamental mechanism of myocardial ischemia and reperfusion. Major determinants of the amount of no-reflow are the duration of occlusion, infarct size, but also the length of reperfusion, as rapid expansion of perfusion defects occurs during reperfusion. Moreover, no-reflow appears to persist over a period of at least four weeks, a period when major steps of infarct healing take place. The significant association of the degree of compromised tissue perfusion at four weeks and indices of infarct expansion, found in chronic animal models of reperfused myocardial infarction, might be the pathoanatomic correlate for the prognostic significance observed in the clinical setting.

Animals↗
PubMed2006

Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics.

Mildronate is a fatty acid oxidation inhibitor approved as an antianginal drug in parts of Europe. We carried out the first study to determine whether a 10-day course of mildronate could reduce myocardial infarct size (IS) during acute myocardial ischemia. Sprague Dawley rats received 200 mg/kg/d of mildronate (treated group, n = 16) or sterile water (control group, n = 14) subcutaneously for 10 days before ischemia-reperfusion. Rats were then subjected to 45 minutes of left coronary artery occlusion and 2 hours of reperfusion. The 2 groups had identical areas at risk: treated 38 +/- 3%; controls 38 +/- 2%. The amount of necrosis was smaller in the mildronate group at 16 +/- 2% of the left ventricle versus controls, 22 +/- 2% (P = 0.05); and for any amount of risk >25%, necrosis was smaller in the treated group (P = 0.0035). Myocardial IS (% of risk zone) was 43+/-3% in the mildronate-treated rats, and 57+/-4% in controls (P = 0.004). During occlusion, there were no differences between the 2 groups in heart rate (216 +/- 12 bpm, mildronate and 210 +/- 9 bpm, control), in mean arterial pressure (60 +/- 2 mm Hg, mildronate and 64 +/- 3 mm Hg, control) or in the frequency of arrhythmias. Our study for the first time demonstrated that a 10-day treatment with mildronate reduced myocardial IS in an experimental model of acute myocardial ischemia, without any effect on hemodynamics.

Angina Pectoris↗
PubMed2006

The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine.

INTRODUCTION: Erectile dysfunction (ED) is a highly prevalent disorder associated with a significant burden of illness. The prevalence and incidence of ED are strongly age-related, affecting more than half of men >60 years. The first Princeton Consensus Conference (Princeton I) in 1999 developed guidelines for safe management of cardiac patients regarding sexual activity and the treatment of ED. AIM: The second conference (Princeton II) was convened to update the recommendations based on the expanding knowledge base and new treatments available. This article reviews and expands on the Princeton II guidelines to address sexual dysfunction and cardiac risk. METHODS: A consensus panel of experts reviewed recent multinational studies in safety and drug interaction data for three phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil), with emphasis on the safety of these agents in men with ED and concomitant cardiovascular disease. RESULTS: Erectile dysfunction is an early symptom or harbinger of cardiovascular disease, due to the common risk factors and pathophysiology mediated through endothelial dysfunction. Major comorbidities include diabetes, hypertension, hyperlipidemia and heart disease. Any asymptomatic man who presents with ED that does not have an obvious cause (e.g., trauma) should be screened for vascular disease and have blood glucose, lipids, and blood pressure measurements. Ideally, all patients at risk but asymptomatic for coronary disease should undergo an elective exercise electrocardiogram to facilitate risk stratification. Lifestyle intervention in ED, specifically weight loss and increased physical activity, particularly in patients with ED and concomitant cardiovascular disease, is literature-supported. CONCLUSIONS: The recognition of ED as a warning sign of silent vascular disease has led to the concept that a man with ED and no cardiac symptoms is a cardiac (or vascular) patient until proven otherwise. Men with ED and other cardiovascular risk factors (e.g., obesity, sedentary lifestyle) should be counseled in lifestyle modification.

Adult↗
PubMed2006

The Bolger conference on PDE-5 inhibition and HIV risk: implications for health policy and prevention.

INTRODUCTION: Recent reports have linked the use of phosphodiesterase type 5 (PDE-5) inhibitors with increased rates of high-risk sexual behavior and HIV transmission in some individuals. AIM: A National Institute of Mental Health (NIMH)-funded, multidisciplinary conference was convened to evaluate scientific research, clinical and ethical considerations, and public policy implications of this topic. MAIN OUTCOME MEASURES: Published and unpublished findings on effects of PDE-5 inhibitors on sexual behavior; published guidelines and management recommendations. METHODS: Leading investigators in relevant disciplines (e.g., public health, epidemiology, medical ethics, urology, psychology) participated in a 2-day meeting, including representatives of government, scientific, and regulatory agencies (the Centers for Disease Control, Food and Drug Administration, NIMH, and the National Institute on Drug Abuse). Panelists provided critical reviews of substantive areas of research, followed by question and answer sessions on each topic. On the second day, working groups were convened to identify critical gaps and priorities in three major areas: (i) research and evaluation needs; (ii) prevention strategies and clinical management issues; and (iii) policy and prevention implications. RESULTS: Research needs and priorities were categorized into four specific areas: (i) basic and clinical/laboratory research; (ii) epidemiology and risk factors; (iii) social-behavioral processes and interventions; and (iv) prevention/policy and educational needs. Identified gaps in the available data include populations at risk (e.g., risk among heterosexuals, risk profiles among subpopulations of men who have sex with men) and the specific role of PDE-5 inhibitors in HIV seroconversion. Specific areas of emphasis were the need for safer sex counseling, comprehensive sexually transmitted infection (STI) screening and follow-up when indicated, avoidance of potentially dangerous drug interactions, and potential benefits of testosterone replacement for HIV-positive men with decreased androgen and other symptoms of hypogonadism. Conclusions. A conference was convened on the topic of PDE-5 inhibition and HIV risk. This "white paper" summarizes the findings of the conference and recommendations for future research.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Molecular aspects of ischemic heart disease: ischemia/reperfusion-induced genetic changes and potential applications of gene and RNA interference therapy.

Molecular biologic techniques have a variety of applications in the study of ischemic heart disease, including roles in elucidating cardiac genetic changes resulting from ischemia as well as in developing therapeutic interventions to treat ischemic heart disease. This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness of gene therapy for stimulating angiogenesis, protecting the heart against reperfusion injury, and treating heart failure. Also discussed are future research directions, including the potential use of RNA interference and combined stem cell therapy and gene therapy for the treatment of cardiovascular disease.

Animals↗
PubMed2006

Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion.

BACKGROUND: Brief periods of reocclusion (postconditioning) during early reperfusion reduce myocardial infarct size. Whether postconditioning has an effect on lethal ventricular arrhythmias independent of infarction in an in-vivo regional ischemia model is unknown. The purpose of this study was to determine if postconditioning limited reperfusion arrhythmias in a necrosis-free model. METHODS: Anesthetized rats were subjected to 5 minutes of proximal coronary artery occlusion; they were randomized to a control group (n = 15) that underwent reperfusion alone or a postconditioning group (n = 15) that received four cycles of 20 seconds reperfusion, 20 seconds reocclusion before final reperfusion. RESULTS: During the final reperfusion phase, ventricular arrhythmias occurred in 14 of 15 control rats and 8 of 15 postconditioning rats (P = .017). Ventricular tachycardia occurred in 10 of 15 control rats vs 4 of 15 postconditioning rats (P = .028). Control rats demonstrated 1.3 runs of ventricular tachycardia per minute vs 0.4 runs in postconditioning rats (P = .026). The average duration of ventricular tachycardia runs was 8.8 +/- 3.2 seconds in the control group vs 5.0 +/- 3.9 seconds in postconditioning rats (P = NS). CONCLUSION: This in-vivo study showed that postconditioning markedly attenuates ventricular arrhythmia after regional ischemia in a noninfarct model.

Animals↗
PubMed2006

Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit.

Ranolazine is a selective inhibitor of the late sodium current relative to peak sodium channel current, and via this mechanism, it may decrease sodium-dependent intracellular calcium overload during ischemia and reperfusion. Ranolazine reduces the frequency of angina attacks, but there is little information on its effects on myocardial stunning after short-term ischemia. The objective of this study was to test the effects of ranolazine on left ventricular (LV) function and myocardial stunning after ischemia/reperfusion in rabbits. Myocardial stunning was induced in rabbits by 15 minutes of coronary artery occlusion (CAO) followed by 3 hours reperfusion. Ten minutes before CAO, rabbits were randomly assigned to vehicle (n = 15) or ranolazine (2 mg/kg bolus plus 60 microg/kg/min infusion, IV, n = 15). Myocardial stunning was assessed by LV 2-dimensional echocardiography using, as a marker of severity, ischemic free-wall fractional thickening (FWft; systolic wall thickness - diastolic wall thickness/diastolic wall thickness). Regional ejection fraction (EF) was also assessed. During CAO, FWft was depressed in both groups, indicating an ischemic insult (FWft was reduced from 0.62 +/- 0.05 at baseline to 0.10 +/- 0.04 in vehicle and from 0.73 +/- 0.05 to 0.26 +/- 0.07 in ranolazine, P < 0.05, ranolazine vs vehicle). After reperfusion, previously ischemic myocardium remained stunned; however, FWft recovered significantly better in ranolazine (0.51 +/- 0.05) than in vehicle (0.35 +/- 0.04, P = .027). Baseline EF was 0.65 +/- 0.02 in the ranolazine and 0.68 +/- 0.02 in vehicle (P = ns). During CAO, EF was reduced by 36% +/- 6% in vehicle versus only 20% +/- 6% in ranolazine (P < .05). At the end of reperfusion, EF remained depressed in both groups, but the reduction in the vehicle group (25% +/- 5%) was significantly worse than in ranolazine (9% +/- 4%, P = .017). Improvement in function was independent of necrosis (negligible) or differences in hemodynamics (no differences between groups). Ranolazine treatment reduced myocardial stunning following brief ischemia/reperfusion suggesting that inhibiting the late sodium channel current may be a novel approach to treating stunning independent of effects on hemodynamics.

Acetanilides↗
PubMed2006

In vivo and in vitro models to test the hypothesis of particle-induced effects on cardiac function and arrhythmias.

Exposure to ultrafine particles (UFPs) by inhalation increases the number and severity of cardiac events. The specific mechanism(s) of action are unknown. This study was designed to examine whether UFPs could exert a direct effect on the cardiovascular system without dependence upon lung-mediated responses. The direct effects of UFPs were determined in normal rats (infused intravenously with UFPs), and in the isolated Langendorff perfused rat heart. UFPs from either ambient air (UFAAs) or diesel engine exhaust (UFDGs) were studied. Infusion of UFDGs prepared in our laboratory caused ventricular premature beats (VPBs) in 2 of 3 rats in vivo. Ejection fraction increased slightly (approximately 4.5%) in rats receiving UFPAA and was unchanged in the UFDG and saline groups in vivo. In the isolated rat heart, perfused according to Langendorff, UFDGs caused a marked increase in left-ventricular end-diastolic pressure (LVEDP; from 12.0 +/- 4.6 mmHg to 24.8 +/- 11.2 mmHg, p < 0.05) after 30 min of exposure. UFPs isolated from industrial diesel particulate matter (UFIDs), obtained from the National Institute of Standards and Technology, caused a significant decrease in left-ventricular systolic pressure (LVSP; from 85.7 +/- 4.0 mmHg to 37.9 +/- 20.3 mmHg, p < 0.05) and +/- dP/dt (from 2,365 +/- 158 mmHg/s to 1,188 +/- 858 mmHg/s, p < 0.05) at 30 min after the start of infusion. This effect was absent when the soluble fraction (containing no particles) isolated from the UFIDs was studied. These findings indicate that UFPs can have direct effects on the cardiovascular system that are independent of effects of particles on the lungs.

Air Pollutants↗
PubMed2006

Myocardial regeneration by embryonic stem cell transplantation: present and future trends.

Embryonic stem cells are a promising source for myocardial regeneration due to their pluripotency and plasticity. In theory, embryonic stem cells are capable of self-renewal in an unlimited fashion, and can differentiate into any cell type required for cell-based therapy, including cardiac myocytes. In recent years, embryonic stem cells have been transplanted for cardiac regeneration in animal models, and the results are encouraging. However, there are still many hurdles to be overcome for the clinical application of embryonic stem cells.

Animals↗
PubMed2006

Cardiovascular effects of phosphodiesterase 5 inhibitors.

Phosphodiesterase 5 inhibitors, such as sildenafil, vardenafil and tadalafil, are now approved for the treatment of erectile dysfunction. They inhibit the cGMP-specific isoform 5 of phosphodiesterase, resulting in cGMP accumulation, which, for example in smooth muscle cells, reduces muscular tone. In the cardiovascular system, they slightly reduce arterial systemic blood pressure. This moderate effect was also shown in combination with many antihypertensive drugs. But the important contraindication is the concomitant use of PDE 5 inhibitors with any drug serving as a nitric oxide donor, as this combination can lead to significant arterial hypotension. Caution is needed in patients on alpha-blocking agents. In general, this class of drugs was not shown to exhibit direct deleterious effects on the myocardium or promote arrhythmias. Furthermore, statistical evaluations did not demonstrate an increased risk for patients taking PDE 5 inhibitors in comparison with an adequate control population. Many patients suffering from erectile dysfunction may be characterized by multiple cardiovascular risk factors or even ischemic heart disease, suggesting an increased baseline risk. While in many forms of erectile dysfunction, these agents seem to be very effective, it becomes clear that endothelial dysfunction is an attractive target of PDE 5 inhibitors and may also be the underlying cause in many types of erectile dysfunction. In addition, these agents seem to be very effective in lowering pulmonary arterial pressure, which might provide the opportunity to treat primary and some forms of secondary pulmonary hypertension, perhaps in combination with inhaled nitric oxide or other pulmonary arterial vasodilators. Sildenafil was approved for treatment of primary arterial hypertension in the U.S. in June 2005. Recently, direct cardioprotective effects were described in animal research, resembling preconditioning-like effects, which may, under certain conditions, also be applicable in clinical research.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Ischemic preconditioning for the clinician.

Ischemic preconditioning is a physiologic phenomenon that occurs in the cardiac muscle in which brief episodes of ischemia protect the heart when exposed to a sustained ischemia. Clinical counterparts include potential benefits of preinfarction angina and less ischemia after a second, compared to a first, coronary angioplasty balloon inflation. This article will discuss how preconditioning might be applied to the clinical setting during acute myocardial infarction, coronary interventions, and cardiac surgery.

Humans↗
PubMed2005

Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference).

Recent studies have highlighted the relation between erectile dysfunction (ED) and cardiovascular disease. In particular, the role of endothelial dysfunction and nitric oxide in ED and atherosclerotic disease has been elucidated. Given the large number of men receiving medical treatment for ED, concerns regarding the risk for sexual activity triggering acute cardiovascular events and potential risks of adverse or unanticipated drug interactions need to be addressed. A risk stratification algorithm was developed by the First Princeton Consensus Panel to evaluate the degree of cardiovascular risk associated with sexual activity for men with varying degrees of cardiovascular disease. Patients were assigned to 3 categories: low, intermediate (including those requiring further evaluation), and high risk. This consensus study from the Second Princeton Consensus Conference corroborates and clarifies the algorithm and emphasizes the importance of risk factor evaluation and management for all patients with ED. The panel reviewed recent safety and drug interaction data for 3 phosphodiesterase (PDE)-5 inhibitors (sildenafil, tadalafil, vardenafil), with emphasis on the safety of these agents in men with ED and concomitant cardiovascular disease. Increasing evidence supports the role of lifestyle intervention in ED, specifically weight loss and increased physical activity, particularly in patients with ED and concomitant cardiovascular disease. Special management recommendations for patients taking PDE-5 inhibitors who present at the emergency department and other emergency medical situations are described. Finally, further research on the role of PDE-5 inhibition in treating patients with other medical or cardiovascular disorders is recommended.

Cardiovascular Diseases↗