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Biomedical subjects

David A Kass

Publications and source records attributed to David A Kass.

At least 73 records · Page 4Linked to original sources
PubMed2004

Reverse remodeling and enhanced inotropic reserve from the cardiac support device in experimental cardiac failure.

Progressive chamber remodeling plays a major role in the pathophysiology of chronic cardiac failure. Recent studies have begun exploring the potential for a passive external containment to impede such progressive dilation. In dogs with ischemic dilated cardiomyopathy, surgical placement of a thin external polyester mesh led to reversal of chronic chamber dilation after 3 to 6 months. Systolic function was preserved compared with the earlier time point. Both end-systolic and end-diastolic chamber volumes were reduced by about 20%, whereas end-diastolic pressure and chamber diastolic stiffness were not altered. These findings differ from the natural progression of this model, which involves progressive dilation and systolic dysfunction. In conjunction with reverse remodeling, cardiac inotropic reserve to beta-receptor agonists was markedly enhanced. Furthermore, these changes were induced without adversely affecting Frank-Starling reserve, supporting the lack of constriction.

Adrenergic beta-Agonists↗
PubMed2004

Quantitative analysis of myocardial inflammation by flow cytometry in murine autoimmune myocarditis: correlation with cardiac function.

Inflammation has been increasingly recognized as an important pathological component of heart failure. Existing methods of assessing myocardial infiltrate are labor-intensive and provide data that are difficult to quantify and not representative of the whole heart. As a result, little effort has been made to systematically assess the components of myocardial inflammation. We established an alternative method of quantitative assessment of myocardial inflammation by flow cytometry after enzymatic digestion of hearts to characterize the infiltrate and study the association between inflammation and cardiac function in murine experimental autoimmune myocarditis. The severity of acute myocarditis uniquely correlated with the proportion of neutrophils, but not T cells, B cells, or macrophages. Both acute and chronic phases were characterized by the presence of CD44high (activated) T cells in the heart, whereas T cells trafficking through normal hearts exhibited CD44low phenotype. During the chronic phase, the proportion of CD4+ T cells was associated with increased left-ventricular volumes and deterioration of systolic function, the hallmarks of dilated cardiomyopathy. We conclude that flow cytometry on uniformly digested mouse hearts provides sensitive and reproducible assessment of myocardial infiltrate and can be used to dissect out the specific role of individual immune components from the overall inflammatory response in the heart.

Animals↗
PubMed2004

Advanced glycation endproduct crosslinking in the cardiovascular system: potential therapeutic target for cardiovascular disease.

Advanced glycation endproducts (AGEs) are formed by a reaction between reducing sugars and biological amines. Because of their marked stability, glycated proteins accumulate slowly over a person's lifespan, and can contribute to age-associated structural and physiological changes in the cardiovascular system such as increased vascular and myocardial stiffness, endothelial dysfunction, altered vascular injury responses and atherosclerotic plaque formation. The mechanisms by which AGEs affect the cardiovascular system include collagen crosslinking, alteration of low-density lipoprotein molecules and impairment of cellular nitric oxide signalling through their interaction with AGE receptors (RAGEs). Thus, the accumulation of AGEs may help to explain the increased cardiac risk associated with aging as well as diabetes mellitus and hypertension, two conditions that accelerate and enhance AGE formation. A variety of new pharmacological approaches are being developed to reduce the pathophysiological impact of AGEs. These agents can prevent AGE and AGE crosslink formation, break pre-existing AGE crosslinks, and block the interaction between AGEs and RAGEs. Such agents have been shown to reduce vascular and myocardial stiffness, inhibit atherosclerotic plaque formation and improve endothelial function in animal models. Improvement in vascular compliance has also been demonstrated with AGE crosslink breakers in clinical trials. These studies offer promise to reduce the cardiac risk associated with isolated systolic hypertension, diastolic dysfunction and diabetes.

Cardiovascular Diseases↗
PubMed2003

Augmented systolic response to the calcium sensitizer EMD-57033 in a transgenic model with troponin I truncation.

Myocardial stunning is a form of acute reversible cardiac dysfunction that occurs after brief periods of ischemia and reperfusion. In several animal models, stunning is associated with proteolytic truncation of troponin I (TnI). Mice expressing the same proteolytic TnI fragment [TnI-(1-193)] demonstrate cardiac depression with a decreased maximal calcium-activated tension. We therefore hypothesized preferential improvement in mice expressing TnI-(1-193) treated with the calcium-sensitizing drug EMD-57033. TnI-(1-193) and nontransgenic myofibrils exhibited significant sensitization to calcium in Mg-ATPase assays after EMD-57033 exposure. However, only transgenic myofibrils exhibited an increase in maximal activity (P = 0.023). EMD-57033 also increased maximal calcium-activated force in TnI-(1-193) muscle, such that it was comparable to nontransgenic cardiac muscle. EMD-57033 enhanced in vivo systolic function modestly in controls but had a marked effect in transgenic mice, with an almost threefold greater leftward shift of the end-systolic pressure-volume relation (P = 0.0005). These data indicate a targeted efficacy of EMD-57033 in offsetting the contractile defect in TnI-(1-193) mice, and this may have therapeutic implications in models displaying this myofilament defect.

Animals↗
PubMed2003

Robust adenoviral and adeno-associated viral gene transfer to the in vivo murine heart: application to study of phospholamban physiology.

BACKGROUND: Viral gene transfer to the whole heart in vivo has been achieved in several mammalian species but remained difficult to accomplish in murine hearts. We postulated that a key impediment derives from the use of proximal aortic occlusion during virus injection, because this eliminates coronary perfusion gradients in mice as aortic root and left ventricle pressures equalize. METHODS AND RESULTS: Pressure-volume analysis confirmed these mechanics. In contrast, descending aortic occlusion with whole-body cooling (20 degrees C) preserved transmyocardial perfusion gradients and allowed for sustained (>10-minute) dwell times in an upper-body perfusion circuit. This approach yielded robust cardiac transfection with adenovirus (AdV) and adeno-associated virus (AAV) injected into the left ventricle cavity or more simply via a central vein. Cardio-specific expression was achieved with a myocyte-specific promotor. Optimal AdV transfection required 9-minute aortic occlusion, versus 5-minute occlusion for AAV. Using this method, we examined the in vivo function of phospholamban (PLB) by stably transfecting PLB-null mice with AAV encoding PLB (AAV(PLB)). AAV(PLB) restored PLB protein to near control levels that colocalized with SERCA2A in cardiomyocytes. At baseline, PLB-null hearts exhibited enhanced systolic and diastolic function, but frequency-dependent reserve was blunted versus wild-type controls. These properties, particularly the frequency response, returned toward control 3 months after AAV(PLB) transfection. CONCLUSIONS: The new simplified approach for murine whole-heart viral transfection should assist molecular physiology studies.

Adenoviridae↗
PubMed2003

Regional alterations in protein expression in the dyssynchronous failing heart.

BACKGROUND: Left ventricular (LV) mechanical dyssynchrony induces regional heterogeneity of mechanical load and is an independent predictor of mortality and sudden death in heart failure (HF) patients. We tested whether dyssynchrony also induces localized disparities in the expression of proteins involved with mechanical stress, function, and arrhythmia susceptibility. METHODS AND RESULTS: Eleven dogs underwent tachycardia-induced HF pacing, either from the right atrium or high right ventricular free wall. Whereas global LV dysfunction was similar between groups, LV contractile coordination assessed by tagged MRI was markedly dyssynchronous with right ventricular pacing but synchronous with right atrial pacing. In dyssynchronous failing hearts, the lateral LV endocardium displayed a 2-fold increase in phosphorylated erk mitogen-activated protein kinase expression (with no change in phospho-p38 or phospho-jnk), a 30% decline in sarcoplasmic reticulum Ca2+-ATPase, an 80% reduction in phospholamban, and a 60% reduction in the gap junction protein connexin43, relative to neighboring myocardial segments. In contrast, hearts from both right atrial-paced HF dogs and an additional 4 noninstrumented control animals showed minimal regional variability in protein expression. CONCLUSIONS: LV dyssynchrony in failing hearts generates myocardial protein dysregulation concentrated in the late-activated, high-stress lateral endocardium. Such molecular polarization within the LV creates transmural and transchamber expression gradients of calcium handling and gap junction proteins that may worsen chamber function and arrhythmia susceptibility.

Animals↗
PubMed2003

A biochemical rationale for the discrete behavior of nitroxyl and nitric oxide in the cardiovascular system.

The redox siblings nitroxyl (HNO) and nitric oxide (NO) have often been assumed to undergo casual redox reactions in biological systems. However, several recent studies have demonstrated distinct pharmacological effects for donors of these two species. Here, infusion of the HNO donor Angeli's salt into normal dogs resulted in elevated plasma levels of calcitonin gene-related peptide, whereas neither the NO donor diethylamine/NONOate nor the nitrovasodilator nitroglycerin had an appreciable effect on basal levels. Conversely, plasma cGMP was increased by infusion of diethylamine/NONOate or nitroglycerin but was unaffected by Angeli's salt. These results suggest the existence of two mutually exclusive response pathways that involve stimulated release of discrete signaling agents from HNO and NO. In light of both the observed dichotomy of HNO and NO and the recent determination that, in contrast to the O2/O2- couple, HNO is a weak reductant, the relative reactivity of HNO with common biomolecules was determined. This analysis suggests that under biological conditions, the lifetime of HNO with respect to oxidation to NO, dimerization, or reaction with O2 is much longer than previously assumed. Rather, HNO is predicted to principally undergo addition reactions with thiols and ferric proteins. Calcitonin gene-related peptide release is suggested to occur via altered calcium channel function through binding of HNO to a ferric or thiol site. The orthogonality of HNO and NO may be due to differential reactivity toward metals and thiols and in the cardiovascular system, may ultimately be driven by respective alteration of cAMP and cGMP levels.

Animals↗
PubMed2003

Endocardial versus epicardial electrical synchrony during LV free-wall pacing.

Cardiac resynchronization therapy has been most typically achieved by biventricular stimulation. However, left ventricular (LV) free-wall pacing appears equally effective in acute and chronic clinical studies. Recent data suggest electrical synchrony measured epicardially is not required to yield effective mechanical synchronization, whereas endocardial mapping data suggest synchrony (fusion with intrinsic conduction) is important. To better understand this disparity, we simultaneously mapped both endocardial and epicardial electrical activation during LV free-wall pacing at varying atrioventricular delays (AV delay 0-150 ms) in six normal dogs with the use of a 64-electrode LV endocardial basket and a 128-electrode epicardial sock. The transition from dyssynchronous LV-paced activation to synchronous RA-paced activation was studied by constructing activation time maps for both endo- and epicardial surfaces as a function of increasing AV delay. The AV delay at the transition from dyssynchronous to synchronous activation was defined as the transition delay (AVt). AVt was variable among experiments, in the range of 44-93 ms on the epicardium and 47-105 ms on the endocardium. Differences in endo- and epicardial AVt were smaller (-17 to +12 ms) and not significant on average (-5.0 +/- 5.2 ms). In no instance was the transition to synchrony complete on one surface without substantial concurrent transition on the other surface. We conclude that both epicardial and endocardial synchrony due to fusion of native with ventricular stimulation occur nearly concurrently. Assessment of electrical epicardial delay, as often used clinically during cardiac resynchronization therapy lead placement, should provide adequate assessment of stimulation delay for inner wall layers as well.

Animals↗
PubMed2003

Orthogonal properties of the redox siblings nitroxyl and nitric oxide in the cardiovascular system: a novel redox paradigm.

Endogenous formation of nitric oxide (NO) and related nitrogen oxides in the vascular system is critical to regulation of multiple physiological functions. An imbalance in the production or availability of these species can result in progression of disease. Nitrogen oxide research in the cardiovascular system has primarily focused on the effects of NO and higher oxidation products. However, nitroxyl (HNO), the one-electron-reduction product of NO, has recently been shown to have unique and potentially beneficial pharmacological properties. HNO and NO often induce discrete biological responses, providing an interesting redox system. This article discusses the emerging aspects of HNO chemistry and attempts to provide a framework for the distinct effects of NO and HNO in vivo.

Animals↗
PubMed2003

Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: independence from beta-adrenergic signaling.

Nitroxyl anion (HNONO(-)), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO/NO(-) augments systolic and diastolic function of failing hearts, and whether contrary to NO/nitrates such modulation enhances rather than blunts beta-adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO/NO(-) generated by Angelis' salt (AS) was infused (10 microg/kg per min, i.v.) to conscious dogs with cardiac failure induced by chronic tachycardia pacing. AS nearly doubled contractility, enhanced relaxation, and lowered cardiac preload and afterload (all P < 0.001) without altering plasma cGMP. This contrasted to modest systolic depression induced by an NO donor diethylamine(DEA)NO or nitroglycerin (NTG). Cardiotropic changes from AS were similar in failing hearts as in controls despite depressed beta-adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA/NO blunted beta-stimulation and NTG was neutral. Administration of propranolol to nonfailing hearts fully blocked isoproterenol stimulation but had minimal effect on AS inotropy and enhanced lusitropy. Arterial plasma CGRP rose 3-fold with AS but was unaltered by DEA/NO or NTG, supporting a proposed role of this peptide to HNO/NO(-) cardiotropic action. Thus, HNO/NO(-) has positive inotropic and lusitropic action, which unlike NO/nitrates is independent and additive to beta-adrenergic stimulation and stimulates CGRP release. This suggests potential of HNO/NO(-) donors for the treatment of heart failure.

Animals↗
PubMed2003

Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials.

CONTEXT: Progressive heart failure is the most common mechanism of death among patients with advanced heart failure. Cardiac resynchronization, a pacemaker-based therapy for heart failure, enhances cardiac performance and quality of life, but its effect on mortality is uncertain. OBJECTIVE: To determine whether cardiac resynchronization reduces mortality from progressive heart failure. DATA SOURCES: MEDLINE (1966-2002), EMBASE (1980-2002), the Cochrane Controlled Trials Register (Second Quarter, 2002), The National Institutes of Health ClinicalTrials.gov database, the US Food and Drug Administration Web site, and reports presented at scientific meetings (1994-2002). Search terms included pacemaker, pacing, heart failure, dual-site, multisite, biventricular, resynchronization, and left ventricular preexcitation. STUDY SELECTION: Eligible studies were randomized controlled trials of cardiac resynchronization for the treatment of chronic symptomatic left ventricular dysfunction. Eligible studies reported death, hospitalization for heart failure, or ventricular arrhythmia as outcomes. Of the 6883 potentially relevant reports initially identified, 11 reports of 4 randomized trials with 1634 total patients were included in the meta-analysis. DATA EXTRACTION: Trial reports were reviewed independently by 2 investigators in an unblinded standardized manner. DATA SYNTHESIS: Follow-up in the included trials ranged from 3 to 6 months. Pooled data from the 4 selected studies showed that cardiac resynchronization reduced death from progressive heart failure by 51% relative to controls (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.25-0.93). Progressive heart failure mortality was 1.7% for cardiac resynchronization patients and 3.5% for controls. Cardiac resynchronization also reduced heart failure hospitalization by 29% (OR, 0.71; 95% CI, 0.53-0.96) and showed a trend toward reducing all-cause mortality (OR, 0.77; 95% CI, 0.51-1.18). Cardiac resynchronization was not associated with a statistically significant effect on non-heart failure mortality (OR, 1.15; 95% CI, 0.65-2.02). Among patients with implantable cardioverter defibrillators, cardiac resynchronization had no clear impact on ventricular tachycardia or ventricular fibrillation (OR, 0.92; 95% CI, 0.67-1.27). CONCLUSIONS: Cardiac resynchronization reduces mortality from progressive heart failure in patients with symptomatic left ventricular dysfunction. This finding suggests that cardiac resynchronization may have a substantial impact on the most common mechanism of death among patients with advanced heart failure. Cardiac resynchronization also reduces heart failure hospitalization and shows a trend toward reducing all-cause mortality.

Cardiac Pacing, Artificial↗
PubMed2003

Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations.

BACKGROUND: Heart failure with preserved ejection fraction (HF-nlEF) is common in aged individuals with systolic hypertension and is frequently ascribed to diastolic dysfunction. We hypothesized that such patients also display combined ventricular-systolic and arterial stiffening that can exacerbate blood pressure lability and diastolic dysfunction under stress. METHODS AND RESULTS: Left ventricular pressure-volume relations were measured in patients with HF-nlEF (n=10) and contrasted with asymptomatic age-matched (n=9) and young (n=14) normotensives and age- and blood pressure-matched controls (n=25). End-systolic elastance (stiffness) was higher in patients with HF-nlEF (4.7+/-1.5 mm Hg/mL) than in controls (2.1+/-0.9 mm Hg/mL for normotensives and 3.3+/-1.0 mm Hg/mL for hypertensives; P<0.001). Effective arterial elastance was also higher (2.6+/-0.5 versus 1.9+/-0.5 mm Hg/mL) due to reduced total arterial compliance; the latter inversely correlated with end-systolic elastance (P=0.0001). Body size and stroke volumes were similar and could not explain differences in ventricular-arterial stiffening. HF-nlEF patients also displayed diastolic abnormalities, including higher left ventricular end-diastolic pressures (24.3+/-4.6 versus 12.9+/-5.5 mm Hg), caused by an upward-shifted diastolic pressure-volume curve. However, isovolumic relaxation and the early-to-late filling ratio were similar in age- and blood pressure-matched controls. Ventricular-arterial stiffening amplified stress-induced hypertension, which worsened diastolic function, and predicted higher cardiac energy costs to provide reserve output. CONCLUSION: Patients with HF-lnEF have systolic-ventricular and arterial stiffening beyond that associated with aging and/or hypertension. This may play an important pathophysiological role by exacerbating systemic load interaction with diastolic function, augmenting blood pressure lability, and elevating cardiac metabolic demand under stress.

Adult↗
PubMed2003

Wall tension is a potent negative regulator of in vivo thrombomodulin expression.

Thrombomodulin (TM), a key component of the anticoagulant protein C pathway, is a major contributor to vascular thromboresistance. We previously found that TM protein expression is dramatically reduced in autologous vein grafts during the first two weeks after implantation, coincident to a local inflammatory response, and remains suppressed for at least 6 weeks. To determine the proximate cause of TM loss, in vivo gene expression was quantified by real-time PCR. TM gene expression in vein grafts declined >85% during the first postoperative week and remained suppressed >55% at 6 weeks, accounting for the observed changes in protein expression. The effects of vein graft inflammation were evaluated in animals rendered leukopenic with vinblastine before graft implantation. Abrogating the local inflammatory response affected neither TM protein nor gene expression. To determine how hemodynamic forces might modulate TM expression, the surgical protocol was modified to alter blood flow and pressure-induced vessel distension. TM protein and gene expression did not correlate to changes in shear stress but highly correlated to changes in wall tension, both acutely and over time. We conclude that the primary stimulus for altered TM expression in vein grafts is the exposure to arterial pressure. Furthermore, these data identify strain as a novel and important pathway for in vivo TM gene regulation.

Animals↗
PubMed2003

Nitroxyl affords thiol-sensitive myocardial protective effects akin to early preconditioning.

Nitric oxide (NO) donors mimic the early phase of ischemic preconditioning (IPC). The effects of nitroxyl (HNO/NO(-)), the one-electron reduction product of NO, on ischemia/reperfusion (I/R) injury are unknown. Here we investigated whether HNO/NO(-), produced by decomposition of Angeli's salt (AS; Na(2)N(2)O(3)), has a cardioprotective effect in isolated perfused rat hearts. Effects were examined after intracoronary perfusion (19 min) of either AS (1 microM), the NO donor diethylamine/NO (DEA/NO, 0.5 microM), vehicle (100 nM NaOH) or buffer, followed by global ischemia (30 min) and reperfusion (30 min or 120 min in a subset of hearts). IPC was induced by three cycles of 3 min ischemia followed by 10 min reperfusion prior to I/R. The extent of I/R injury under each intervention was assessed by changes in myocardial contractility as well as lactate dehydrogenase (LDH) release and infarct size. Postischemic contractility, as indexed by developed pressure and dP/dt(max), was similarly improved with IPC and pre-exposure to AS, as opposed to control or DEA/NO-treated hearts. Infarct size and LDH release were also significantly reduced in IPC and AS groups, whereas DEA/NO was less effective in limiting necrosis. Co-infusion in the triggering phase of AS and the nitroxyl scavenger, N-acetyl-L-cysteine (4 mM) completely reversed the beneficial effects of AS, both at 30 and 120 min reperfusion. Our data show that HNO/NO(-) affords myocardial protection to a degree similar to IPC and greater than NO, suggesting that reactive nitrogen oxide species are not only necessary but also sufficient to trigger myocardial protection against reperfusion through species-dependent, pro-oxidative, and/or nitrosative stress-related mechanisms.

Animals↗