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Kenneth B Margulies

Publications and source records attributed to Kenneth B Margulies.

32 records · Page 2Linked to original sources
PubMed2003

Is depressed myocyte contractility centrally involved in heart failure?

This review examines the evidence for and against the hypothesis that abnormalities in cardiac contractility initiate the heart failure syndrome and drive its progression. There is substantial evidence that the contractility of failing human hearts is depressed and that abnormalities of basal Ca2+ regulation and adrenergic regulation of Ca2+ signaling are responsible. The cellular and molecular defects that cause depressed myocyte contractility are not well established but seem to culminate in abnormal sarcoplasmic reticulum uptake, storage, and release. There are also strong links between Ca2+ regulation, Ca2+ signaling pathways, hypertrophy, and heart failure that need to be more clearly delineated. There is not substantial direct evidence for a causative role for depressed contractility in the initiation and progression of human heart failure, and some studies show that heart failure can occur without depressed myocyte contractility. Stronger support for a causal role for depressed contractility in the initiation of heart failure comes from animal studies where maintaining or improving contractility can prevent heart failure. Recent clinical studies in humans also support the idea that beneficial heart failure treatments, such as beta-adrenergic antagonists, involve improved contractility. Current or previously used heart failure treatments that increase contractility, primarily by increasing cAMP, have generally increased mortality. Novel heart failure therapies that increase or maintain contractility or adrenergic signaling by selectively modulating specific molecules have produced promising results in animal experiments. How to reliably implement these potentially beneficial inotropic therapies in humans without introducing negative side effects is the major unanswered question in this field.

Animals↗
PubMed2003

Cellular basis of abnormal calcium transients of failing human ventricular myocytes.

Depressed contractility is a central feature of the failing human heart and has been attributed to altered [Ca2+]i. This study examined the respective roles of the L-type Ca2+ current (ICa), SR Ca2+ uptake, storage and release, Ca2+ transport via the Na+-Ca2+ exchanger (NCX), and Ca2+ buffering in the altered Ca2+ transients of failing human ventricular myocytes. Electrophysiological techniques were used to measure and control V(m) and measure I(m), respectively, and Fluo-3 was used to measure [Ca2+]i in myocytes from nonfailing (NF) and failing (F) human hearts. Ca2+ transients from F myocytes were significantly smaller and decayed more slowly than those from NF hearts. Ca2+ uptake rates by the SR and the amount of Ca2+ stored in the SR were significantly reduced in F myocytes. There were no significant changes in the rate of Ca2+ removal from F myocytes by the NCX, in the density of NCX current as a function of [Ca2+]i, ICa density, or cellular Ca2+ buffering. However, Ca2+ influx during the late portions of the action potential seems able to elevate [Ca2+]i in F but not in NF myocytes. A reduction in the rate of net Ca2+ uptake by the SR slows the decay of the Ca2+ transient and reduces SR Ca2+ stores. This leads to reduced SR Ca2+ release, which induces additional Ca2+ influx during the plateau phase of the action potential, further slowing the decay of the Ca2+ transient. These changes can explain the defective Ca2+ transients of the failing human ventricular myocyte.

Action Potentials↗
PubMed2003

Unloading-induced remodeling in the normal and hypertrophic left ventricle.

To date, no study has assessed the degree of similarity between left ventricular (LV) reverse remodeling and atrophic remodeling. Stable LV hypertrophy was induced by creation of an arteriovenous fistula (AVF) in Lewis rats (32 days). LV unloading was induced by heterotopic transplantation of normal (NL-HT) and/or hypertrophic (AVF-HT) hearts (7 days). We compared indexes of remodeling in AVF, NL-HT, and AVF-HT groups with those of normal controls. LV unloading induced decreases in cardiomyocyte size in NL-HT and AVF-HT hearts. NL-HT and AVF-HT LV were both characterized by relative increases in collagen concentration that were largely a reflection of decreases in myocyte volume. NL-HT and AVF-HT LV were associated with similar increases in matrix metalloproteinase (MMP-2 and -9) zymographic activity, without change in the abundance of the tissue inhibitors of the MMPs. In contrast, AVF-HT, but not NL-HT, was associated with a dramatic increase in collagen cross-linking. Our findings suggest an overall similarity in the response of the normal and hypertrophic LV to surgical unloading. However, the dramatic increase in collagen cross-linking after just 1 wk of unloading suggests a potential difference in the dynamics of collagen metabolism between the two models. Further studies will be required to determine the precise molecular mechanisms responsible for these differences in extracellular matrix regulation. However, with respect to these and related issues, heterotopic transplantation of hypertrophied hearts will be a useful small animal model for defining mechanisms of myocyte-matrix interactions during decreased loading conditions.

Algorithms↗
PubMed2003

Gender differences in post-infarction hypertrophy in end-stage failing hearts.

OBJECTIVES: We explored whether there are gender differences in cardiac remodeling and whether etiology influences organ and cellular remodeling in advanced heart failure (HF). BACKGROUND: Several studies have shown a survival benefit for women compared to men with symptomatic HF. This observation may be related to gender differences in cardiac remodeling. METHODS: We studied hearts from 100 patients (72 men and 28 women) receiving cardiac transplantation at our institution. Cardiac morphology was assessed with echocardiography and direct measurement of cardiac mass. Cardiac myocyte volume, length, width, cross-sectional area, and contraction were measured using previously validated techniques. RESULTS: Among 50 patients with idiopathic cardiomyopathy (CM), we observed no gender-based differences in cardiac or cellular remodeling. In contrast, among 50 patients with ischemic cardiomyopathy (ICM), the heart weight index was significantly greater in men, and there was a strong trend toward an increased left ventricular (LV) mass index as well. These gender differences in cardiac and LV mass were paralleled by marked gender differences in myocyte volume, such that average myocyte volume was 36% greater in men than in women, in association with a 14% increase in resting cell length. CONCLUSIONS: Our studies demonstrate a multilevel gender difference in post-infarction remodeling, with women exhibiting reduced hypertrophy. Our studies further demonstrate that gender differences in cardiac remodeling in ICM are largely related to fundamental differences in cellular remodeling rather than simply differences in infarct size or expansion. Distinctions observed between ischemic and idiopathic CM suggest that gender may influence local myocardial responses to injury.

Cardiac Catheterization↗
PubMed2003

Early and late results of left ventricular reshaping by passive cardiac-support device in canine heart failure.

BACKGROUND: We tested whether the CardioClasp, a passive non-blood-contacting device could decrease excessive geometric burden in dilated cardiomyopathy and improve left ventricular systolic function and contractility by reshaping the left ventricle (LV) and by decreasing LV wall stress (LVWS) without decreasing arterial blood pressure. METHODS: In mongrel dogs (n = 6, the early group; n = 6, the chronic group; 25-27 kg), 4 weeks of rapid right ventricular pacing (210 to 240 bpm) induced dilated cardiomyopathy with heart failure. In the early group, we used hemodynamic data and echocardiography to evaluate LV systolic function immediately after placing the CardioClasp device. In the chronic group, we also evaluated LV systolic function immediately after placing the device on dilated hearts and then left the device in place for 30 days. At the end of 30 days, before explantation of the device, we again assessed LV systolic function. We measured fractional area of contraction (FAC), LVWS, and hemodynamic data in both groups. RESULTS: In the early group, use of the CardioClasp device decreased the LV end-diastolic anterior-to-posterior dimension by 27.8% +/- 2.6% at implantation (p < 0.05). In the chronic group, use of the CardioClasp decreased the LV end-diastolic anterior-to-posterior dimension by 19.4% +/- 2.0% at implantation (p < 0.05) and by 22.0% +/- 3.10% at explantation (p < 0.05). Use of the CardioClasp did not alter LV end-diastolic and peak pressure, LV dP/dts, or cardiac output at implantation or at explantation. In the early group, use of the CardioClasp decreased the LVWS by 43.4% +/- 3.1% at implantation (p < 0.05). In the chronic group, LVWS decreased by 28.8% +/- 2.1% at implantation (p < 0.05) and by 43.3% +/- 5.2% at explantation (p < 0.05). In the early group, FAC increased significantly, by 28.9% +/- 7.8% at implantation (p < 0.05). In the chronic group, FAC increased significantly, by 18% +/- 12% at implantation (p < 0.05) and by 19% +/- 12% at explantation (p < 0.05). CONCLUSIONS: As expected, use of the CardioClasp device increased FAC and decreased LVWS by reshaping the LV. Use of the CardioClasp device maintained cardiac output and arterial pressure. In 30-day experiments, the increased FAC and decreased LVWS were maintained at explantation.

Animals↗
PubMed2002

L-type Ca2+ channel density and regulation are altered in failing human ventricular myocytes and recover after support with mechanical assist devices.

Ca2+ influx through the L-type calcium channel (LTCC) induces Ca2+ release from the sarcoplasmic reticulum (SR) and maintains SR Ca2+ loading. Alterations in LTCC properties, their contribution to the blunted adrenergic responsiveness in failing hearts and their recovery after support with LV assist devices (LVAD) were studied. L-type Ca2+ current (I(Ca,L)) was measured under basal conditions and in the presence of isoproterenol (ISO), dibutyryl-cAMP (db-cAMP), Bay K 8644 (BayK), Okadaic acid (OA, a phosphatase inhibitor), and phosphatase 2A (PP2A) in nonfailing (NF), failing (F), and LVAD-supported human left ventricular myocytes (HVMs). Basal I(Ca,L) density was not different in the 3 groups but I(Ca,L) was activated at more negative voltages in F- and LVAD- versus NF-HVMs (V(0.5): -7.18+/-1.4 and -7.0+/-0.9 versus 0.46+/-1.1 mV). Both ISO and db-cAMP increased I(Ca,L) in NF- and LVAD- significantly more than in F-HVMs (NF >LVAD> F: ISO: 90+/-15% versus 77+/-19% versus 24+/-12%; db-cAMP: 235%>172%>90%). ISO caused a significant leftward shift of the I(Ca,L) activation curve in NF- and LVAD- but not in F-HVMs. After ISO and db-cAMP, the I(Ca,L) activation was not significantly different between groups. BayK also increased I(Ca,L) more in NF- (81+/-30%) and LVAD- (70+/-15%) than in F- (51+/-8%) HVMs. OA increased I(Ca, L) by 85.6% in NF-HVMs but had no effect in F-HVMs, while PP2A decreased I(Ca, L) in F-HVMs by 35% but had no effect in NF-HVMs. These results suggest that the density of LTCC is reduced in F-HVMs but basal I(Ca,L) density is maintained by increasing in LTCC phosphorylation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2002

Reversal mechanisms of left ventricular remodeling: lessons from left ventricular assist device experiments.

The mechanical left ventricular assist device (LVAD) has become a reliable means of stabilizing the conditions of medically refractory patients with severe heart failure who are awaiting heart transplantation. At the same time, a substantial and growing body of evidence indicates that LVAD support triggers a multitude of adaptations within the failing human heart that seem to be triggered by hemodynamic unloading of the failing heart and changes in intracardiac and systemic neurohumoral activity. At the cell and tissue level, virtually every type of pathologic defect associated with failing human hearts demonstrates changes during LVAD support, and these adaptations are usually towards a less pathologic phenotype. This review summarizes the available literature concerning the phenomenology of so-called reverse remodeling. From this review it is clear that myocardial responses to LVAD support reveal the remarkable plasticity of even the most severely failing hearts. The composite literature on myocardial responses to LVAD support supports the thesis that mechanical overload is a primary factor sustaining the pathologic phenotype of the failing heart and suggests that the study of reverse remodeling provides a valuable opportunity to discover adaptive signaling pathways capable of mediating myocardial recovery.

Electrophysiology↗
PubMed2002

Modulation of contractility in failing human myocytes by reverse-mode Na/Ca exchange.

A decrease in the peak systolic [Ca](i) and slow decay of the Ca(i) transient are common features of the end-stage failing human ventricular myocyte and may underlie the contractile abnormalities observed in congestive heart failure. The role of the Na/Ca exchanger has been a great area of interest given the changes observed at the molecular level. Results from these experiments have been inconsistent, however, and therefore cellular-based experiments may be required to characterize the role of the Na/Ca exchanger in failing human myocardium. We review recent data that suggest an increased ability of the Na/Ca exchanger to transport Ca into the cytoplasm in failing human myocytes. We hypothesize that this increased Ca influx can explain the slowed decay and impaired relaxation of failing human ventricular myocytes.

Animals↗
PubMedDate not supplied

Mechanical approaches to alter remodeling.

Regression of pathologic cardiac hypertrophy and dilation, so-called reverse remodeling, has emerged as an important therapeutic target in the treatment of dilated cardiomyopathies. Although pharmacologic therapies may promote regression of pathologic remodeling, the magnitude of reverse remodeling is usually small. In contrast, reverse remodeling associated with cardiovascular devices, as highlighted in this review, often has been more rapid and reliable. For example, circulatory support with a left ventricular assist device produces the dramatic reverse remodeling in severely diseased hearts and typically provides myocardial tissue samples to generate new insights into the basic biology of reverse remodeling. Alternatively, multisite ventricular pacing to improve the synchrony of ventricular contraction has demonstrated clinical efficacy that includes the ability to reduce cardiac dilation and hypertrophy, and improvements in symptoms and functional capacity. Passive cardiac support devices comprise another promising strategy to prevent or reverse detrimental cardiac remodeling in patients with dilated cardiomyopathies.

Cardiomyopathy, Dilated↗
PubMedDate not supplied

CardioClasp changes left ventricular shape acutely in enlarged canine heart.

BACKGROUND: In dilated cardiomyopathy (DCM), eliminating or reducing extra-geometric burden to the myocardial cells would directly reduce myocardial wall stress leading to improved LV systolic performance. In acute experiments, we tested whether a passive non-blood contacting CardioClasp device, which employs two indenting bars to reshape the left ventricle (LV), could reduce extra-geometric burden, LV wall stress (LVWS) and improve LV systolic function and contractility without decreasing arterial blood pressure. METHODS: In mongrel dogs (n = 5), 4 weeks of right ventricular pacing (210-220-230-240 ppm) induced DCM with severe heart failure. After placing the CardioClasp device, LV performance was evaluated immediately by measuring hemodynamics, echocardiography, and Sonometrics crystal data. Eleven sonometric crystals were placed into endocardial positions (8 in anterior, posterior, mid-anterior, mid-posterior, apex, base, free and septal wall) and in myocardial (2 as regional) and epicardial (1) positions to assess the LV end-systolic pressure-segment length relationships (ESPSR) and cross-sectional area (ESPAR) relationship. RESULTS: CardioClasp decreased the LV end-diastolic anterior-posterior (A-P) dimensions at two levels (15% and 25%). With CardioClasp, LVWS decreased from 93.1 +/- 7.2 to 59.1 +/- 3.2 g/cm2 (P < 0.05) and fractional area of contraction (FAC) increased from 27.6 +/- 3.8 to 33.1 +/- 3.7% (P < 0.01). Peak LV and arterial pressures, LV +dP/dt, LV -dP/dt, and cardiac output were unaltered with CardioClasp. CardioClasp placement significantly increased the slopes of LV pressure versus anterior-posterior segment relationship from 7.3 +/- 0.6 to 15.8 +/- 1.8 mmHg/mm and septal-free wall segment relationship from 6.3 +/- 0.9 to 9.8 +/- 0.5 mmHg/mm. At both 15% and 25% LV A-P dimension reductions, the slopes of ESPAR showed significant steepening and increased from 10.1 +/- 0.7 (baseline) to 15.5 +/- 1.7 (15% reduction) and 19.0 +/- 1.4 mmHg/cm2 (25% reduction). The larger the reduction, the greater was the steepening of the slopes of ESPSR and ESPAR. CONCLUSIONS: CardioClasp reduced LV diameter and thereby decreased LVWS and increased FAC. CardioClasp was able to reshape the left ventricle, while preserving the contractile mass, which increased the slopes of ESPSR and ESPAR. This reshaping was associated with maintained systolic pressures, cardiac output, and increased contractility.

Animals↗