Sonny J. Stetson

Regression of fibrosis and hypertrophy in failing myocardium following mechanical circulatory support.

BACKGROUND The cellular and structural changes that occur during long-term ventricular unloading leading to cardiac recovery are poorly understood. However, we have previously demonstrated that left ventricular assist device (LVAD) support leads to a significant decrease in intracardiac tumor necrosis factor-alpha (TNF-alpha), a protein capable of producing hypertrophy and fibrosis. METHODS To further define the beneficial effects of long-term ventricular unloading on cardiac function, we determined the effect of mechanical circulatory support on fibrosis and hypertrophy in paired myocardial samples of 18 patients with end-stage cardiomyopathy obtained at the time of LVAD implantation and removal. RESULTS We determined total collagen as well as collagen I and III by a semiquantitative analysis of positive immune-stained areas in pre- and post-LVAD myocardial samples. We found that total collagen content was reduced by 72% (p < 0.001), whereas collagen I content decreased by 66% (p < 0.001) and collagen III content was reduced by 62% (p < 0.001). Next, we determined myocyte size by direct analysis of cellular dimensions utilizing a computerized edge detection system in pre- and post-LVAD myocardial samples. We found that myocyte size decreased in all patients studied for an average reduction of 26% (33.1 +/- 1.32 to 24.4 +/- 1.64 microm, p < 0.001). CONCLUSION These data demonstrate that long-term mechanical circulatory support significantly reduces collagen content and decreases myocyte size. We suggest that the reduction of fibrosis and hypertrophy observed may in part contribute to the recovery of cardiac function associated with long-term mechanical circulatory support.

Molecular remodelling of dystrophin in patients with end-stage cardiomyopathies and reversal in patients on assistance-device therapy

BACKGROUND Mutations that lead to disruption of cytoskeletal proteins have been recorded in patients with familial dilated cardiomyopathy. We postulated that changes in cytoskeletal and sarcolemmal proteins provide a final common pathway for dilation and contractile dysfunction in dilated cardiomyopathy. In this study, we investigated the integrity of dystrophin in the myocardium of patients with end-stage heart failure due to ischaemic or dilated cardiomyopathy, and the response to treatment with left-ventricular assistance devices (LVAD). METHODS We assessed the expression and integrity of dystrophin in myocardial biopsy samples by immunohistochemistry and western-blot analysis using antibodies against the amino-terminal, carboxyl-terminal, and midrod domains. We took samples from the myocardia of ten controls, ten patients with dilated cardiomyopathy, ten with ischaemic heart disease, and six with dilated cardiomyopathy who underwent placement of a left-ventricular assistance device for progressive refractory heart failure. FINDINGS Immunohistochemical staining identified a disruption to the amino-terminus of dystrophin in 18 of 20 patients with end-stage cardiomyopathy (dilated or ischaemic), whereas staining with antibodies against other domains of dystrophin was normal. Western-blot analysis confirmed these observations, suggesting that remodelling of dystrophin is a common pathway for dysfunction of failing cardiomyocytes. Furthermore, this disruption was reversible in four patients after LVAD support. INTERPRETATION Dystrophin remodelling is a useful indicator of left-ventricular function in patients with dilated and ischaemic cardiomyopathy. Our results lend support to the hypothesis that changes in cytoskeletal proteins and, in particular, dystrophin might provide a final common pathway for contractile dysfunction in heart failure and these changes might be reversible by reduction of mechanical stress.

Decreased Expression of Tumor Necrosis Factor-α and Regression of Hypertrophy After Nonsurgical Septal Reduction Therapy for Patients With Hypertrophic Obstructive Cardiomyopathy

BackgroundNonsurgical septal reduction therapy (NSRT) is a novel therapeutic strategy for patients with hypertrophic obstructive cardiomyopathy (HOCM). Although the clinical benefits of this technique appear to be clear, the structural and functional changes that lead to improvements in cardiac function are not completely defined. In these studies, we sought to define the effect of NSRT on myocardial function as well as various markers of hypertrophy including the expression of tumor necrosis factor (TNF)-&agr;, a cytokine capable of producing fibrosis, left ventricular hypertrophy (LVH), and cardiomyopathy. Methods and ResultsWe performed endomyocardial biopsies of the RV side of the septum and echocardiograms on 15 HOCM patients at baseline and after successful NSRT. Comparative analysis on paired myocardial samples were performed to determine the effects of NSRT on LVH, end-diastolic volume and chamber stiffness, myocyte size, collagen content, and TNF-&agr; levels. At baseline, myocardial TNF-&agr; levels were increased in all patients. After NSRT, myocyte size, collagen content, and TNF-&agr; were significantly decreased. These changes were accompanied by an increase in left ventricular volumes and a reduction in LVH and chamber stiffness. ConclusionsWe suggest that pressure overload in HOCM patients contributes to the development of hypertrophy. These data provide the initial experimental evidence to suggest that TNF-&agr; may play a pathogenetic role in the hypertrophy of pressure overload.

The implications for cardiac recovery of left ventricular assist device support on myocardial collagen content.

BACKGROUND To define the beneficial cellular changes that occur with chronic ventricular unloading, we determined the effect of left ventricular assist device (LVAD) placement on myocardial fibrosis. METHODS We obtained paired myocardial samples (before and after LVAD implantation) from 10 patients (aged 43 to 64 years) with end-stage cardiomyopathy. We first determined regional collagen expression of an explanted heart by a computerized semiquantitative analysis of positive picro-sirius red stained areas. RESULTS We found that there was no statistically significant difference in collagen content between regions of the failed heart studied. Next we determined collagen content in these paired myocardial biopsies pre- and post-LVAD implantation. All 10 patients had significant reductions in collagen content after LVAD placement with a mean reduction of 82% (percent of tissue area stained decreased from 32% +/- 4% to 4% +/- 0.8%, P < 0.001). CONCLUSION In summary, these data demonstrate that chronic mechanical circulatory support significantly reduces fibrosis in the failing myocardium.

Evidence of improved right ventricular structure after LVAD support in patients with end-stage cardiomyopathy.

BACKGROUND Although many reports demonstrate the hemodynamic benefits of left ventricular assist devices (LVAD) in right-sided circulation, it is not known whether the right ventricular myocardium goes through reverse remodeling after left ventricular mechanical circulatory support. Accordingly, the purposes of our studies were 1). to investigate the right ventricular changes that occur in fibrosis, in cellular hypertrophy, and in intra-myocardial tumor necrosis factor alpha (TNF-alpha) levels in patients receiving LVAD support; and 2). to determine whether the type of LVAD used influences right ventricular myocardial changes. METHODS AND RESULTS We measured myocyte size, total collagen content, and TNF-alpha levels using semi-quantitative immunohistochemical analysis of myocardial samples from the right and left ventricles of control and failing myocardia, either supported by 1 of 2 distinct forms of LVADs or without support. We found that when compared with control, although myocyte size was not increased in the right ventricle of failing myocardia (p = not significant), total collagen content and myocardial TNF-alpha levels were decreased in the right ventricle compared with controls (p < 0.01 and p < 0.001, respectively). CONCLUSION These data demonstrate that chronic left ventricular unloading with either pulsatile or continuous-flow devices decreases right ventricular total collagen and myocardial TNF-alpha content. We suggest that the decreased fibrosis and normalization of cytokine milieu observed may in part contribute to the recovery of right-sided cardiac function associated with chronic mechanical circulatory support.

Managing heart failure with immunomodulatory agents.

The evidence in favor of immune activation as an operative mechanism that contributes to the progression of heart failure continues to accumulate. Indeed, a number of clinical trials have demonstrated the clinical interest of interventions in this area for many years, but none have proven useful. The only trial ever conducted to define the effect of immunotherapy in mortality, however, is the one currently ongoing using Etanercept in patients with symptomatic heart failure. Irrespective of the final outcome of the study, the growing interest in inflammation as a contributory pathway in disease progression has now opened the field to develop new strategies for intervention. Whether specific or non-specific therapies may prove useful will be defined only by the results of randomized clinical trials.

New strategies for the management of acute decompensated heart failure.

Acute heart failure in adults is the unfolding of heart failure in minutes, hours or a few days. Low output heart failure describes a form of heart failure in which the heart pumps blood at a rate at rest or with exertion that is below the physiological range and the metabolizing tissues extract their required oxygen from blood at a lower rate, causing a proportionately smaller oxygen amount remaining in the blood. Therefore, a widened arterial-venous oxygen difference occurs. High output heart failure is characterized by pumping blood with a rate above the physiological range at rest or during exertion, resulting in an arterial-venous oxygen difference, which is normal or low. This may be caused by peripheral vasodilatation during sepsis or thyrotoxicosis, blood shunting, or reduced blood oxygen content/viscosity (Fig. 1). The differentiation between low output heart failure versus high output heart failure is of highest importance for the choice of therapy and therefore the information and the monitoring of the systemic vascular resistance. Patients who present with acute heart failure suffer from a severe complication of different cardiac disorders. Most often they have an acute injury that affects their myocardial performance (eg, myocardial infarction) or valvular/chamber integrity (mitral regurgitation, ventricular septal rupture), which leads to an acute rise in left-ventricular filling pressures resulting in pulmonary edema.

Tumor necrosis factor-α in the failing human heart: Does it play a role in disease progression?

An increasing body of clinical and experimental evidence suggesting that TNFα may play a pathogenetic role in failing hearts continues to accumulate. Perhaps the most direct evidence for the role of TNFα in heart failure will come from the analysis of the phase I study in which a soluble recombinant human TNF receptor: Fc fusion protein was utilized in patients with moderate to severe heart failure Enrollment in that trial was recently completed; the results will soon be available for analysis. But perhaps more importantly, the knowledge gained from studying the role of TNFα in cardiac function draws attention to a series of molecules previously unrecognized as potential mediators in the pathogenesis of heart failure. Various cytokines and TNFα, in particular, represent new targets for therapeutic intervention in patients with heart failure.

Improved right ventricular structure following LVAD support in patients with end-stage cardiomyopathy

Background: Although there are many reports demonstrating hemodynamic benefits of left ventricular assist devices (LVAD) on right-sided circulation, it is not known whether the right ventricular myocardium goes through reverse remodeling following LVAD support. Accordingly, the purpose of our studies were: first, to investigate the changes that occur on fibrosis, cellular hypertrophy and intra-myocardial TNFa levels on the right ventricle of LVAD supported patients; second, to define whether the type of LVAD used may influence right ventricular myocardial changes. Methods: We determined the changes that occurred on right ventricular structure following LVAD support by measuring myocyte size, TNFa and total collagen content by semi-quantitative immunohistochemistry on myocardial samples from the right and left ventricles of control, failing, and myocardium supported by two distinct forms of LVADs. We found that when compared with control, while myocyte size was not increased in the RV of failing mycardium (22.5 1.6 m vs. 18.2 1.1 m, p ns), both total collagen content (27.6 2.9% vs. 13.2 0.7%, p 0.001), and TNFa levels were increased (35.4 2.8% vs. 1.2 0.4%, p 0.001). Following LVAD support there was a significant reduction in collagen content (20.4 1.1% vs. 27.6 2.9%, p ns and 14.3 1.4% vs. 27.6 2.9%, p 0.01 for pulsatile vs. none and continuous vs. none, respectively) and TNFa levels (3.0 0.5% vs. 35.4 2.8%, p 0.001 and 0.8 0.1% vs. 35.4 2.8%, p 0.001 for pulsatile vs. none and continuous vs. none, respectively) on the right ventricle. Results: This data demonstrates that chronic left ventricular unloading reduces right ventricular collagen and TNFa content. We suggest that the reduction of fibrosis and normalization of cytokine milieu observed may in part contribute to the recovery of right-sided cardiac function associated with chronic mechanical circulatory support.

The Effect of Cytokines on Cardiac Allograft Function: Tumor Necrosis Factor α a Mediator of Chronic Injury

Cardiac transplantation has evolved as the treatment of choice for the patient with advanced heart failure. However, the long-term survival of heart transplant recipients is limited by the development of complications associated with the immune response against the graft or complications that result from long-term use of immunosuppressive therapy. Despite the fact that cardiac transplantation represents the only treatment modality that radically alters the prognosis of the terminally ill heart failure patient, the function of the transplanted heart is not normal. For example, only 27% of heart transplant recipients are able to return to work full-time; while their functional class and exercise tolerance is better than prior to transplantation, it is not normal [1]. The mechanisms for abnormal graft function are the rapid progression of coronary arteriopathy and the development of left ventricular hypertrophy, which eventually leads to cardiac failure. In this review, we will discuss the potential effects of acute and chronic injury by cytokines expressed in the allograft.