Cellular and hemodynamics responses of failing myocardium to continuous flow mechanical circulatory support using the DeBakey-Noon left ventricular assist device: a comparative analysis with pulsatile-type devices.

BACKGROUND: An increasing number of continuous flow pumps are currently under clinical studies, however very little data exist on the hemodynamic and cellular responses of the failing heart to continuous flow support. The purpose of this investigation was to characterize the response of the failing myocardium to continuous flow support. METHODS: We compared echocardiographic and cellular markers of failing myocardium at the time of left ventricular assist device (LVAD) implantation and explantation in 20 consecutive patients (12 pulsatile flow [Novacor] and 8 continuous flow [DeBakey-Noon]). RESULTS: The use of mechanical support with both continuous- or pulsatile-type LVADs resulted in a reduction of left ventricular end-diastolic dimension (LVEDD), end-diastolic volume (EDV), end-systolic volume (ESV) and left atrial volume (LAV), as well as a decrease in mitral E/A ratio, tricuspid regurgitation velocity (TRV) and pulmonary valve acceleration time (PVAT). Comparative analyses for patients treated with a continuous- vs pulsatile-type LVAD support showed a greater degree of unloading with the latter type, as shown by the effect on LVEDD (-13.7% vs -33.7%, p = 0.0.004), EDV (-23.5% vs -41.2%, p = 0.015), ESV (-25.6% vs -57.6%, p = 0.001) and LAV (-25.2% vs -40.4%, p = 0.071). The hemodynamic effects of continuous vs pulsatile LVAD support were similar, as shown by their effect on mitral E/A ratio (-23.9% vs -39.9%, p = NS), TRV (-26.4% vs -23.8%, p = NS) and PVAT (28.5% vs 38.5%, p = NS). Only pulsatile support demonstrated a statistically significant percent change in mass (-6.3% vs -20.6%, p = 0.038). Continuous and pulsatile forms of mechanical support demonstrated equivalent reductions in myocardial tumor necrosis factor-alpha (TNF-alpha), total collagen and mycocyte size. CONCLUSIONS: Our findings show that, although there are differences between these 2 devices in magnitude of unloading, both forms of support effectively normalize cellular markers of the failing phenotype.

Simvastatin decreases myocardial tumor necrosis factor alpha content in heart transplant recipients.

BACKGROUND: Statins improve patient survival and decrease rejection episodes in heart transplant recipients. We studied the effects of simvastatin treatment on myocardial tumor necrosis factor alpha (TNF-alpha) expression; TNF-alpha is a potent pro-inflammatory cytokine associated with hypertrophy and fibrosis in heart transplant recipients. METHODS: We randomized 10 consecutive heart transplant recipients to receive either 20 mg/day simvastatin (n = 5) or placebo (n = 5) for 6 months after cardiac transplantation. Routine surveillance endomyocardial biopsy specimens were obtained from all patients. We analyzed tissues for myocardial TNF-alpha content, total collagen content, and myocyte size using semiquantitative immunohistochemistry. RESULTS: Myocyte size and total collagen content of placebo and simvastatin groups did not show a statistically significant difference at any biopsy time point. Myocardium TNF-alpha content (% tissue area stained) at 1 week after transplantation was similar in the simvastatin and placebo groups. At the 24(th) week after transplantation, when compared with Week 1 values, we found a significant decrease in myocardium TNF-alpha content in the simvastatin group (15.0% +/- 2.3% vs 5.8% +/- 2.4%, p = 0.02) that was not observed in the placebo group (15.0% +/- 1.5% vs 12.0% +/- 2.6%, p = not significant). CONCLUSION: Simvastatin treatment in heart transplant recipients decreased myocardium TNF-alpha expression. This decrease did not translate into a difference in the markers of hypertrophy. However, decreased myocardial TNF-alpha may be a marker of a general statin-mediated decrease in inflammation in the transplanted heart that leads to improved graft and patient survival.

Molecular normalization of dystrophin in the failing left and right ventricle of patients treated with either pulsatile or continuous flow-type ventricular assist devices.

OBJECTIVES: We investigated the integrity of dystrophin in left ventricle (LV) and right ventricle (RV) of patients with end-stage heart failure due to ischemic cardiomyopathy (IHD) or dilated cardiomyopathy (DCM), and compared the efficacy of pulsatile or continuous flow assist devices on dystrophin reverse remodeling. BACKGROUND: Recently we demonstrated that the amino (N)-terminus of dystrophin is preferentially disrupted in failing LV myocardium irrespective the underlying etiology, and that this defect is reversed by mechanical unloading using left ventricular assist device (LVAD) therapy. METHODS: Myocardial samples were obtained from seven normal controls, seven failing hearts (either DCM or IHD), and 14 failing-heart patients who underwent placement of either pulsatile (7 patients) or continuous flow (7 patients) LVADs for progressive refractory HF. The expression and integrity of dystrophin in these samples were determined by immunohistochemistry using antibodies against the N-terminal and carboxyl (C)-terminal domains. RESULTS: Immunohistochemical staining identified disruption of the N-terminal dystrophin in both LVs and RVs of all seven failing-heart patients, whereas the C-terminus was normal. Furthermore, this disruption was reversed in 12 of the 14 patients after LVAD therapy using either pulsatile or continuous devices; the degree of the reverse remodeling was similar in both ventricles, although greater recovery was noted in patients treated with pulsatile flow devices. CONCLUSIONS: Integrity of the N-terminus of dystrophin is a useful indicator of both LV and RV function. In addition to improving LV hemodynamics, LVAD therapy results in amelioration of the myocardial structure of the right cardiac chamber.

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.

Dobutamine stress echocardiography predicts myocardial improvement in patients supported by left ventricular assist devices (LVADs): hemodynamic and histologic evidence of improvement before LVAD explantation.

BACKGROUND: Cardiac function may improve in patients with end-stage heart failure who receive long-term support (>30 days) with left ventricular assist devices (LVADs). Dobutamine stress echocardiography (DSE) has been used to quantitate myocardial recovery in patients with heart failure supported with LVADs. By recording the hemodynamic response with the use of DSE, we evaluated and applied the resulting data to patients receiving LVAD support. METHODS AND RESULTS: The study population included 16 patients who underwent LVAD implantation, regained functional capacity on full LVAD support, and tolerated decreased mechanical support with no worsening of dyspnea or fatigue. All 16 patients underwent dobutamine stress with increasing doses of dobutamine (from 5 to 40 mcg/kg/min). Hemodynamics and 2-dimensional (2-D) echocardiography was performed at each dose level. In addition, paired myocardial samples were obtained and analyzed histologically to determine myocyte size and collagen content. Dobutamine stress separated the study population into 2 groups: those who had favorable responses to dobutamine (9/16) and those who had unfavorable responses (i.e., experienced hemodynamic deterioration; 7/16). Favorable dobutamine responses were characterized by improved cardiac index, improved force-frequency relationship in the left ventricle (dP/dt), improved left ventricular ejection fraction, and decreased left ventricular end-diastolic dimension. All 9 favorable responders underwent LVAD explantation, and 6 survived for more than 12 months. In all patients studied, LVAD support resulted in decreased myocyte size (n = 14, 33.9 +/- 0.9 microm before vs 16.6 +/- 0.8 microm after support, p = 0.0001; normal, 5-15 microm) but resulted in no consistent changes in collagen content. CONCLUSIONS: Dobutamine stress echocardiography with hemodynamic assessment may be a useful tool in assessing physiologic improvement in myocardial function of patients with end-stage heart failure who receive LVAD support. It may help predict which patients can tolerate LVAD removal. Prospective analysis of cardiac function is now warranted to better define myocardial recovery in patients supported with LVADs.

The role of tumor necrosis factor alpha blockade in the treatment of congestive heart failure.

The experimental evidence in support of the role of tumor necrosis factor in heart failure stems from the observations that tumor necrosis factor exerts negative inotropic effects and is capable of promoting fibrosis, hypertrophy, and cardiomyopathy in animal models. More importantly, cardiac specific tumor necrosis factor levels are regulated by pressure and volume load in animals and in humans. Therefore, a series of clinical small trials were conducted with etanercept, a highly specific anti-tumor necrosis factor-blocking agent that indicated a potential therapeutic role. However, two large randomized clinical trials powered to determine the effect of etanercept and infliximab on mortality have demonstrated no clinical benefit. The explanation of those findings are not clear; however, based on the strength of the experimental evidence one can conclude that perhaps other nonspecific approaches to manipulate the immune system may be of benefit.

The role of inflammation in the pathogenesis of heart failure.

Heart failure is not a simple defect in the pumping function of cardiac muscle, but rather a complex systemic inflammatory disease affecting many organ systems. Recognition of this fact has led to new therapeutic interventions such as angiotensin-converting enzyme inhibitors and beta-blockers, which have a significant impact on the quality of life and survival of patients with heart failure. During the course of heart failure, the steps involved in the activation of inflammation are now better understood. As a result, new therapies will develop that block, modify, or prevent these inflammatory changes, and supplement our armamentarium for providing better and longer lives for patients.

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.

Trasplante cardiaco heterotópico: experiencia de trece años en el Hospital Metodista del Colegio de Medicina de Baylor / Heterotopic cardiac transplantation. A thirteen years experience at Baylor Methodist Hospital

Para evaluar la experiencia en nuestra institución, realizamos un análisis retrospectivo de los expedientes clínicos de pacientes sometidos a trasplante cardiaco heterotópico. Resultados: De 405 trasplantes cardiacos realizados, en 24 (5.9 por ciento), el injerto fue colocado en posición heterotópica. En 12 pacientes, la indicación fue hipertensión pulmonar irreversible (grupo I) y en los 12 restantes, la obtención de órganos marginales o diferencias en superficie corporal (grupo II). Ambos grupos mostraron características demográficas similares y la tasa de sobrevida fue discretamente superior en el grupo 1. Nueve pacientes del grupo I mostraron una reducción temprana de las presiones pulmonares, con normalización de las mismas a un año. Conclusiones: El trasplante cardiaco heterotópico permite la asistencia de la función de ambos ventriculos nativos por los ventrículos del injerto. En nueve pacientes, el trasplante cardiaco heterotópico propició la reversión de un estado de hipertensión pulmonar, previamente considerado como irreversible. Tal hallazgo, nos obliga a utilizar crónicamente vasodilatadores pulmonares o sistemas de asistencia ventricular izquierda en dichos pacientes previo al trasplante. Así se intenta normalizar tales presiones y convertirlos en candidatos para un trasplante cardiaco ortotópico, evitando asi, las inconveniencias del trasplante cardiaco heterotópico. Por supuesto, tal conducta reducirá la utilización de este procedimiento en el futuro

Factor de necrosis tumoral-Ó: Un mediador en la patogénesis de la insuficiencia cardiaca / Tumor necrosis factor-Ó. A mediator in the pathogenesis of heart failure

La evidencia clínica y experimental que sugiere que el factor de necrosis tumoral alfa desempeña un papel en la patogénesis de la insuficiencia cardiaca es cada vez mayor. El factor de necrosis tumoral alfa es producido en el miocardio insuficiente pero no en el normal y es inducido experimentalmente por condiciones hemodinámicas de sobrecarga de presión y/o volumen. La expresión de receptores específicos para ésta citocina se encuentra incrementada en el miocardio insuficiente. El factor de necrosis tumoral alfa induce disfunción contráctil, promueve fibrosis, induce cardiomiopatía en animales de experimentación y es un mediador de apoptosis in vivo e in vitro. Dichos efectos generan un fenotipo de miocardio insuficiente. El conocimiento alcanzado al analizar el papel de esta citocina en la función cardiaca dirige la atención a una serie de moléculas no reconocidas en el pasado como mediadores potenciales en la patogénesis de la insuficiencia cardiaca