Decreased expression of tumor necrosis factor-alpha and regression of hypertrophy after nonsurgical septal reduction therapy for patients with hypertrophic obstructive cardiomyopathy.

BACKGROUND: Nonsurgical 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)-alpha, a cytokine capable of producing fibrosis, left ventricular hypertrophy (LVH), and cardiomyopathy. METHODS AND RESULTS: We 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-alpha levels. At baseline, myocardial TNF-alpha levels were increased in all patients. After NSRT, myocyte size, collagen content, and TNF-alpha were significantly decreased. These changes were accompanied by an increase in left ventricular volumes and a reduction in LVH and chamber stiffness. CONCLUSIONS: We suggest that pressure overload in HOCM patients contributes to the development of hypertrophy. These data provide the initial experimental evidence to suggest that TNF-alpha may play a pathogenetic role in the hypertrophy of pressure overload.

Decreased expression of tumor necrosis factor-alpha in failing human myocardium after mechanical circulatory support : A potential mechanism for cardiac recovery.

BACKGROUND: An increasing number of observations in patients with end-stage heart failure suggest that chronic ventricular unloading by mechanical circulatory support may lead to recovery of cardiac function. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine capable of producing pulmonary edema, dilated cardiomyopathy, and death. TNF-alpha is produced in the myocardium in response to volume overload; however, the effects of normalizing ventricular loading conditions on myocardial TNF-alpha expression are not known. We hypothesize that chronic ventricular unloading by the placement of a left ventricular assist device (LVAD) may eliminate the stress responsible for persistent TNF-alpha expression in human failing myocardium. METHODS AND RESULTS: Myocardial tissue was obtained from normal hearts and from paired samples of 8 patients with nonischemic end-stage cardiomyopathy at the time of LVAD implantation and removal. Tissue sections were stained for TNF-alpha, and quantitative analysis of the stained area was performed. We found that TNF-alpha content decreased significantly after LVAD support. Furthermore, the magnitude of the changes did not correlate with the length of LVAD support, although greater reductions in myocardial TNF-alpha content were found in patients who were successfully weaned off the LVAD who did not require transplantation. CONCLUSIONS: These data show for the first time that chronic mechanical circulatory assistance decreases TNF-alpha content in failing myocardium; furthermore, we suggest that the magnitude of the change may predict which patients will recover cardiac function.

Cardiac hypertrophy after transplantation is associated with persistent expression of tumor necrosis factor-alpha.

BACKGROUND: The mechanisms that contribute to cardiac allograft hypertrophy are not known; however, the rapid progression and severity of hypertrophy suggest that nonhemodynamic factors may play a contributory role. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine produced in cardiac allografts and capable of producing hypertrophy and fibrosis; therefore, we suggest that TNF-alpha may play a contributory role. Accordingly, the aims of our study were to define the role of systemic hypertension in the development of hypertrophy, characterize the histological determinants of hypertrophy, and characterize the expression of myocardial TNF-alpha after heart transplantation. METHODS AND RESULTS: To separate the effect of hypertension from immune injury in the development of cardiac allograft hypertrophy, we measured the gain in left ventricular mass by 2D echocardiography in heart transplant recipients and lung transplant recipients who developed similar rates of systemic hypertension. The gain in left ventricular mass was 73% in heart transplant recipients and 7% in lung transplant recipients (P<0.0001). By comparing myocardial samples obtained during the first week after transplant and at 1 year, we found that there was a significant increase in total collagen content (P<0.0001), collagen I (P<0.0001), collagen III (P<0.0001), and myocyte size (P<0.0001). These changes were associated with persistent myocardial TNF-alpha expression. CONCLUSIONS: We suggest that the contribution of hypertension to cardiac allograft hypertrophy is minimal and that persistent intracardiac expression of TNF-alpha may contribute to the development of cardiac allograft hypertrophy.

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.

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.

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.

[Heterotopic heart transplantation: 13-year experience at the Methodist Hospital of the Baylor Medical College]. / Trasplante cardiaco heterotópico: experiencia de trece años en el Hospital Metodista del Colegio de Medicina de Baylor.

UNLABELLED: In order to evaluate our experience in heterotopic cardiac transplantation, we conducted a retrospective analysis of the clinical files of patients who underwent this procedure. RESULTS: A total of 405 heart transplants were performed in our institution. In 24 (5.9%), the grafts were placed heterotopically. In group I (12 patients), the indication was irreversible pulmonary hypertension and in group II (remaining 12 patients), it was marginal grafts or size mismatch. Both groups demonstrated similar demographics and the survival rate was slightly better in group I. Nine patients from group I demonstrated an early reduction in pulmonary pressures which normalized in one year. CONCLUSIONS: The heterotopic heart supports the function of the native ventricles. In 9 patients, the heterotopic heart enables the reversal of a state of pulmonary hypertension previously thought to be irreversible. This finding supports the use of pulmonary vaso-dilators on a chronic basis or the use of a left ventricular assist device pre-transplant with the intention of normalizing pulmonary pressures and allowing the patients to become candidates for orthotopic cardiac transplantation and thereby avoiding the necessity of heterotopic cardiac transplantation.

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-alpha: a mediator in the pathogenesis of cardiac insufficiency]. / Factor de necrosis tumoral-alpha: un mediador en la patogénesis de la insuficiencia cardiaca.

An increasing body of experimental and clinical work suggesting that tumor necrosis factor alpha plays a pathogenic role in heart failure continues to accumulate. This cytokine is produced in failing but not in normal hearts and experimentally, it's expression is induced by hemodynamic conditions of pressure or volume overload. Specific receptors for this cytokine are present in the heart and dynamic regulation in tumor necrosis factor receptor expression occurs in failing myocardium. In addition, tumor necrosis factor alpha may exert major cardiac effects that contribute to the development of the failing phenotype: induces negative contractil dysfunction, promotes fibrosis, induces cardiomyopathy in experimental animals and it is a major mediator of apoptosis in vivo and in vitro. The knowledge gained from studying the role of tumor necrosis factor alpha in cardiac function draws attention to a series of molecules previously unrecognized as potential mediators in the pathogenesis of heart failure.