Showing papers by "Guillermo Torre-Amione published in 2004"

Altered Titin Expression, Myocardial Stiffness, and Left Ventricular Function in Patients With Dilated Cardiomyopathy

Abstract: Background—The role of the giant protein titin in patients with heart failure is not well established. We investigated titin expression in patients with end-stage heart failure resulting from nonischemic dilated cardiomyopathy, in particular as it relates to left ventricular (LV) myocardial stiffness and LV function. Methods and Results—SDS-agarose gels revealed small N2B (stiff) and large N2BA (compliant) cardiac titin isoforms with a mean N2BA:N2B expression ratio that was significantly (P0.003) increased in 20 heart failure patients versus 6 controls. However, total titin was unchanged. The coexpression ratio was highest in a subsample of patients with an impaired LV relaxation pattern (n7), intermediate in those with pseudonormal filling (n6), and lowest in the group with restrictive filling (n7). Mechanical measurements on LV muscle strips dissected from these hearts (n8) revealed that passive muscle stiffness was significantly reduced in patients with a high N2BA:N2B expression ratio. Clinical correlations support the relevance of these changes for LV function (assessed by invasive hemodynamics and Doppler echocardiography). A positive correlation between the N2BA:N2B titin isoform ratio and deceleration time of mitral E velocity, A wave transit time, and end diastolic volume/pressure ratio was found. These changes affect exercise tolerance, as indicated by the positive correlation between the N2BA:N2B isoform ratio and peak O2 consumption (n10). Upregulated N2BA expression was accompanied by increased expression levels of titin-binding proteins (cardiac ankyrin repeat protein, ankrd2, and diabetes ankyrin repeat protein) that bind to the N2A element of N2BA titin (studied in 13 patients). Conclusions—Total titin content was unchanged in end-stage failing hearts and the more compliant N2BA isoform comprised a greater percentage of titin in these hearts. Changes in titin isoform expression in heart failure patients with dilated cardiomyopathy significantly impact diastolic filling by lowering myocardial stiffness. Upregulation of titin-binding proteins indicates that the importance of altered titin expression might extend to cell signaling and regulation of gene expression. (Circulation. 2004;110:155-162.)

The hemodynamic and neurohormonal effects of low doses of tezosentan (an endothelin A/B receptor antagonist) in patients with acute heart failure

Abstract: Background: In previous studies (the RITZ project), tezosentan, an intravenous (i.v.)-balanced dual endothelin (ET-A/B) antagonist, in doses of 50 and 100 mg/h, improved the hemodynamics but not the clinical outcome of patients with acute heart failure (AHF). Objective: To evaluate the effect of lower doses of tezosentan in patients with AHF. Subjects and methods: Included were 130 patients hospitalized due to AHF with dyspnea at rest, despite initial treatment, and were in need of hemodynamic monitoring with cardiac index (CI)<2.5 l/min/m2 and wedge pressure≥20 mm Hg. Patients were randomized in a double-blind fashion to receive placebo or tezosentan: 0.2, 1, 5, or 25 mg/h for 24 h. Results: The primary endpoint of the study, CI increase at 6 h of treatment, was significant in the 5 and 25 mg/h groups. Tezosentan induced a dose-dependent increase in CI and a decrease in wedge pressure, peaking after 3 h in the 5 and 25 mg/h groups. In the 1-mg/h group, this effect was smaller during the first 6 h and increased gradually, becoming significant at 24 h and beyond treatment discontinuation. There was no hemodynamic effect in the 0.2 mg/h arm. Type-B natriuretic peptide (BNP) decreased in the 1, 5, and 25 mg/h groups but not on placebo. Endothelin levels were significantly increased by the 5 and 25 mg/h groups but not in the lower (≤1 mg/h) tezosentan doses. Urine output decreased on the 25-mg/h dose. There was a trend towards improvement in patients' subjective dyspnea score and worsening heart failure events, mainly in the 1 mg/h group. Conclusions: In patients admitted with AHF, tezosentan doses of 1–25 mg/h are efficacious in improving the hemodynamics and reducing BNP. Tezosentan doses beyond 1 mg/h increased plasma endothelin levels and reduced urine output, probably limiting their clinical efficacy, as compared to tezosentan 1 mg/h.

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

Abstract: 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 α (TNF-α) 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-α 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-α levels were decreased in the right ventricle compared with controls ( p p Conclusion: These data demonstrate that chronic left ventricular unloading with either pulsatile or continuous-flow devices decreases right ventricular total collagen and myocardial TNF-α 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.

Simvastatin decreases myocardial tumor necrosis factor α content in heart transplant recipients

Abstract: 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 α (TNF-α) expression; TNF-α 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-α 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-α 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-α 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-α expression. This decrease did not translate into a difference in the markers of hypertrophy. However, decreased myocardial TNF-α may be a marker of a general statin-mediated decrease in inflammation in the transplanted heart that leads to improved graft and patient survival.

Aldosterone antagonism and congestive heart failure: a new look at an old therapy.

Abstract: PURPOSE OF REVIEW More than 5 million people in the United States alone have congestive heart failure, and an estimated 40 million have established risks and warrant therapy. Mineralocorticoid antagonists have emerged as a new paradigm for the treatment of congestive heart failure. They have established benefits among patients with chronic symptomatic systolic dysfunction, and recent studies have demonstrated substantial effect on the morbidity and mortality among patients with heart failure after myocardial infarction. The exact biologic mechanism is thus far unknown. RECENT FINDINGS Within the last 5 years, efforts have intensified to help define better the biologic mechanisms by which mineralocorticoid receptor antagonisms exert the observed clinical benefit. Elegant human studies have demonstrated some important observations. First, under conditions of increased plasma aldosterone concentrations, the heart will extract aldosterone. Second, aldosterone extraction in the heart stimulates increased collagen turnover culminating in ventricular remodeling. Third, among people with chronic systolic or diastolic heart failure, aldosterone is actually produced and secreted by the heart. Finally, antagonism of the mineralocorticoid receptor will attenuate or abrogate many of these deleterious effects. SUMMARY Combined clinical and detailed mechanistic investigations have established mineralocorticoid receptor antagonism as the new treatment paradigm for congestive heart failure. Recent clinical data have demonstrated that treatment of patients with a combination of mineralocorticoid receptor antagonism (eplerenone) and angiotensin converting enzyme-inhibitor (ACE-I) results in substantial reduction in left ventricular mass. Furthermore, a federally funded initiative to treat more than 6000 patients with diastolic heart failure with spironolactone is in its final phases of planning. It is foreseeable that, along with ACE-I and beta-blockers, mineralocorticoid receptor antagonism will become part of the treatment paradigm for people across the entire spectrum of cardiovascular disease.

Betreuung von patienten an linksventrikulären unterstü tzungssystemen mittels koordinator: Erfahrungen des Methodist DeBakey Heart Centers

Abstract: Linksventrikulare mechanische Supportsysteme, left ventricular assist devices oder kurz LVAD, erlauben, Patientien mit terminalen Herzversagen bis zur Transplantation zu unterstutzen. Dies hat positiven Einfluss zum einen auf die Uberlebensrate als auch auf mogliche peri-operative Komplikationen. Wir berichten uber unsere Erfahrungen mit einem LVAD-Koordinator, insbesondere hinsichtlich Patientengenesung und Inzidenz an Komplikationen. In der Zeit vom Juni 2000 und Januar 2002 erhielten 28 Patienten mit terminaler therapierefrakterer Herzinsuffizienz ein linksventrikulares Assist Device, 14 Patienten in der Zeit vor Einsatz eines LVAD-Koordinators und weitere 14 Patienten unter der Betreuung eines LVAD-Koordinators. Die untersuchten Kriterien waren dabei Auftreten von Infektionen, lebensbedrohlichen Thromboembolien, Blutungsereignissen und Kostenaufwand, definiert als reine Krankenhauskosten ohne Personal- und Materialkosten. In der Pra-Koordinator-Gruppe wurden 2 Patienten mit Ihrem LVAD nach Hause entlassen, 7 Patienten (50%) entwickelten eine therapiepflichtige Infektion, 5 Patienten (35%) hatten lebensbedrohliche thrombembolische Komplikationen. 6 Patienten aus dieser Gruppe wurden transplantiert und 8 Patienten verstarben an dem Unterstutzungssystem, woraus sich eine Uberlebensrate von 42% errechnet. In der von einem LVAD-Koordinator betreuten Patientengruppe wurden 7 Patienten mit ihrem LVAD nach Hause entlassen, 4 Patienten entwickelten Infektionen und 1 Patient cerebrale Thrombembolien mit irreversiblen neurologischen Schaden. 10 Patienten wurden transplantiert, 3 Patienten verstarben am Assist Device und 1 Patient war bei Studienende noch am Assist Device. Die Uberlebensrate in dieser Gruppe war 78%. Der Einsatz eines LVAD-Koordinators fur die Betreuung von an linksventrikularen Assist Devices befindlichen Patienten trug in unserem Patienten-Kollektiv zu einer hoheren Uberlebensrate, niedrigeren Komplikationsrate und auch niedrigeren Krankenhauskosten bei.

The response of the failing heart to chronic mechanical unloading.

Abstract: PURPOSE OF REVIEW The authors present a comprehensive analysis of the evidence in support of improvements at the cellular, structural, and hemodynamic levels after left ventricular assist device support. RECENT FINDINGS The use of left ventricular assist devices as a strategy to bridge patients to cardiac transplantation and, more recently, as a form of destination therapy has provided a great opportunity to study failing myocardium at various time points. Specifically, myocardial samples can be obtained from patients at the time of left ventricular assist device implantation and again at explant, thereby allowing comparisons between paired samples of failing myocardium obtained before and after mechanical unloading. SUMMARY A body of knowledge has been generated that illustrates the ability of the myocardium to "heal." This information may give us better insight into cellular and molecular mechanisms of heart failure and potential new therapies for patients with end-stage heart failure.