Bariatric surgery improves cardiac function in morbidly obese patients with severe cardiomyopathy.

BACKGROUND: Longstanding morbid obesity can be associated with severe cardiomyopathy. However, the safety and efficacy of bariatric surgery in patients with severe cardiomyopathy has not been studied, and the effect of surgical weight loss on postoperative cardiac function is also unknown. In addition, morbidly obese patients have significantly increased mortality associated with cardiac transplantation, often precluding them from becoming recipients. METHODS: A retrospective study of patients with a left ventricular ejection fraction < or =35% who underwent bariatric surgery (1998-2005) was performed. Short-term morbidity/mortality, length of stay, excess weight loss, pre- and postoperative left ventricular ejection fraction, and New York Heart Association (NYHA) functional class were assessed. RESULTS: A total of 14 patients (10 men and 4 women) with a mean preoperative body mass index of 50.8 +/- 2.04 kg/m(2) underwent bariatric surgery (10 underwent laparoscopic Roux-en-Y gastric bypass, 1 open Roux-en-Y gastric bypass, 2 sleeve gastrectomy, and 1 laparoscopic gastric banding). The complications were pulmonary edema in 1, hypotension in 1, and transient renal insufficiency in 2. The median length of stay was 3.0 days (range 2-9). The mean excess weight loss at 6 months was 50.4%, with a decrease in the mean body mass index from 50.8 +/- 2.04 kg/m(2) to 36.8 +/- 1.72 kg/m(2). The mean left ventricular ejection fraction at 6 months had significantly improved from 23% +/- 2% to 32% +/- 4% (P = .04), correlating with improved functional capacity, as measured by the NYHA classification. Preoperatively, 2 patients (14%) had an NYHA classification of IV, 6 (43%) a classification of III, and 6 (43%) a classification of II. At 6 months postoperatively, no patient had an NYHA classification of IV, 2 (14%) had a classification of III, and 12 (86%) an NYHA classification of II. Two patients had undergone cardiac transplant evaluations preoperatively and underwent successful transplantation after weight loss. CONCLUSION: The results of our study have shown that bariatric surgery for patients with cardiomyopathy is feasible and effective. Surgically induced weight loss results in both subjective and objective improvement in cardiac function. In addition, surgical weight loss can provide a bridge to transplantation in patients who were prohibited secondary to their morbid obesity.

Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts.

Sequestration of tumor necrosis factor-alpha (TNFalpha) by TNF-receptor immunoglobulin G (IgG)-Fc fusion proteins can limit heart failure progression in rodent models. In this study we directly injected an adeno-associated viruses (AAV)-2 construct encoding a human TNF receptor II IgG-Fc fusion protein (AAV-TNFRII-Fc) into healthy baboon hearts and assessed virally encoded gene expression and clinical response. Adult baboons received direct cardiac injections of AAV-TNFRII-Fc ( approximately 5 x 10(12) viral/genomes/baboon) or an equivalent dose of AAV-2 empty capsids, and were analyzed after 5 or 12 weeks. Viral genomes were restricted to the myocardium, and routine analyses (blood cell counts, clinical chemistries) remained unremarkable. Echocardiograms were unchanged but electrocardiograms revealed marked ST- and T-wave changes consistent with myocarditis only in baboons receiving AAV-TNFRII-Fc. TNFRII serum levels peaked at approximately 3 times the baseline levels at 1-2 weeks postinjection and subsequently declined to baseline levels. TNFRII-Fc protein and transcripts were detected in the heart at harvest. After AAV injection, anti-AAV-2 antibody levels increased in all baboons, while anti-TNFRII-Fc could not be detected. Baboons that received AAV-TNFRII-Fc developed myocardial infiltrates including CD8+ cells. Thus, a cellular immune response to cardiac delivery of AAV encoding foreign proteins may be an important consideration for AAV-based cardiac gene therapy.

Role of cardiac nerves in the cardiovascular response to cocaine in conscious dogs.

BACKGROUND: Although the cardiovascular toxicity of cocaine is well recognized, considerable controversy remains as to the relative contribution of local norepinephrine reuptake inhibition versus central stimulatory effects of cocaine in eliciting its cardiovascular actions. The purpose of the present study was to determine the role of cardiac nerves in mediating the left ventricular (LV) and coronary hemodynamic responses to cocaine. METHODS AND RESULTS: We studied the cardiovascular response to acute cocaine administration (1 mg/kg) in 10 intact, conscious dogs and 6 dogs with ventricular denervation (VD). There were no significant differences in baseline hemodynamic parameters or plasma catecholamines between the 2 groups. In response to acute cocaine, LV and coronary hemodynamic responses were enhanced in the VD dogs. The enhanced systemic pressor and heart rate responses in VD dogs suggest that cardiac nerves mitigate the response to cocaine through ventricular mechanoreceptors rather than mediating the responses. CONCLUSIONS: These data suggest that peripheral blockade of norepinephrine reuptake is not the principal mechanism of the acute cardiac effects of cocaine. Rather, cardiac nerves modulate the effects of cocaine through baroreflex mechanisms. Thus, individual differences in baroreflex sensitivity may explain the hemodynamic variability observed in response to cocaine.

Coronary vascular responses to short-term cocaine administration in conscious baboons compared with dogs.

OBJECTIVES: Cardiovascular complications of cocaine use represent an important clinical problem, yet the mechanisms by which cocaine predisposes to myocardial ischemia are poorly understood. BACKGROUND: The effects of cocaine on the coronary circulation have been studied extensively in experimental animal models, but have failed to recapitulate the clinical findings reported in humans who use cocaine. METHODS: We studied 12 conscious, chronically instrumented dogs and 5 conscious, chronically instrumented baboons to determine whether there were important species differences in the response to cocaine. RESULTS: Comparable doses of intravenous cocaine caused similar increases in left ventricular systolic, diastolic and mean arterial pressure in the two species. However, the peak coronary blood flow response in baboons (+8 +/- 3 from 47 +/- 6 ml/min) was less compared with dogs (+15 +/- 4 from 41 +/- 4 ml/min), while the coronary vascular resistance response was greater in baboons (+0.60 +/- 0.09 from 1.94 +/- 0.09 mm Hg/ml/mm) compared with dogs (+0.35 +/- 0.09 from 2.24 +/- 0.10 mm Hg/ml/min). Although myocardial oxygen consumption responses were similar between species, there was a significant difference (p < 0.05) in oxygen delivery between baboons (+164 +/- 47 from 705 +/- 59 ml of oxygen per minute) and dogs (+397 +/-51 from 656 +/- 33 ml of oxygen per minute) that was attributable to a significant (p < 0.05) increase in hemoglobin concentration in dogs (+2.1 +/- 0.5 g/dl) that was not observed in baboons. Consequently, cocaine caused a significant increase in myocardial oxygen extraction and decreased coronary sinus pH in baboons, but not dogs. CONCLUSIONS: Cocaine caused greater coronary vasoconstriction and greater requirements for oxygen extraction in baboons compared with dogs.

Dilated cardiomyopathy associated with simian AIDS in nonhuman primates.

BACKGROUND: Cardiomyopathy is being recognized with increasing frequency in patients with AIDS, yet the relationship between HIV infection and cardiac contractile dysfunction remains obscure. The purpose of the present study was to determine if infection with simian immunodeficiency virus (SIV) in nonhuman primates is associated with cardiac dysfunction and myocardial injury. METHODS AND RESULTS: Left ventricular size and function were determined by 2D echocardiography in 16 rhesus macaques before and at weekly intervals following infection with cloned pathogenic SIV(mac) 239 or the highly attenuated SIV(mac) 239 nef deletion mutant. A second group of 15 rhesus macaques chronically infected with pathogenic (n=6) or nonpathogenic (n=9) virus were studied at >2 years following infection. Cardiac tissues from 24 rhesus macaques chronically infected (>2 years) with pathogenic SIV were reviewed for evidence of cardiac pathology. Acute infection (<6 weeks) with either pathogenic or nonpathogenic SIV caused neither contractile dysfunction nor cardiac pathology. However, LV ejection fraction was significantly (P<0.05) depressed (43+/-7%) in rhesus macaques chronically infected with pathogenic SIV compared with rhesus macaques chronically infected with nonpathogenic SIV (61+/-3%). Furthermore, two thirds of rhesus macaques that succumbed to simian AIDS had myocardial pathology including lymphocytic myocarditis (n=9) and coronary arteriopathy (n=6), with complete vessel occlusion (n=4) and associated myocardial infarction and necrosis. CONCLUSIONS: This unique model is valuable in understanding the pathogenesis of cardiac injury associated with retroviral infection in a relevant nonhuman primate model of AIDS.

Progressive loss of myocardial ATP due to a loss of total purines during the development of heart failure in dogs: a compensatory role for the parallel loss of creatine.

BACKGROUND: Whether myocardial ATP content falls in heart failure is a long-standing and controversial issue. The mechanism(s) to explain any decrease in ATP content during heart failure have not been identified. METHODS AND RESULTS: Cardiac dysfunction, heart failure, and a prolonged steady state of heart failure were induced by chronic right ventricular pacing for 1 to 2 weeks, 3 to 4 weeks, and 7 to 9 weeks in dogs. Cardiac function and myocardial O(2) consumption (Mf1.gif" BORDER="0">O(2)) were measured with the dogs in the conscious state. ATP, total purine, and creatine were measured in biopsy specimens obtained at each stage. ATP and the total purine pool progressively fell at rates of 0.12 and 0.15 nmol. mg protein(-1). d(-1), despite an increase in Mf1.gif" BORDER="0">O(2). The rate of loss of creatine was 1.06 nmol. mg protein(-1). d(-1), 7 times faster than the depletion of total purine. CONCLUSIONS: (1) ATP contents progressively decreased during heart failure as a result of a loss of the total purine pool. The loss of purines may be due to inhibition of de novo purine synthesis. (2) Loss of creatine is an early marker of heart failure and may serve as a compensatory mechanism minimizing the reduction of the total purine pool in the failing heart.

Lack of desensitization and enhanced efficiency of calcium channel promoter in conscious dogs with heart failure.

The goal of this study was to compare responses to a calcium promoter, BAY y 5959, and dobutamine (Dob) in heart failure (HF). Dogs (n = 9) were chronically instrumented and studied in the conscious state before and after pacing-induced HF. In the control state, BAY y 5959 (20 microgram. kg-1. min-1) increased the first derivative of left ventricular (LV) pressure (dP/dt) by 83 +/- 8% and mean arterial pressure (MAP) by 8 +/- 2% and decreased heart rate (HR) by 30 +/- 3%. With Dob (10 microgram. kg-1. min-1) LV dP/dt rose similarly (+80 +/- 6%), but HR also rose (+25 +/- 4%) (P < 0.05 vs. BAY y 5959). After HF developed, BAY y 5959 still increased LV dP/dt by 108 +/- 8% and MAP by 21 +/- 2% and decreased HR by 28 +/- 4%, whereas Dob increased LV dP/dt by only 50 +/- 7% (P < 0.05 vs. BAY y 5959) and MAP by 7 +/- 3%, and HR did not change (+3 +/- 3%) (P < 0.05 vs. BAY y 5959). In HF, cardiac work increased more (P < 0. 05) with BAY y 5959 (+105 +/- 13%) compared with Dob (+47 +/- 11%), yet myocardial oxygen consumption increased similarly with the two drugs. Accordingly, mechanical efficiency increased more (P < 0.05) with BAY y 5959 (+73 +/- 14%) than with Dob (+17 +/- 12%). These data indicate that 1) increases in contractility mediated directly by Ca2+ are relatively resistant to desensitization in HF; and 2) the calcium-channel promoter can produce increases in myocardial contractility and cardiac work similar to those of Dob at a significantly lower oxygen cost, thereby enhancing mechanical efficiency in HF.

Coronary endothelial dysfunction in patients with acute-onset idiopathic dilated cardiomyopathy.

OBJECTIVES: This study sought to determine whether coronary endothelial dysfunction exists in patients with acute-onset idiopathic dilated cardiomyopathy (DCM) and to explore its relation to recovery of left ventricular systolic function in this patient population. BACKGROUND: Coronary endothelial dysfunction exists in chronic DCM, but its importance in the development and progression of ventricular dysfunction is not known. To address this issue we studied coronary endothelial function in patients with idiopathic DCM <6 months in duration and explored the relation between coronary endothelial function and subsequent changes in left ventricular ejection fraction (LVEF). METHODS: Ten patients with acute-onset idiopathic DCM (duration of heart failure symptoms 2.0 +/- 0.4 months [mean +/- SEM]) and 11 control patients with normal left ventricular function underwent assessment of coronary endothelial function during intracoronary administration of the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator adenosine. Coronary cross-sectional area (CSA) was determined by quantitative coronary angiography and coronary blood flow (CBF) by the product of coronary CSA and CBF velocity measured by an intracoronary Doppler catheter. Patients with DCM underwent assessment of left ventricular function before and several months after the study. RESULTS: Acetylcholine infusion produced no change in coronary CSA in control patients but significant epicardial constriction in patients with DCM (-36 +/- 11%, p < 0.01). These changes were associated with increases in CBF in control patients (+118 +/- 49%, p < 0.01) but no change in patients with DCM. Infusion of adenosine produced increases in coronary caliber and blood flow in both groups. Follow-up assessment of left ventricular function was obtained in nine patients with DCM 7.0 +/- 1.7 months after initial study, at which time LVEF had improved by > or =0.10 in four patients. Multiple linear regression revealed a positive correlation between both the coronary CSA (r2 = 0.57, p < 0.05) and CBF (r2 = 0.68, p < 0.01) response to acetylcholine and the subsequent improvement in LVEF. CONCLUSIONS: Coronary endothelial dysfunction exists at both the microvascular and the epicardial level in patients with acute-onset idiopathic DCM. The preservation of coronary endothelial function in this population is associated with subsequent improvement in left ventricular function.

Left ventricular end-diastolic volume index, age, and maximum heart rate at peak exercise predict survival in patients referred for heart transplantation.

BACKGROUND: This study sought to define clinical predictors of survival in patients under consideration for heart transplantation and demonstrate possible improvements in the prediction of outcome when considering the identified predictors in addition to peak oxygen consumption. Peak oxygen consumption is currently the most important criterion for determining the timing and appropriateness of heart transplantation in ambulatory patients. METHODS: To identify other possible predictors of survival in patients with heart failure, we reviewed clinical, exercise, and radionuclide ventriculographic data on 112 patients referred for heart transplantation evaluation. Predictors of 1-year (n = 86) and overall (n = 112) survival to the combined end point of freedom from death or pretransplantation admission for inotropic or mechanical support were identified in multivariate analysis. RESULTS: The mean age was 51+/-9 years, and the mean duration of follow-up was 408+/-366 days. The mean left ventricular ejection fraction was 0.22+/-0.07, and the mean peak oxygen consumption was 12.3+/-3.7 ml/min/kg. Age (odds ratio 1.087, 95% confidence interval [CI] 1.021 to 1.157), percentage of the maximum predicted heart rate at peak exercise (odds ratio 0.958, 95% CI 0.924 to 0.992), and left ventricular end-diastolic volume index (odds ratio 1.019, 95% CI 1.006 to 1.033) were independent predictors of the 1-year combined end point. CONCLUSION: Age, heart rate at peak exercise, and left ventricular end-diastolic volume index are independent predictors of prognosis in patients with advanced heart failure and may provide additional prognostic information for the risk-stratification of potential heart transplant recipients.

beta-Arrestin1 knockout mice appear normal but demonstrate altered cardiac responses to beta-adrenergic stimulation.

beta-Arrestin1 knockout mice were studied to define the physiological role of beta-arrestin1 in the regulation of G protein-coupled receptors. beta-Arrestin1 is thought to be involved in the desensitization of many G protein-associated cell surface receptors, particularly beta-adrenergic receptors. Homozygous knockout mice are overtly normal. Resting cardiovascular parameters modulated by beta-adrenergic receptors such as heart rate, blood pressure, and left ventricular ejection fraction are not changed. However, homozygous mutants are more sensitive to beta-receptor agonist-stimulated increases in ejection fraction, consistent with a role of beta-arrestin1 in beta-adrenergic receptor desensitization. We conclude that beta-arrestin1 is important for in vivo G protein-coupled receptor desensitization and that this aspect of desensitization represents a mechanism for fine-tuning responses. However, beta-arrestin1 does not appear to be required for development or for other essential biological functions.

Effects of renin inhibition compared to angiotensin converting enzyme inhibition in conscious dogs with pacing-induced heart failure.

OBJECTIVE: To compare the effects of angiotensin converting enzyme inhibition (ACEI) (captopril 1 mg/kg i.v.) to direct renin inhibition (CP80794 3 mg/kg i.v.) on left ventricular and systemic hemodynamics and peripheral blood flows in advanced congestive heart failure (CHF). METHODS: Conscious chronically instrumented dogs (n = 14) were treated with captopril, 1 mg/kg, i.v., or CP80794, 3 mg/kg, i.v., before and after development of advanced CHF induced by 4-7 weeks of rapid ventricular pacing. After advanced CHF, comparisons between the inhibitors were made at equihypotensive doses. RESULTS: In advanced CHF, both agents caused comparable reductions in mean arterial pressure (MAP) (-22% from 79 +/- 4 mmHg) and comparable increases (P < 0.01) in cardiac output (CP80794, 1.4 +/- 0.3 to 1.8 +/- 0.1 l/min; captopril, 1.4 +/- 0.1 to 1.9 +/- 0.1 l/min). Neither agent had a significant effect on LV contractility. In contrast, CP80794 caused a greater (P < 0.05) increase in renal blood flow (66 +/- 6% from 64 +/- 5 ml/min) compared to captopril (33 +/- 4% from 66 +/- 7 ml/min). CONCLUSIONS: Renin inhibition with CP80794 and ACEI with captopril caused comparable hemodynamic effects in advanced CHF. However, CP80794 caused significantly greater increases in renal blood flow and suppressed renin activity to a greater degree than captopril.

The six-minute walk test predicts peak oxygen uptake and survival in patients with advanced heart failure.

BACKGROUND: The 6-min walk test (6'WT) is a simple measure of functional capacity and predicts survival in patients with moderate heart failure (HF). METHODS: To assess the role of the 6'WT in the evaluation of patients with advanced HF, 45 patients (age 49 +/- 8 years, mean +/- SD; New York Heart Association class 3.3 +/- 0.6; left ventricular ejection fraction 0.20 +/- 0.06; right ventricular ejection fraction 0.31 +/- 0.11) underwent symptom-limited cardiopulmonary exercise testing and the 6'WT during cardiac transplant evaluation. RESULTS: Mean 6'WT distance ambulated was 310 +/- 100 m and peak oxygen uptake (peak Vo2) was 12.2 +/- 4.5 mL/kg/min. There was a significant correlation between 6'WT distance ambulated and peak Vo2 (r = 0.64, p < 0.001). Multivariate analysis of patient characteristics, resting hemodynamics, and 6'WT results identified the distance ambulated during the 6'WT as the strongest predictor of peak Vo2 (p < 0.001). 6'WT distance ambulated less than 300 m predicted an increased likelihood of death or pretransplant hospital admission for continuous inotropic or mechanical support within 6 months (p = 0.04), but did not predict long-term overall or event-free survival with a mean follow-up of 62 weeks. Peak Vo2 was the best predictor of long-term overall and event-free survival. CONCLUSIONS: In patients with advanced HF evaluated for cardiac transplantation, distance ambulated during the 6'WT predicts (1) peak Vo2 and (2) short-term event-free survival.

Left ventricular dysfunction after heart transplantation: incidence and role of enhanced immunosuppression.

BACKGROUND: The purpose of this study was to examine the incidence, natural history, and outcome of left ventricular dysfunction in 102 consecutive heart transplant recipients. Left ventricular dysfunction (defined as a decline in the echocardiographic ejection fraction to < 0.45) occurred in 16 of 102 transplant recipients (16%) at a mean of 9.7 +/- 8.6 (standard deviation) months after transplantation. METHODS: Diagnostic evaluation included right heart catheterization and endomyocardial biopsy in all patients and coronary angiography in 13 patients. RESULTS: Four patients were found to have moderate cellular rejection (International Society for Heart and Lung Transplantation grade 2 or higher) and were treated with enhanced immunosuppression. Two patients had angiographically apparent coronary allograft vasculopathy; both died of electromechanical dissociation within 4 months. The remaining ten patients had no or mild cellular rejection (International Society for Heart and Lung Transplantation grade 0 or 1). Therapy in these ten patients included corticosteroids (n = 8). OKT3 (n = 5), and plasmapheresis (n = 2). Three patients died within 2 months of diagnosis, two from undetected severe coronary allograft vasculopathy and one from unrecognized constrictive pericarditis. The echocardiographic ejection fraction improved in the surviving patients after enhanced immunosuppressive therapy (0.33 to 0.53, p < 0.005). With the benefit of long-term clinical follow-up and autopsy data, the origins of left ventricular dysfunction in the 16 patients included moderate cellular rejection (n = 4), vascular rejection (n = 1), coronary allograft vasculopathy (n = 3), intercurrent cytomegalovirus infection (n = 1), constrictive pericarditis (n = 1), and either mild or no evident rejection (n = 6). Survival of the 16 patients with left ventricular dysfunction was similar to that of the 86 patients without left ventricular dysfunction. CONCLUSIONS: The cause of left ventricular dysfunction after heart transplantation includes cellular rejection, vascular rejection, coronary allograft vasculopathy, cytomegalovirus infection, constrictive pericarditis, and unexplained mechanisms. Given the improvement in left ventricular function observed after empiric therapy with enhanced immunosuppression in patients with left ventricular dysfunction, immune-mediated phenomena may play an important pathogenic role.

Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure.

OBJECTIVES: This study was undertaken to determine which exercise and radionuclide ventriculographic variables predict prognosis in advanced heart failure. BACKGROUND: Although cardiopulmonary exercise testing is frequently used to predict prognosis in patients with advanced heart failure, little is known about the prognostic significance of ventriculographic variables. METHODS: The results of maximal symptom-limited cardiopulmonary exercise testing and first-pass radionuclide ventriculography in patients with advanced heart failure referred for evaluation for cardiac transplantation were analyzed. RESULTS: Sixty-seven patients with advanced heart failure (mean [+/- SD]; age 51 +/- 10 years, New York Heart Association functional classes III (58%) and IV (18%); mean left ventricular ejection fraction 0.22 +/- 0.07) underwent simultaneous upright bicycle ergometric cardiopulmonary exercise testing and first-pass rest/exercise radionuclide ventriculography. Mean peak oxygen consumption (VO2) was 11.8 +/- 4.2 ml/kg per min, and mean peak age- and gender-adjusted percent predicted oxygen consumption (%VO2) was 38 +/- 11.9%. Univariate predictors of overall survival included right ventricular ejection fraction > or = 0.35 at rest and > or = 0.35 at exercise and %VO2 > or = 45% (all p < 0.05). In a multivariate proportional hazards survival model, right ventricular ejection fraction > or = 0.35 at exercise (p < 0.01) and %VO2 > or = 45% (p = 0.01) were selected as independent predictors of overall survival. Univariate predictors of event-free survival included right ventricular ejection fraction > or = 0.35 at rest (p = 0.01) and > or = 0.35 at exercise (p < 0.01), functional class II (p < 0.05) and %VO2 > or = 45% (p = 0.05). Right ventricular ejection fraction > or = 0.35 at exercise (p = 0.01) was the only independent predictor of event-free survival in a multivariate proportional hazards model. Cardiac index at rest, VO2, left ventricular ejection fraction at rest, and exercise-related increase or decrease > 0.05 in left or right ventricular ejection fraction were not predictive of overall or event-free survival in any univariate or multivariate analysis. CONCLUSIONS: 1) Right ventricular ejection fraction > or = 0.35 at rest and exercise is a more potent predictor of survival in advanced heart failure than VO2 or %VO2; 2) %VO2 rather than VO2 predicts survival in advanced heart failure; 3) neither %VO2 nor VO2 predicts survival to the combined end point of death or admission for inotropic or mechanical support in patients with advanced heart failure.