Biomedical subjects
Publications and source records attributed to G W Dec.
Fourteen cardiac transplant candidates were studied with cardiopulmonary exercise testing at baseline and while breathing nitric oxide (40 ppm). Oxygen consumption at the anaerobic threshold was improved by breathing nitric oxide in patients with pulmonary hypertension and in patients with an elevated left ventricular end-diastolic volume index.
We used a catheter-based technique to achieve generalized cardiac gene transfer in vivo and to alter cardiac function by overexpressing phospholamban (PL) which regulates the activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). By using this approach, rat hearts were transduced in vivo with 5 x 10(9) pfu of recombinant adenoviral vectors carrying cDNA for either PL, beta-galactosidase (beta-gal), or modified green fluorescent protein (EGFP). Western blot analysis of ventricles obtained from rats transduced by Ad.PL showed a 2.8-fold increase in PL compared with hearts transduced by Ad.betagal. Two days after infection, rat hearts transduced with Ad.PL had lower peak left ventricular pressure (58.3 +/- 12.9 mmHg, n = 8) compared with uninfected hearts (92.5 +/- 3.5 mmHg, n = 6) or hearts infected with Ad.betagal (92.6 +/- 5.9 mmHg, n = 6). Both peak rate of pressure rise and pressure fall (+3, 210 +/- 298 mmHg/s, -2, 117 +/- 178 mmHg/s, n = 8) were decreased in hearts overexpressing PL compared with uninfected hearts (+5, 225 +/- 136 mmHg/s, -3, 805 +/- 97 mmHg/s, n = 6) or hearts infected with Ad.betagal (+5, 108 +/- 167 mmHg/s, -3, 765 +/- 121 mmHg/s, n = 6). The time constant of left ventricular relaxation increased significantly in hearts overexpressing PL (33.4 +/- 3.2 ms, n = 8) compared with uninfected hearts (18.5 +/- 1.0 ms, n = 6) or hearts infected with Ad.betagal (20.8 +/- 2.1 ms, n = 6). These differences in ventricular function were maintained 7 days after infection. These studies open the prospect of using somatic gene transfer to modulate overall cardiac function in vivo for either experimental or therapeutic applications.
BACKGROUND: Vesnarinone has yielded controversial results on morbidity in patients with congestive heart failure. We tested the hypothesis that vesnarinone may have a beneficial effect on cardiac remodeling and function. METHODS: Thirty-four patients with left ventricular ejection fraction (LVEF) <30% (17 treated with vesnarinone) underwent an echocardiography at baseline and at 12+/-5 months. Left ventricular end-diastolic and end-systolic volume, mitral regurgitation, diastolic filling, and right ventricular area change were quantified and compared. RESULTS: When the vesnarinone group was considered as a whole, there was no significant effect of vesnarinone on cardiac systolic and diastolic function or remodeling. However, an increase in LVEF >7% was observed in six of the vesnarinone patients and none of the control group. Vesnarinone improved right and left ventricular systolic function significantly in patients with initial LVEF <25%. CONCLUSIONS: In severe congestive heart failure, vesnarinone induces variable responses but improves biventricular performance in patients with the most impaired initial function.
Apoptosis is a tightly regulated, energy-requiring process of programmed cell death. While necrosis is a form of cell death that results from acute cellular injury, apoptosis is controlled autodigestion of the cell that occurs through activation of endogenous proteases. This process results in the cleavage of chromatin into oligonucleosome-length DNA fragments and its multiples. This DNA fragmentation demonstrates a characteristic laddering pattern on DNA agarose gel electrophoresis. The heart undergoes extensive remodeling during embryogenesis wherein apoptosis significantly contributes to the development of the cardiac chambers and correct routing of the great vessels. Pathologic stimuli can also result in apoptosis and include ischemia, hypoxia, inflammation, cytokines, growth factors, and toxic agents. Better understanding of the molecular mechanisms responsible for regulating apoptosis in the failing myocardium may soon lead to strategies aimed at preventing further myocyte loss and enhancing myocyte replacement through regulated cell growth.
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.
Although apoptosis contributes significantly to remodeling of the fetal heart during evolution of cardiac chambers and correct routing of the great vessels, it has been believed that apoptosis does not occur in terminally differentiated adult cardiac muscle cells. However, apoptosis has recently been demonstrated in animal models of heart failure as well as in explanted hearts from patients with end-stage heart failure undergoing cardiac transplantation. Ventricular dilatation and neurohormonal activation, the hall-marks of heart failure, lead to upregulation of transcription factors, induce muscle cell hypertrophy and prepare cells for entry into the cell-division cycle. However, since terminally differentiated myocytes cannot divide, they die by apoptosis. It has been proposed that low-grade apoptosis in failing heart may be responsible for inexorable decline in left ventricular function. Better understanding of the molecular and cellular basis of apoptosis in the failing myocardium may lead to development of strategies aimed at preventing progressive myocyte loss and deterioration in left ventricular function.
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.
BACKGROUND: Controversy exists regarding donor and recipient factors that promote the development and progression of coronary artery disease after heart transplantation and the likelihood of coronary artery disease causing death or retransplantation. METHODS: To investigate this issue in a large cohort of patients, we analyzed 5963 postoperative angiograms performed in 2609 of the 3837 patients undergoing heart transplantation at 39 institutions between January 1990 and December 1994. Coronary artery disease was classified as mild, moderate, or severe on the basis of left main involvement, primary vessel stenoses, and branch stenoses. Coronary artery disease was considered severe if left main stenosis was > 70% or 2 or more primary vessels stenoses were > 70% or branch stenoses were > 70% in all 3 systems. RESULTS: By the end of 5 years after heart transplantation, coronary artery disease was present in 42% of the patients, mild in 27%, moderate in 8%, and severe in 7%. Coronary artery disease-related events (death or retransplantation) had an actuarial incidence of 7% at 5 years and occurred in 2 of 3 of the patients with development of angiographically severe coronary artery disease. By multivariable logistic analysis, risk factors for donor coronary artery disease included older donor age (P < .0001) and donor hypertension (P=.0002). By multivariable analysis in the hazard function domain, risk factors identified for the earlier onset of allograft coronary artery disease included older donor age (P < .0001 ), donor male sex (P=.0006), donor hypertension (P=.07), recipient male sex (P=.02), and recipient black race (P=.01). The actuarial incidence of severe coronary artery disease was 9% at 5 years. CONCLUSIONS: Angiographic coronary artery disease is very common after heart transplantation, occurring in approximately 42% of the patients by 5 years. Older donor age, donor hypertension, and male donor or recipient predict earlier onset of angiographic allograft coronary artery disease. Although severe angiographic allograft coronary artery disease occurs in only 7% of the patients at 5 years, its presence is highly predictive of subsequent coronary artery disease-related events or retransplantation.
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In patients awaiting heart transplantation, end-stage disease of a second organ may occasionally require consideration of simultaneous multiorgan transplantation. Outcome statistics in multiorgan transplant recipients are needed to define optimal utilization of scarce donor resources. Incidence of cardiac allograft rejection, actuarial recipient survival, and cardiac allograft rejection-free survival were evaluated in 82 recipients of 84 simultaneous heart and kidney transplants. Twenty-three of the 82 dual-organ recipients have died with 1, 6, 12, and 24-month actuarial survival rates of 92%, 79%, 76%, and 67%, respectively. The actuarial survival rates in the heart-kidney recipients were similar to those observed in 14,340 isolated heart recipients (United Network for Organ Sharing Scientific Registry) during the same period (92%, 86%, 83%, and 79%, respectively; P=0.20). Clinical data on all episodes of treated rejection in either organ and on immunosuppressive regimens were available on 56 patients; 48% of these patients have had no rejection in either organ, 27% experienced heart rejection alone, 14% experienced kidney rejection alone, and 11% had both heart and kidney allograft rejection. Heart allograft rejection was less common in heart-kidney recipients, as compared with isolated heart transplant recipients; 0, 1, and > or = 2 treated cardiac allograft rejection episodes occurred in 63%, 20%, and 18% of heart-kidney recipients compared with 46%, 27%, and 28% of 911 isolated heart recipients reported by Transplant Cardiologists' Research Database (P=0.02). The rejection-free survival rates at 1, 3, and 6 months were 88%, 74%, and 71% in the double-organ recipients, as compared with 66%, 44%, and 39%, respectively, in the single-organ recipients. Compared with isolated heart transplantation, combined heart-kidney transplantation does not adversely affect intermediate survival and results in a lower incidence of treated cardiac allograft rejection. The findings suggest that combined heart-kidney transplantation may be an acceptable option in a small subset of potential heart transplant recipients with severe renal dysfunction.
RATIONALE AND OBJECTIVES: The purpose of the study was to determine the relationship between pulmonary artery (PA) size at computed tomography (CT) and PA pressures, to develop a noninvasive CT method of PA pressure measurement, and to determine a PA diameter that can enable differentiation of normal subjects from those with pulmonary hypertension. METHODS: PA vessel diameters in 55 candidates for lung and heart-lung transplantation were measured at CT and correlated with PA pressures with both linear and stepwise multiple regression. The multiple regression equations were then tested prospectively in 35 pretransplantation patients. RESULTS: Combined main and left main PA cross-sectional area corrected for body surface area showed the best correlation with mean PA pressure (r = .87). The multiple regression equations helped predict mean PA pressure within 5 mm Hg in 50% of patients with chronic lung disease and in only 8% of patients with pulmonary vascular disease. CONCLUSION: There was a very good correlation between main and left main PA size and mean PA pressure. At present, however, CT has not demonstrated sufficient accuracy to be used clinically.
BACKGROUND AND PURPOSE: Persons with chronic heart failure (HF) have poor ventilatory muscle strength, and this weakness is associated with dyspnea. The purpose of this study was to examine the effects of inspiratory muscle training (IMT) on ventilatory muscle strength and dyspnea in patients with chronic HF. SUBJECTS: Fourteen patients (mean age [+/-SD] = 52 +/- 8.5 years) with end-stage cardiomyopathy and chronic HF (mean left ventricular ejection fraction = 23% +/- 13% and New York Heart Association class = 3.6 +/- 0.6) participated in the study. METHODS: Inspiratory muscle training was performed at 20% of maximal inspiratory pressure (MIP) for 5 to 15 minutes, three times a day, for 8 weeks. Dyspnea was evaluated at rest and during exercise. RESULTS: Both MIP and maximal expiratory pressure (MEP) were greater after 2 weeks of IMT (51 +/- 21 to 63 +/- 23 cm H2O and 85 +/- 22 to 96 +/- 19 cm H2O, representing 24% and 13% improvement). Dyspnea scores at rest and during exercise decreased after 2 weeks (2.0 +/- 0.7 to 1.3 +/- 0.5 and 3.6 +/- 0.5 to 2.6 +/- 0.6, representing 29% and 28% improvement) and plateaued throughout the remainder of IMT. Baseline MEP was related to the percentage of change in MEP after IMT (r = -.72), and several measures of pulmonary function were related to the degree of improvement in dyspnea after IMT (r = -.57 to -.82) and in MIP after IMT (r = .71). CONCLUSION AND DISCUSSION: Improvements in MIP, MEP, and dyspnea were found after 2 weeks of IMT. Greater pulmonary function was associated with greater improvement in dyspnea and ventilatory muscle strength after IMT. These improvements may decrease the dependency and impairment associated with chronic HF.
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BACKGROUND: The purpose of this study was to identify predictors of survival in patients referred for heart transplantation evaluation who had a peak oxygen uptake of 10 to 14 ml/kg/min measured during initial cardiopulmonary exercise testing. METHODS: Seventy-two patients were identified retrospectively from a database of 304 patients who underwent heart transplantation evaluations at our center from 1985 to 1995. All 72 patients underwent right-sided heart catheterization and first-pass right and left ventricular radionuclide ventriculography during cardiopulmonary exercise testing. RESULTS: There were 14 women and 58 men in the study (mean age 52 +/- 9 years, 80% male, 79% New York Heart Association class III/IV, left ventricular ejection fraction of 0.24 +/- 0.9, and left ventricular end-diastolic volume index of 144 +/- 59 ml). During a mean follow-up of 19 +/- 23 months, two women and 32 men (47%) reached the combined end point of death (n = 20) or pretransplantation admission for inotropic or mechanical support (n = 14). For the entire cohort, analysis of clinical, ventriculographic, and exercise parameters identified female sex, younger age, and age/ sex-adjusted peak oxygen uptake as independent predictors of survival. In men only, age, left ventricular end-diastolic volume index, and age/sex adjusted peak oxygen uptake were independent predictors of survival. CONCLUSIONS: Among patients referred for heart transplantation evaluation with a peak oxygen uptake between 10 to 14 ml/kg/min, younger age, female sex, and higher age/ sex-adjusted peak oxygen uptake predict longer survival to the combined end point of death or pretransplantation admission for inotropic or mechanical support. These measures may be useful in additional risk stratification of such patients.
BACKGROUND: This study tested the hypothesis that in patients with suspected heart failure, peak oxygen consumption was the best predictor of heart muscle failure. Failing human myocardium is characterized by an abnormal force-frequency relationship, which has been previously shown to be altered in parallel with the severity of heart failure. METHODS: We examined whether seven different functional parameters of isolated electrically driven ventricular trabeculae carneae obtained from 34 explanted hearts of patients undergoing heart transplantation for end-stage heart failure correlated with any of 47 separate pretransplantation clinical parameters. The functional muscle parameters were active force at 0.33 Hz, time to 80% relaxation (RT 80%) of twitch force at 0.33 Hz, optimal frequency (OF), active force at 1.0 Hz (AF1), diastolic force at 1.0 Hz (DF1), active force at 2.0 Hz (AF2), and diastolic force at 2.0 Hz (DF2). RESULTS: Before transplantation the mean left ventricular ejection fraction was 21% +/- 10%, and all patients were in New York Heart Association class III or IV. Mean peak whole body VO2 was 10.9 +/- 3.3 ml/min/kg and percent body mass/age/sex-adjusted maximum VO2 oxygen consumption was 34.7% +/- 10.4%. Univariate analysis of VO2 yielded the following significant correlations: active force at 33 Hz, RT80%, OF, AF1, DF1, AF2, DF2; whereas univariate analysis of percent body mass/age/sex-adjusted VO2 yielded the following significant correlations: RT80%, OF, DF1, AF2, DF2. Multivariate analysis showed that OF and DF1 were independent predictors of peak VO2. CONCLUSION: In this study we show that peak oxygen uptake measured during cardiopulmonary exercise testing obtained before transplantation is correlated with the force-frequency behavior of isolated muscles at the time of transplantation. Peak VO2 seems to be a strong indicator of the severity of cardiac contractile dysfunction in patients with heart failure.
BACKGROUND: Heart failure can result from a variety of causes, including ischemic, hypertensive, toxic, and inflammatory heart disease. However, the cellular mechanisms responsible for the progressive deterioration of myocardial function observed in heart failure remain unclear and may result from apoptosis (programmed cell death). METHODS: We examined seven explanted hearts obtained during cardiac transplantation for evidence of apoptosis. All seven patients had severe chronic heart failure: four had idiopathic dilated cardiomyopathy, and three had ischemic cardiomyopathy. DNA fragmentation (an indicator of apoptosis) was identified histochemically by in situ end-labeling as well as by agarose-gel electrophoresis of end-labeled DNA. Myocardial tissues obtained from four patients who had had a myocardial infarction one to two days previously were used as positive controls, and heart tissues obtained from four persons who died in motor vehicle accidents were used as negative controls for the end-labeling studies. RESULTS: Hearts from all four patients with idiopathic dilated cardiomyopathy and from one of the three patients with ischemic cardiomyopathy had histochemical evidence of DNA fragmentation. All four myocardial samples from patients with dilated cardiomyopathy also demonstrated DNA laddering, a characteristic of apoptosis, whereas this was not seen in any of the samples from patients with ischemic cardiomyopathy. Histological evidence of apoptosis was also observed in the central necrotic zone of acute myocardial infarcts, but not in myocardium remote from the infarcted zone. Rare isolated apoptotic myocytes were seen in the myocardium from the four persons who died in motor vehicle accidents. CONCLUSIONS: Loss of myocytes due to apoptosis occurs in patients with end-stage cardiomyopathy and may contribute to progressive myocardial dysfunction.
Damage to the tricuspid valve apparatus has been described after endomyocardial biopsy and may be associated with hemodynamically significant tricuspid regurgitation (TR). This study was performed to determine the prevalence of TR and flail tricuspid leaflet in cardiac transplant recipients and to evaluate the use of a 45 cm sheath placed directly in the right ventricle during endomyocardial biopsy to reduce the incidence of these complications. Echocardiograms and right heart catheterization data of 72 orthotopic cardiac transplant recipients were assessed for the presence of flail tricuspid leaflet, TR, and right-sided cardiac dysfunction 29 +/- 20 months (mean +/- SD) after transplantation. Moderate or severe TR was present in 23 patients (32%). Ten patients (14%) had flail tricuspid leaflet, with 7 of these having severe TR. Right atrial pressure (10 +/- 5 vs 6 +/- 5 mm Hg, p < 0.05) was higher, cardiac index (2.0 +/- 0.2 vs 2.5 +/- 0.7 L/min/m2, p < 0.05) was lower, and right-sided cardiac dimensions were greater in patients with flail leaflets than in those without flail leaflets. Both the prevalence of flail tricuspid leaflet (41% to 6%, p < 0.0001) and mean grade of TR (2 to 1, p < 0.0001) were reduced after the use of a 45 cm sheath. We conclude that TR secondary to biopsy-induced damage to the valve apparatus occurs in cardiac transplant recipients and is associated with signs of early right-sided heart failure. Use of a 45 cm sheath during endomyocardial biopsy reduces the prevalence of flail tricuspid leaflet and the severity of TR.
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.