Left ventricular inotropic reserve and right ventricular function predict increase of left ventricular ejection fraction after beta-blocker therapy in nonischemic cardiomyopathy.

OBJECTIVES: The purpose of this study was to determine whether higher left ventricular inotropic reserve, defined as the increase in left ventricular ejection fraction (LVEF) in response to intravenous dobutamine infusion, or other ventriculographic variables predict the increase in LVEF after beta-blocker therapy in patients with nonischemic cardiomyopathy (NICM). BACKGROUND: Long-term beta-blocker therapy increases LVEF in some patients with NICM. Other than dose, there are no definite predictors of LVEF increase. METHODS: Thirty patients with LVEF < or = 0.35 and NICM underwent assessment of LVEF at rest and after a 10-min intravenous infusion of dobutamine at 10 microg/kg/min, using equilibrium radionuclide ventriculography. Age was 49 +/- 11 years, 33% women, functional class 2.6 +/- 0.5, duration of chronic heart failure 3.2 +/- 2.9 years, LVEF 0.21 +/- 0.07, left ventricular end-diastolic volume index 180 +/- 64 ml/m2. Right ventricular ejection fraction (RVEF) was abnormal in 37%. Mean dobutamine-induced augmentation of LVEF (DoALVEF) was 0.12 +/- 0.08. Patients were started on one of three beta-blockers (carvedilol, bucindolol or metoprolol) and the dose was advanced to the maximum tolerated. RESULTS: Left ventricular ejection fraction, reassessed 7.4 +/- 5.9 months after maximum beta-blocker dose was reached, increased to 0.34 +/- 0.13 (p = 0.0006). The following baseline variables correlated with improvement of LVEF: DoALVEF (p = 0.001), RVEF (p = 0.005), systolic blood pressure at end of dobutamine infusion (p = 0.02) and dose of beta-blocker (p = 0.07). In a multivariate analysis, only DoALVEF (p = 0.0003) and RVEF (p = 0.002) were predictive of the increase in LVEF. CONCLUSIONS: Patients with nonischemic cardiomyopathy who have higher left ventricular inotropic reserve and normal RVEF derive higher increase in LVEF from beta-blocker therapy.

Dobutamine-induced augmentation of left ventricular ejection fraction predicts survival of heart failure patients with severe non-ischaemic cardiomyopathy.

AIMS: The prognosis of patients with severe non-ischaemic dilated cardiomyopathy is variable. The predictive value of currently utilized tests is suboptimal. The purpose of this study was to determine the prognostic value of dobutamine-induced augmentation of left ventricular ejection fraction in patients with non-ischaemic dilated cardiomyopathy. METHODS AND RESULTS: Sixty-two patients with left ventricular ejection fraction < or =0.30 underwent exercise testing with gas exchange analysis and assessment of left ventricular ejection fraction at rest and after a 10-min intravenous infusion of dobutamine at 10 microg x kg(-1) x min(-1), using equilibrium radionuclide ventriculography. Age was 48+/-11 years, 32% females, functional class 2.6+/-0.6, resting left ventricular ejection fraction 0.20+/-0.06, and peak exercise oxygen consumption (mVO2) 19+/-6 ml x kg(-1) x min(-1). Mean dobutamine-induced augmentation of left ventricular ejection fraction (DeltaLVEF) was 0.09+/-0.06 (median 0.08, range -0.03 to 0.26). Follow-up was 25+/-15 months during which there were 12 deaths and five transplantations. Patients were divided into two groups based on median DeltaLVEF. The transplant-free survival was better in the group with higher DeltaLVEF (94% vs 64%, P<0.008). In multivariate analysis incorporating age, gender, duration of chronic heart failure, functional class, right and left ventricular ejection fraction, DeltaLVEF, left ventricular end-diastolic volume index, and mVO2, only DeltaLVEF was predictive of 1-year, 3-year, and overall transplant-free survival (RR 0.09, 0.03, and 0.13;P 0.03, 0.09, and 0.08 respectively). The linear correlation between DeltaLVEF and mVO2(r=0.3) and between DeltaLVEF and left ventricular ejection fraction (r=0.5) was weak. CONCLUSION: Dobutamine-induced augmentation of left ventricular ejection fraction is a strong prognostic variable, independent of exercise capacity and resting ventriculographic variables, in severe non-ischaemic systolic dysfunctional heart failure.

Expanded role for ARBs in cardiovascular and renal disease? Recent observations have far-reaching implications.

The ARBs are a new class of drugs with broad therapeutic potential in cardiovascular disease. These agents act by selectively inhibiting the AT1 subtype of the angiotensin II receptors. They are effective antihypertensive agents with promise, theoretically, in the prevention and regression of ventricular hypertrophy. They are safe and well tolerated in patients with CHF and might be effective in improving survival and reducing morbidity. ARBs also might have a similar role in improving the clinical outcomes of patients with coronary artery disease and chronic nephropathy. Their precise role in the treatment and prevention of cardiovascular and renal disease should be established by several ongoing clinical trials.

Serum complement activation in congestive heart failure.

BACKGROUND: Although activation of the complement system in myocardial infarction and cardiopulmonary bypass has been shown to contribute to myocardial injury, its role in congestive heart failure (CHF) is unknown. The purpose of this study was to determine the presence of terminal complement activation and its relation to clinical outcomes in patients with CHF. METHODS: We measured serum levels of the terminal complement complex C5b-9 in 36 patients with symptomatic heart failure and left ventricular ejection fraction <40%. We compared the serum C5b-9 levels of these patients with CHF with a group of 12 age-matched control patients. Combined clinical outcomes (death, urgent heart transplantation, or hospitalization with worsening heart failure) at 6 months were determined. RESULTS: The serum C5b-9 [median (25th to 75th percentiles)] levels in 36 patients with CHF [101.5 ng/mL (40 to 164)] were significantly (P =.003) higher than in the 12 control patients [36.5 ng/mL (22 to 50)]. Significantly more of the patients with CHF with the highest levels of C5b-9 (highest 50th percentile) had New York Heart Association class IV symptoms (67% vs 33%; P =.04) and adverse clinical outcomes by 6 months (56% vs 17%; P =.02) compared with the patients with CHF with lower levels (lowest 50th percentile). CONCLUSIONS: We have described a significant elevation in circulating C5b-9, the terminal complement complex, in patients with symptomatic heart failure and have observed an association between high levels of C5b-9 and near-term adverse events.

Clinic dosing of beta blockers in chronic heart failure.

Beta blockers improve survival and reduce morbidity of patients with chronic heart failure. Stringent dosing guidelines calling for a 1-hour observation period after initiation or up-titration of beta-blocker therapy might limit the use of beta blockers and increase the expense involved. This study was conducted to determine the usefulness of this observation period. Data were collected from 130 in-clinic postdosing observation periods for 34 stable chronic heart failure patients started on carvedilol. The mean left ventricular ejection fraction was 0.22±0.09, and the mean functional class was 2.5±0.6. No patient had greater than first-degree heart block. Carvedilol was started at 3.125 or 6.25 mg b.i.d., and the dose was doubled every 1-3 weeks. All patients were observed for 1-2 hours after initiation or dosage increase, and blood pressure and heart rate were measured hourly. The maximal daily dose was 50±31 mg. In none of the observation periods was there a decrease in the dose of beta blockers administered in the clinic. The predosing mean blood pressure was 110±15/71±10 mm Hg, and the mean heart rate was 78±13 bpm; the 1-hour postdosing mean blood pressure was 101±14/67±10 mm Hg (p is less than 0.001), and the heart rate was 78±13 bpm. The dose was decreased in six patients and medication was discontinued in three, all consequent to symptoms reported several days after dosage increase. Beta blockers can be safely initiated and up-titrated at home in properly selected and evaluated stable patients with chronic heart failure and severe left ventricular dysfunction resulting in mild or moderate impairment of functional capacity. (c)2001 by CHF, Inc.

Effect of heart failure program on cardiovascular drug utilization and dosage in patients with chronic heart failure.

BACKGROUND: Utilization and dosage of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF) remain low. Recent data suggest that care of patients with CHF in specialized heart failure programs is associated with improved clinical outcomes. HYPOTHESIS: Specialized heart failure care is associated with better utilization and higher dose of cardiovascular drugs. METHODS: Data from 133 patients with CHF referred to a heart failure program were analyzed. Mean functional class 3.1 +/- 0.5, left ventricular ejection fraction 19 +/- 8. Utilization and doses of cardiovascular drugs were examined at initial evaluation and at last visit, after an average period of 17 +/- 14 months. Hospitalization and survival data were determined. RESULTS: Utilization of ACE inhibitors and angiotensin-receptor blockers increased from 87 to 100% (p < 0.001). Average daily dose increased by 60%, from the equivalent of captopril 105 +/- 78 mg to 167 +/- 86 mg (p < 0.001). Utilization of the following drugs increased significantly: beta blockers (16-37%, p < 0.001), metolazone (10-23%, p = 0.007), spironolactone (1-36%, p < 0.001), amiodarone (7-15%, p = 0.05), hydralazine (1-9%, p = 0.004), and nitrates (20-33%, p = 0.03). One-year survival was 90%. The 3- and 6-month hospitalization rates for heart failure were 4 and 7%, and for all cardiovascular causes they were 6 and 11%, respectively. CONCLUSIONS: Care of patients with CHF in a specialized heart failure program was associated with significant increase in the utilization and doses of all beneficial cardiovascular drugs, especially ACE inhibitors. It was also associated with excellent clinical outcomes.

Beta blocker therapy for chronic heart failure.

Recent studies have shown that beta blocker therapy improves survival and reduces hospitalizations in patients who have chronic heart failure and left ventricular systolic dysfunction, the majority of whom are under the management of primary care physicians. Appropriate patient selection is essential to the successful initiation of beta blocker therapy. Candidates should be stable in New York Heart Association functional class II or III. Patients with severe heart failure, especially inotrope-dependent and hospitalized patients, and those with hypotension, bradycardia or higher than first-degree heart block are not considered appropriate candidates for beta blocker therapy. Optimal diuresis is essential for maximal tolerability. Beta blockers should be started at the lowest dose, with the dose increased every two to four weeks until the target dose or highest tolerated dose is reached. Close monitoring allows for the detection and appropriate management of side effects, such as hypotension, bradycardia and increased congestion. The treatment goal is long-term improvement of prognosis, rather than immediate improvement of symptoms.

Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure: results of the ELITE ventricular function substudy.

BACKGROUND: The mechanism by which angiotensin-converting enzyme inhibitors reduce mortality rates and disease progression in patients with heart failure is likely mediated in part through prevention of adverse ventricular remodeling. This study examined the effects of the angiotensin-converting enzyme inhibitor captopril and the angiotensin II type 1 receptor antagonist losartan on ventricular volumes and function in elderly patients with heart failure and reduced left ventricular ejection fraction (< or =40%). METHODS: Patients underwent radionuclide ventriculograms (RVG) at baseline and were randomized to either captopril (n = 16) or losartan (n = 13). After 48 weeks, another RVG was obtained. Therapy was then withdrawn for at least 5 days, and the RVG was repeated while the patient was not receiving the drug. RESULTS: At 48 weeks both captopril and losartan significantly reduced left ventricular (LV) end-diastolic volume index (135 +/- 26 to 128 +/- 23 mL/m(2) for losartan, P <.05 vs baseline; 142 +/- 25 to 131 +/- 20 mL/m(2) for captopril, P <.01; mean (SD). Captopril also reduced LV end-systolic volume index (98 +/- 24 to 89 +/- 21 mL/m(2), P <.01 vs. baseline), whereas a nonsignificant trend was observed for the losartan group (97 +/- 23 to 90 +/- 16 mL/m(2), P = not significant). The between-group differences in the changes in LV volumes were not statistically significant. After drug withdrawal, LV end-diastolic volume index remained significantly lower than baseline in the captopril group (P <.01). CONCLUSIONS: Both captopril and losartan prevent LV dilation, representing adverse ventricular remodeling, previously seen with placebo treatment. Reverse remodeling was observed in the captopril group. On the basis of these results, the relative effects on LV remodeling do not provide a rationale for a survival benefit of losartan over captopril.

Optimum maintenance trough levels of cyclosporine in heart transplant recipients given corticosteroid-free regimen.

BACKGROUND: Standard immunosuppressive therapy for heart transplant recipients consists of cyclosporine, azathioprine, and corticosteroids. Long-term use of steroids results in serious side effects. Steroid-free maintenance immunosuppressive regimens have been shown to be safe and effective in selected heart transplant recipients. Cyclosporine is the cornerstone of immunosuppressive therapy in such regimens. The ideal dose of cyclosporine, providing adequate immunosuppression while minimizing toxicity, remains controversial in the standard triple immunosuppressive regimen. This study attempted to define the optimal level of cyclosporine (whole blood radioimmunoassay) for heart transplant recipients given a steroid-free regimen. METHODS: We retrospectively analyzed data from 583 endomyocardial biopsies and corresponding cyclosporine trough levels obtained from 48 orthotopic heart transplant recipients maintained without steroids. We used maximum likelihood probit techniques to examine the correlation between cyclosporine level and the probability of rejection (International Society for Heart and Lung Transplantation [ISHLT] grades higher than 1A). The data were adjusted for age at the time of transplantation, sex, race, time elapsed since transplantation, and azathioprine dose. RESULTS: Higher cyclosporine levels were associated with a lower probability of acute cellular rejection (p < .03). The lowest probability of rejection, ISHLT grades higher than 1A (1.7%), was associated with a cyclosporine level of 322 ng/mL. In this database, higher levels of cyclosporine were not associated with higher serum creatinine levels (p = .6). CONCLUSIONS: Cyclosporine trough levels of 300 to 350 ng/mL (whole blood radioimmunoassay) are associated with the lowest probability of cellular rejection in patients given a steroid-free regimen of cyclosporine and azathioprine. There was no association between cyclosporine levels and serum creatinine.

Reduction ventriculoplasty for the cardiomyopathic heart: a case report.

A 44-year-old morbidly obese and hypertensive woman had been diagnosed with idiopathic cardiomyopathy seven years previously. She was referred for consideration for heart transplantation because of progression of symptoms to class IV. Massive obesity and pulmonary hypertension were strong relative contraindications to transplantation. During outpatient evaluation, the patient developed pulmonary edema, was hospitalized, and became intensive care unit-bound and immobile. Exercise radionuclide angiocardiography revealed left ventricular ejection fraction of 17%, and left ventricular end-diastolic volume of 408 mL. A reduction ventriculoplasty procedure was performed by resection of the lateral wall of the left ventricle. The patient did very well, and was discharged on postoperative day nine. Two weeks after the procedure, exercise radionuclide angiocardiography demonstrated left ventricular ejection fraction of 30% (76% increase) and left ventricular end-diastolic volume of 293 mL (28% decrease). The patient remains in stable New York Heart Association class II, now three months postprocedure. This initial positive experience in New England encourages-continued investigation of the reduction ventriculoplasty procedure, either as a bridge or as an alternative to heart transplantation in patients with dilated cardiomyopathy.

Prognostic value of noninvasive testing one year after orthotopic cardiac transplantation.

OBJECTIVES: We sought to evaluate the prognostic value of routine noninvasive testing--stress thallium-201 imaging, rest two-dimensional echocardiography and rest equilibrium radionuclide angiography--1 year after cardiac transplantation. BACKGROUND: Coronary artery vasculopathy is the most important cause of late death after orthotopic cardiac transplantation. Several clinical variables have been identified as risk factors for development of coronary vasculopathy. Traditional noninvasive diagnostic testing has been shown to be relatively insensitive for identifying patients with angiographic vasculopathy. METHODS: Results of prospectively acquired noninvasive testing in 47 consecutive transplant recipients alive 1 year after transplantation were related to subsequent survival. Other clinical variables previously shown to be associated with the development of coronary artery vasculopathy were also included in the analysis. RESULTS: The 5-year survival rate after cardiac transplantation was 81%. By univariate analysis, echocardiography (chi-square 9.21) and stress thallium-201 myocardial perfusion imaging (chi-square 16.76) were predictive for survival, whereas rest equilibrium radionuclide angiography was not. Clinical contributors to survival were donor age (chi-square 4.56), number of human leukocyte antigen mismatches (chi-square 3.06) and cold ischemic time (chi-square 3.23). By multivariate analysis, stress myocardial imaging remained the only significant predictor of survival (risk ratio 0.27; 95% confidence interval 0.06 to 0.89). CONCLUSIONS: Normal thallium-201 stress myocardial perfusion imaging 1 year after cardiac transplantation is an important predictor of 5-year survival.

Medical therapy and prognosis in chronic heart failure. Lessons from clinical trials.

The past two decades have witnessed tremendous advances in the pharmacologic therapy of patients with left ventricular dysfunction and chronic heart failure. The pharmacologic repertoire has been and continues to be expanded with newer agents carefully subjected to the rigor of well-designed clinical trials. Treatment has consequently evolved from pathophysiologically guided therapy predicated on older concepts to evidence-guided therapy supported by results of major clinical trials that continue to expand the understanding of the pathophysiology of this complex syndrome. The goals of therapy have ambitiously evolved from the immediate symptomatic relief offered by diuretics; to the short-term hemodynamic improvement in the circulation produced by direct vasodilators; to the intermediate-term improvement in functional capacity and exercise tolerance associated with vasodilators, nitrates, and digoxin; and to the final frontier of long-term improvement in morbidity and survival associated with ACE inhibitor therapy. In addition to the expansion of the understanding of the epidemiology, natural history, and pathophysiology of chronic heart failure, several important lessons in clinical pharmacology have been learned from the clinical trials of the last decade. Many other questions, however, remain unanswered. The role of diuretics, although uncontested in the acute stabilization of congested patients, has yet to be rigorously evaluated in stable patients with chronic left ventricular dysfunction on ACE inhibitors. The long-term effects of nitrates on morbidity and mortality have not yet been established in patients with either ischemic or nonischemic ventricular dysfunction. Vasodilators as a class, and perhaps because they are not a homogeneous class, have had a mixture of successes and failures. There is no evidence that pure vasodilation in and by itself improves survival. There is ample evidence, however, that it improves the circulation and consequently the response to diuretics. This improvement may translate into intermediate-term improvement in functional capacity, but this benefit is seldom sustained. Hemodynamic improvement in the circulation may not always translate into longer-term improvement in morbidity and reduction in mortality. The syndrome of chronic heart failure from systolic left ventricular dysfunction has emerged as a disease of mechanical dysfunction and maladaptation. The maladaptation is a consequence of deleterious effects of compensatory neurohormonal mechanisms: the sympathetic nervous system, renin-angiotensin-aldosterone system, arginine vasopressin, and most likely a host of other mechanisms. The degree of activation of these mechanisms has been established as a marker of prognosis, and the effects of pharmacologic agents on these mechanisms may well determine their long-term effect.(ABSTRACT TRUNCATED AT 400 WORDS)