Partial left ventriculectomy with mitral valve preservation in the treatment of patients with dilated cardiomyopathy

OBJECTIVE: This study reports initial results of partial left ventriculectomy performed with preservation of the mitral valve in the treatment of 27 patients with idiopathic dilated cardiomyopathy. METHODS: Patients were in New York Heart Association class III or IV. Partial ventriculectomy was performed as an isolated procedure in four patients and associated with mitral annuloplasty in 23 patients. There were four hospital deaths (14.8%) and the remaining patients were followed for 11.2 +/- 6 months. RESULTS: Decrease of left ventricular diastolic diameter (81.8 +/- 8.7 to 68.5 +/- 7.6 mm, p < 0.001) and improvement of left ventricular wall shortening (12% +/- 3.1% to 18.1% +/- 3.9%, p < 0.001) were demonstrated by echocardiography after the operation. Left ventricular radioisotopic angiography showed reduction of diastolic volume (495 +/- 124 ml to 352 +/- 108 ml, p < 0.001) and increase of ejection fraction (17.7% +/- 4.6% to 23.7% +/- 8.8%, p < 0.001). Right-sided heart catheterization demonstrated improvement of stroke index (24.3 +/- 7.7 ml/m2 to 28.3 +/- 7.6 ml/m2, p < 0.01) and decrease of pulmonary wedge pressure (23.2 +/- 8.8 mm Hg to 17 +/- 7 mm Hg, p < 0.01). Similar results were documented at 6 and 12 months of follow-up. Functional class improved from 3.6 +/- 0.5 to 1.4 +/- 0.6 (p < 0.001). However, seven patients died at midterm follow-up because of heart failure progression or arrhythmia-related events, and survival rate was 59.2% +/- 9.4% from 6 to 24 months of follow-up. CONCLUSIONS: Partial left ventriculectomy performed with preservation of the mitral valve improves left ventricular function and congestive heart failure in patients with dilated cardiomyopathy. Nevertheless, the high incidences of heart failure progression and arrhythmia-related deaths observed after this procedure preclude its wide clinical application.     

The impact of beta-receptor blocker addition to high-dose angiotensin-converting enzyme inhibitor-nitrate therapy in heart failure

BACKGROUND: The natural history of heart failure is one of continued worsening of cardiac function. Beta-receptor blocker therapy has been effective in improving clinical status and left ventricular function in patients with heart failure. Similarly, high doses of angiotensin-converting enzyme (ACE) inhibitors with nitrates partially reverse the ventricular remodeling of heart failure. HYPOTHESIS: We tested the hypothesis that beta-blocker therapy added to high-dose ACE inhibitor-nitrates would potentiate the reversal of heart failure. METHODS: Thirteen patients, aged 52 +/- 8 years, with moderate to severe heart failure, 12 of whom were referred for transplant consideration, with heart failure duration of 4.8 +/- 2.2 years, were prospectively followed for 12 months. Baseline echocardiographic ejection fraction was 19 +/- 8%, and presenting New York Heart Association class was 2.9 +/- 0.7. Angiotensin-converting enzyme inhibitors and nitrates were uptitrated over 6 months to a final dose of lisinopril 53 +/- 31 mg/day, and isosorbide dinitrate 217 +/- 213 mg/day. At 6 months, beta-blocker therapy with atenolol was initiated and titrated to a final dose of 46 +/- 23 mg/day. Two-dimensional Doppler echocardiography and metabolic stress testing were performed at baseline, at 6 months on lisinopril-nitrates only, and at 12 months on combined ACE inhibitor-nitrate and beta-blocker therapy. RESULTS: New York Heart Association classification improved from 2.9 +/- 0.7 to 1.8 +/- 0.8 on lisinopril-nitrates (p < 0.05), and to 1.5 +/- 0.5 with the addition of beta blockade (p = NS). On follow-up, peak oxygen consumption rose from 17 +/- 7 ml O2/kg/min at baseline to 21 +/- 5 ml O2/kg/min at 6 months on lisinopril-nitrates (p = 0.06) without further change on beta blockade. Ejection fraction rose from 19 +/- 8 to 33 +/- 14% on lisinopril-nitrates at 6 months (p = 0.005) and to 36 +/- 18% on beta blockade at 12 months (p = NS). CONCLUSION: High-dose ACE inhibitor-nitrate therapy significantly improved patient clinical status and left ventricular systolic function in heart failure. The addition of beta-receptor blockade over and above high-dose ACE inhibitor-nitrates was well tolerated but had no further impact on symptomatic status, exercise tolerance, or left ventricular systolic function. The potential for pharmacologic reversal of heart failure remodeling may be finite despite the use of complementary therapies. Larger placebo-controlled and randomized trials of beta-receptor blockade added to high-dose ACE inhibitor-nitrate therapy are needed to confirm these observations.     

Effects of late percutaneous transluminal coronary angioplasty of an occluded infarct-related coronary artery on left ventricular function in patients with a recent (< 6 weeks) Q-wave acute myocardial infarction (Total Occlusion Post-Myocardial Infarction Intervention Study [TOMIIS]--a pilot study)

The effect of late percutaneous transluminal coronary angioplasty (PTCA) of an occluded infarct-related artery on left ventricular ejection fraction was studied in patients with a recent, first Q-wave myocardial infarction in a prospective, randomized study. Forty-four patients (31 men and 13 women, mean age 58 +/- 12 years) with an occluded infarct-related coronary artery were randomized to PTCA (n = 25) or no PTCA (n = 19). Patients received acetylsalicylic acid, a beta blocker and an angiotensin-converting enzyme inhibitor unless contraindicated. Left ventricular ejection fraction was determined at baseline and 4 months. Coronary angiography was repeated at 4 months. Baseline ejection fraction measured 20 +/- 12 days after myocardial infarction was 45 +/- 12% in both groups. PTCA was performed 21 +/- 13 days after the event. The primary PTCA success rate was 72%. One patient in each group died before angiographic follow-up, which was completed in 37 of the remaining 42 patients (88%; 21 with and 16 without PTCA). At 4 months, the infarct-related artery was patent in 43% of PTCA patients and in 19% of no PTCA patients (p = NS). Reocclusion occurred in 40% of patients after successful PTCA. Secondary analyses showed that the change in left ventricular ejection fraction was significantly greater in patients with a patent infarct-related artery (+9.4 +/- 6.2%) than in those with an occluded artery (+1.6 +/- 8.8%; p = 0.0096). Baseline ejection fraction also independently predicted improvement in left ventricular ejection fraction (p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Perindopril postmarketing surveillance: a 12 month study in 47,351 hypertensive patients

We investigated the effect of electrical cardioversion of atrial fibrillation in patients with heart failure. The study group consisted of 24 patients with mild to moderate heart failure [13 men, mean age 67+/-7 years, mean peak oxygen consumption (peak VO2) 16.3+/-2.8 ml/min/kg] and chronic atrial fibrillation (median duration 19 (1-228) months). Patients were stable on digoxin, diuretics, nitrates and angiotensin converting enzyme inhibitors; no prophylaxis with antiarrhythmics was started after cardioversion. Cardioversion was unsuccessful in 6 patients; of the 18 patients in whom sinus rhythm was obtained 9 had a relapse of atrial fibrillation within 6 weeks after cardioversion. The remaining 9 patients with maintenance of sinus rhythm and the 15 (6+9) patients with atrial fibrillation at follow-up after 6 weeks did not differ with respect to any baseline characteristic, including age, peak VO2, duration of atrial fibrillation, echocardiographic left ventricular and left atrial dimensions, plasma atrial natriuretic peptide and norepinephrine. In the patients with maintenance of sinus rhythm, baseline measurements were repeated at follow-up. Peak VO2 did not change significantly (16.7+/-2.8 to 17.6+/-3.3 ml/min/kg, P=0.29); also, echo parameters, atrial natriuretic peptide and norepinephrine were not significantly affected. These results indicate that it is difficult to achieve lasting sinus rhythm through electrical cardioversion in patients with atrial fibrillation and mild to moderate heart failure. Moreover, in patients with maintenance of sinus rhythm after cardioversion no significant benefit in terms of peak VO2, cardiac dimensions, and neurohumoral status is to be expected. Hence, indiscriminate cardioversion of atrial fibrillation in the setting of heart failure does not appear to be useful.     

Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart

BACKGROUND: The basic pharmacology of the third-generation beta-blocking agent carvedilol differs considerably from second-generation compounds such as metoprolol. Moreover, carvedilol may produce different, ie, more favorable, clinical effects in chronic heart failure. For these reasons, we compared the effects of carvedilol and metoprolol on adrenergic activity, receptor expression, degree of clinical beta-blockade, hemodynamics, and left ventricular function in patients with mild or moderate chronic heart failure. METHODS AND RESULTS: The effects of carvedilol versus metoprolol were compared in two concurrent placebo-controlled trials with carvedilol or metoprolol that had common substudies focused on adrenergic, hemodynamic, and left ventricular functional measurements. All subjects in the substudies had chronic heart failure resulting from idiopathic dilated cardiomyopathy. Carvedilol at 50 to 100 mg/d produced reductions in exercise heart rate that were similar to metoprolol at 125 to 150 mg/d, indicating comparable degrees of beta-blockade. Compared with metoprolol, carvedilol was associated with greater improvement in New York Heart Association functional class. Although there were no significant differences in hemodynamic effects between the carvedilol and metoprolol active-treatment groups, carvedilol tended to produce relatively greater improvements in left ventricular ejection fraction, stroke volume, and stroke work compared with changes in the respective placebo groups. Carvedilol selectively lowered coronary sinus norepinephrine levels, an index of cardiac adrenergic activity, whereas metoprolol did not lower coronary sinus norepinephrine and actually increased central venous norepinephrine levels. Finally, metoprolol was associated with an increase in cardiac beta-receptor density, whereas carvedilol did not change cardiac beta-receptor expression. CONCLUSIONS: The third-generation beta-blocking agent carvedilol has substantially different effects on left ventricular function, hemodynamics, adrenergic activity, and beta-receptor expression than dose the second-generation compound metoprolol. Some or all of these differences may explain the apparent differences in clinical results between the two compounds.     

In situ detection of DNA fragmentation and expression of bcl-2 in human neuroblastoma: relation to apoptosis and spontaneous regression

In patients with alcoholic cardiomyopathy there is evidence that mild heart failure is reversible if patients abstain from alcohol, but there is no consensus whether the disease is progressive once structural myocardial dilation has evolved. The aim of the present study was to compare the long-term course of congestive heart failure due to alcoholic and idiopathic dilated cardiomyopathy. Of 75 patients with overt congestive heart failure, 23 had alcoholic cardiomyopathy and were compared to 52 patients with idiopathic cardiomyopathy. The mean age was 48 +/- 12 years. Despite medical therapy, heart failure class New York Heart Association III-IV was present in 52% of patients with alcoholic and 47% of patients with idiopathic cardiomyopathy (not significant). Their mean left ventricular ejection fraction was 30 +/- 12% vs 28 +/- 12% and left ventricular end-diastolic volumes were 264 +/- 125 ml and 254 +/- 100 ml respectively (not significant). Overall survival at 1, 5 and 10 years was 100%, 81% and 81% for the group with alcoholic dilated cardiomyopathy and 89%, 48% and 30% for the group with idiopathic cardiomyopathy, respectively (P = 0.041), and the difference was even greater for transplant-free survival P = 0.005). Clinical and invasive signs of left and right heart failure as well as left ventricular dimensions were predictive of a fatal outcome; however, symptom duration and left ventricular volumes were only predictive in patients with idiopathic cardiomyopathy, suggesting that in the two patient groups different mechanisms may lead to death. Mortality in patients with severe congestive heart failure and left ventricular dilatation due to alcoholic cardiomyopathy is significantly lower than that in patients with idiopathic cardiomyopathy and similar degrees of heart failure. Thus, despite structural changes inherent in marked left ventricular dilatation, disease progression in alcoholic dilated cardiomyopathy is different from that in idiopathic cardiomyopathy and thus may have implications for the choice of therapy.     

Polyclonal/monoclonal ratio in kidney and bone marrow transplanted patients treated with cyclosporine

OBJECTIVE: To examine the hypothesis that suppression of frequent premature ventricular contractions may be associated with improvement in left ventricular function in patients with presumed idiopathic dilated cardiomyopathy. DESIGN: We conducted a retrospective case study and statistical analysis of the effect of cardiac medical therapy on outcome. MATERIAL AND METHODS: The study population consisted of 14 patients with more than 20,000 premature ventricular contractions in 24 hours recorded by Holter monitoring and associated left ventricular dysfunction (ejection fraction, 40% or less). Clinical characteristics, number of premature ventricular contractions per hour on 24-hour ambulatory Holter monitoring, and ejection fraction based on transthoracic echocardiography were compared before and after cardiac therapeutic intervention. RESULTS: Of the 14 patients, 10 had presumed idiopathic dilated cardiomyopathy, and 4 had ischemic heart disease. Of the overall study group, seven had received additional cardiac medical therapy after the index evaluation, including four patients who had amiodarone therapy. A significant reduction (75% or more from baseline) in premature ventricular contractions after medical therapeutic intervention was observed in five patients at the first follow-up examination. The mean interval to the first follow-up examination was 6 +/- 3 months. Of the five patients, four had significant improvement in clinical functional status and the ejection fraction. The mean ejection fraction of these five patients increased from 27 +/- 10% at baseline to 49 +/- 17% after medical therapy (P = 0.04). CONCLUSION: The suppression of frequent premature ventricular contractions may be associated with improvement of left ventricular function in patients with presumed idiopathic dilated cardiomyopathy.     

Effects of histamine type 2-receptor antagonists cimetidine and famotidine on left ventricular systolic function in chronic congestive heart failure

Twelve patients with stable congestive heart failure and left ventricular dysfunction were enrolled in a double-blind, randomized crossover trial of famotidine, cimetidine and placebo to determine whether histamine type 2 (H2) antagonists adversely affect left ventricular systolic performance. Two-dimensional echocardiograms were obtained at baseline, after 4 days of oral treatment with standard doses of famotidine and cimetidine, and placebo, and at the conclusion of the trial. The baseline mean ejection fraction was 19 +/- 7%. The changes in ejection fraction were +2 +/- 11% (95% confidence interval [CI] -5 to 9%) with famotidine, +3 +/- 10% (95% CI -3 to 10%) with cimetidine, and -3 +/- 7% (95% CI -8 to 2%) with placebo. There were no significant differences in changes in ejection fraction among the 3 experimental treatments (p = 0.22; analysis of variance). The changes in end-systolic wall stress/volume ratios from baseline were +6 +/- 21% (95% CI -6 to 18%) for famotidine, +8 +/- 29% (95% CI -8 to 25%) for cimetidine, and +2% +/- 29% (95% CI -15 to 18%) for placebo (p = 0.69; analysis of variance). No patient had a worsening of symptoms during therapy. Despite previous reports that H2 antagonists may depress left ventricular systolic function, at standard doses these agents result in no decrease in left ventricular systolic function in patients with chronic congestive heart failure.     

Intermediate-term outcome of mitral reconstruction in cardiomyopathy

OBJECTIVE: Severe mitral regurgitation is a frequent complication of end-stage cardiomyopathy that contributes to heart failure and predicts a poor survival. We studied the intermediate-term outcome of mitral reconstruction in 48 patients who had cardiomyopathy with severe mitral regurgitation and were operated on between June 1993 and June 1997. METHODS: Ages ranged from 33 to 79 years (63 +/- 6 years) with left ventricular ejection fractions of 8% to 25% (16% +/- 3%). All patients were receiving maximal drug therapy and were in New York Heart Association class III-IV with severe, refractory 4+ mitral regurgitation. Operatively, all 48 had undersized flexible annuloplasty rings inserted, 7 had coronary bypass grafts for incidental disease, 11 had prior bypass grafts, and 11 also had tricuspid valve repair. RESULTS: One operative death occurred as a result of right ventricular failure. Postoperative transesophageal echocardiography revealed mild mitral regurgitation in 7 patients and no mitral regurgitation in 41. There were 10 late deaths, 2 to 47 months after mitral reconstruction. The 1- and 2-year actuarial survivals have been 82% and 71%. At a mean follow-up of 22 months, the number of hospitalizations for heart failure has decreased, and 1 patient has had heart transplantation. Significantly, New York Heart Association class improved from 3.9 +/- 0.3 before the operation to 2.0 +/- 0.6 after the operation. Twenty-four months after the operation, left ventricular volume and sphericity have decreased, whereas ejection fraction and cardiac output have increased. CONCLUSION: Whether this favorable modification of left ventricular function and geometry will persist remains unknown. However, mitral repair for cardiomyopathy with mitral regurgitation allows new strategies for these patients.     

Carvedilol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders

Carvedilol competitively blocks beta 1, beta 2 and alpha 1 receptors. The drug lacks sympathomimetic activity and has vasodilating properties that are exerted primarily through alpha 1-blockade. Animal models indicate that carvedilol confers protection against myocardial necrosis, arrhythmia and cell damage caused by oxidising free radicals, and the drug has no adverse effects on plasma lipid profiles. Recent data have confirmed the antihypertensive efficacy of carvedilol in patients with mild to moderate essential hypertension. Carvedilol has similar efficacy to other beta-blocking agents, calcium antagonists, ACE inhibitors and hydrochlorothiazide. Carvedilol also improves exercise tolerance and ischaemic symptoms in patients with stable angina pectoris. Significant reductions in serious cardiac events after acute myocardial infarction and in frequency and severity of ischaemic events in patients with unstable angina have also been demonstrated. Interest in the use of carvedilol in patients with congestive heart failure (CHF) has culminated in the publication of a cumulative analysis of data from 1094 patients with mild to severe CHF who participated in the US Carvedilol Heart Failure Study Program (4 trials). After a median follow-up of 6.5 months, a significant overall reduction in mortality relative to placebo (3.2 vs 7.8%) was revealed in patients who had received carvedilol 6.25 to 50 mg twice daily (plus diuretics and ACE inhibitors). All-cause mortality, risk of hospitalisation for cardiovascular reasons and hospitalisation costs were also reduced significantly (by 65, 28% and 62%, respectively) in these trials. In addition, the Australia and New Zealand Heart Failure Research Collaborative Group showed a 26% reduction in the combined risk of death or hospitalisation with carvedilol 12.5 to 50 mg/day relative to placebo after a mean 19-month follow-up period in 415 patients with CHF (relative risk 0.74). Adverse events with carvedilol appear to be less frequent than with other beta-blocking agents, are dosage-related and are usually seen early in therapy. Events most commonly reported are related to the vasodilating (postural hypotension, dizziness and headaches) and the beta-blocking (dyspnoea, bronchospasm, bradycardia, malaise and asthenia) properties of the drug. Carvedilol appears to date to have little effect on the incidence of worsening heart failure. Concomitant administration of carvedilol with some medications requires monitoring. Carvedilol is therefore likely to have a beneficial role in the management of controlled CHF, but further clinical studies are required to show the place of beta-adrenoceptor blocking therapy in general in this indication, and the position of carvedilol relative to other similar agents. Carvedilol is also confirmed as effective in the management of mild to moderate hypertension and ischaemic heart disease.     

Altered myocardial phenotype after mechanical support in human beings with advanced cardiomyopathy

BACKGROUND: Left ventricular assist devices (LVAD) provide lifesaving circulatory support to patients awaiting heart transplantation. To date, the extent to which sustained mechanical unloading alters the phenotype of pathologic myocardial hypertrophy in dilated cardiomyopathy is unknown. METHODS: We examined left ventricular size, myocyte and myocardial immunoreactivity for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in eight patients with advanced dilated cardiomyopathy before and after LVAD support. The mean duration of congestive heart failure was 18 +/- 5 months, and LVAD support averaged 42 +/- 4 days before heart transplantation. RESULTS: Echocardiographically determined left ventricular mass decreased from 505 +/- 83 to 297 +/- 52 gm (p < 0.05) during LVAD support, whereas minimum myocyte diameter decreased from 28.1 +/- 0.9 to 21.7 +/- 0.6 microns (p < 0.01) in transmural myocardial tissue specimens. Overall left ventricular ANP immunopositivity decreased from 48% at LVAD placement to 12% at transplantation (p < 0.05), whereas BNP immunopositivity decreased from 28% to 4% after LVAD support. Moreover, a gradient of ANP and BNP immunostaining from subendocardium to epicardium observed before mechanical unloading diminished after LVAD support. Analysis of the relationship between left ventricular mass and ANP immunopositivity revealed a close and highly significant correlation between these variables. CONCLUSIONS: These studies demonstrate remarkable left ventricular plasticity even in the presence of advanced cardiomyopathy. Parallel reductions in myocardial mass and myocyte size with reductions in ventricular ANP and BNP immunostaining indicate a novel regression of the phenotype of pathologic hypertrophy within the human myocardium after LVAD support.     

Antitumor activity of human umbilical cord blood cells: A comparative analysis with peripheral blood and bone marrow cells

OBJECTIVES: To determine the predictive value of quantitative evaluation of myocardial viability on changes in left ventricular function, exercise capacity, and quality of life after coronary artery bypass grafting in patients with ischemic heart failure (congestive heart failure, New York Heart Association class > or = III) with and without angina. METHODS: Thirty-five patients, 14 with congestive heart failure and angina (CHF-angina) and 21 with congestive heart failure without angina (CHF-no angina) were studied at baseline and 6 months after coronary bypass grafting. Left ventricular function was evaluated with transthoracic echocardiography and radionuclide ventriculography. Myocardial viability was assessed with [18F]-2-fluoro-2-deoxy-D-glucose using positron emission tomography. Peak aerobic capacity (peak oxygen consumption) and anaerobic threshold were assessed with treadmill exercise test and quality of life with a questionnaire. RESULTS: A total of 286 of 336 dysfunctional left ventricular segments were viable. There were two perioperative deaths (5.7%) and three late deaths. Left ventricular ejection fraction increased from 23% +/- 7% to 32% +/- 9% (p < 0.0001), and a linear correlation was found between the number of viable segments and the changes in ejection fraction (r = 0.65; p = 0.0001). Receiver operating characteristics curve identified eight viable segments as the best predictor for increase of ejection fraction more than 5 percentage points. Peak oxygen consumption increased from 15 +/- 4 to 22 +/- 5 ml/kg per minute (p < 0.0001). Preoperatively, anaerobic threshold was identified in one patient from the CHF-angina group and in all from the CHF-no angina group and increased from 13 +/- 4 to 19 +/- 4 ml/kg per minute (p < 0.0001). Quality of life scores improved significantly in both groups. No correlation was found between the amount of viable dysfunctional myocardium and changes in exercise capacity or quality of life. CONCLUSIONS: In patients with postischemic congestive heart failure the amount of viable myocardium dictates the degree of improvement in left ventricular function after revascularization.     

Scatter rejection in modular gamma cameras for use in dynamic 3D spect brain imaging system

This study examined the effects of Albunex (sonicated 5% human serum albumin) infusion on left ventricular inflow velocity by Doppler echocardiography. Left ventricular pressure and left ventricular inflow velocity were recorded simultaneously under eight different conditions in dogs: 1) baseline 1 (control), 2) Albunex 0.2 ml/kg, 3) baseline 2, 4) Albunex 0.5 ml/kg, infusion of dextran 100 ml, 5) baseline 3, 6) Albunex 0.2 ml/kg, 7) baseline 4, and 8) Albunex 0.5 ml/kg. In the normal state (no dextran), Albunex (0.2 ml/kg) caused no hemodynamic changes or inflow velocity changes. In contrast, infusion of Albunex (0.5 ml/kg) caused time velocity integrals of early filling to increase from the baseline (5.51 +/- 1.13 vs 7.19 +/- 1.14 cm, p < 0.05). After dextran infusion (100 ml), Albunex (0.2 ml/kg) caused peak early filling velocity to increase (62.4 +/- 6.9 vs 67.3 +/- 9.4 cm/sec, p < 0.05), and infusion of Albunex (0.5 ml/kg) also caused peak early filling velocity to increase from baseline (64.6 +/- 8.5 vs 73.7 +/- 14.5 cm/sec, p < 0.05). Infusion of Albunex (0.5 ml/kg) after dextran infusion caused increases in left ventricular pressure at the mitral valve opening (12.7 +/- 3.1 vs 15.2 +/- 3.3 mmHg, p < 0.05) and in left atrial driving force (13.5 +/- 3.6 vs 16.7 +/- 5.9 mmHg, p < 0.05). Clinicians should be cautious about using Albunex at doses of greater than 0.2 ml/kg when evaluating the pressure gradient of the left ventricle in patients with elevated left ventricular diastolic pressure. In patients with normal hemodynamics, Albunex infusion at doses of less than 0.2 ml/kg apparently did not affect the velocity measurement.     

Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise

BACKGROUND: Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials. METHODS AND RESULTS: We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fraction < or = 0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n = 145) or carvedilol (n = 133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (P = .014) or by a global assessment of progress judged either by the patient (P = .002) or by the physician (P < .001). In addition, treatment with carvedilol was associated with a significant increase in ejection fraction (P < .001) and a significant decrease in the combined risk of morbidity and mortality (P = .029). In contrast, carvedilol therapy had little effect on indirect measures of patient benefit, including changes in exercise tolerance or quality-of-life scores. The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure. CONCLUSIONS: These findings indicate that, in addition to its favorable effects on survival, carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin, diuretics, and an ACE inhibitor.     

Chronic carvedilol reduces mortality and renal damage in hypertensive stroke-prone rats

The effects of carvedilol, a novel vasodilating beta-blocker and antioxidant, and propranolol on survival, neurobehavioral deficits, cardiovascular parameters, plasma renin, plasma aldosterone levels and renal pathology were determined in stroke-prone spontaneously hypertensive rats. Stroke-prone spontaneously hypertensive rats were allowed access to 1% NaCl as the drinking solution and a high fat diet supplemented with carvedilol (1200 or 2400 ppm) or propranolol (2400 ppm). The control group consisted of stroke-prone spontaneously hypertensive rats placed on the same diet with no drug supplement. Animals fed propranolol had a blood level of 864 +/- 68 ng/ml, whereas carvedilol-fed animals had blood levels of 24 +/- 4 ng/ml at 1200 ppm and 471 +/- 145 ng/ml at 2400 ppm. Carvedilol and propranolol treatment resulted in significant beta adrenoceptor blockade. Both compounds reduced heart rate, but had no significant effects on systolic arterial blood pressure. Carvedilol- and propranolol-treated animals also exhibited significant, prolonged protection from neurobehavioral deficits and mortality (P < .01). Elevated plasma renin activity and aldosterone levels seen in untreated controls were significantly decreased by propranolol (P < .05), and to a considerably greater extent by the same dose of carvedilol (P < .01). Carvedilol decreased renal histopathological damage and cardiac hypertrophy to a greater extent (P < .01) than propranolol (at equal doses). Both carvedilol (P < .01)- and propranolol (P < .01)-treated animals had considerably reduced renal damage at 18 weeks of treatment. Carvedilol reduced renal damage more than propranolol (P < .05). In addition, the lower (1200 ppm) dose of carvedilol, which decreased neurobehavioral deficits and mortality, had no significant effects on organ mass or renal function, but significantly (P < .01) reduced renal damage. These data indicate that both beta adrenoceptor blockers, especially carvedilol to a considerably greater degree, convey significant protection in a genetic model of severe hypertension that results in renal and cardiovascular organ pathology, neurobehavioral deficits and premature death.     

Comparison of metoprolol and carvedilol pharmacology and cardioprotection in rabbit ischemia and reperfusion model

Carvedilol, a selective alpha1 and non-selective beta-adrenoceptor antagonist and antioxidant, has been shown to provide significant cardiac protection in animal models of myocardial ischemia. To further explore the mechanisms contributing to carvedilol cardioprotection efficacy, the effects of carvedilol on hemodynamic variables, infarct size and myeloperoxidase activity (an index of neutrophil accumulation) were compared with a beta1-selective adrenoceptor antagonist, metoprolol. Carvedilol (1 mg/kg) or metoprolol (1 mg/kg or 1 mg/kg + 0.5 mg/kg 90 min later) was given intravenously 5 min before reperfusion. In vehicle-treated rabbits, ischemia (60 min) and reperfusion (180 min) resulted in significant increments in left ventricular end diastolic pressure, large infarcts (59+/-2.6% of area-at-risk) and marked increase in myeloperoxidase activity (0.59+/-0.09 U/100 mg tissue). Carvedilol treatment resulted in sustained reduction of pressure-rate-index and significantly smaller infarcts (22.0+/-2.5%, P < 0.01 vs. vehicle) as well as decreased myeloperoxidase activity (0.186+/-0.056 U/100 mg tissue, P < 0.01 vs. vehicle). The highest dose of metoprolol, 1 mg/kg + 0.5 mg/kg, that resulted in pressure-rate-index comparable to that of 1.0 mg/kg carvedilol, failed to reduce myeloperoxidase activity in the ischemic myocardial tissue, and the infarct size (35+/-3.1%) was significantly larger than in carvedilol-treated animals. Taken together, this study suggests that the superior cardioprotection of carvedilol over metoprolol is not a consequence of hemodynamic variances but possibly the result of the additional pharmacological properties of carvedilol such as the antioxidant and anti-neutrophil effects.     

Sensory hyperreactivity--a possible mechanism underlying cough and asthma-like symptoms

BACKGROUND: Partial left ventriculectomy has been recently introduced as a surgical therapy for end-stage heart failure. We performed a prospective study of partial left ventriculectomy in patients with end-stage idiopathic dilated cardiomyopathy (IDCM). METHODS: Patients considered as candidates for partial left ventriculectomy had IDCM, left ventricular end-diastolic diameter greater than 7 cm (LVEDD), refractory New York Heart Association class IV symptoms (NYHA), and severely impaired exercise oxygen consumption. All patients underwent a complete heart transplantation evaluation. RESULTS: Partial left ventriculectomy was performed in 16 patients with a mean follow-up of 11.1 months. Fourteen patients were male with a mean age of 49.6+/-10.5 years. After surgery there were significant changes in NYHA class, left ventricular ejection fraction, LVEDD, and degree of mitral regurgitation at up to 12 months follow-up. The operative mortality rate was 6.25% and 12-month Kaplan-Meier was 86%. Twelve-month freedom from need for listing for orthotopic heart transplantation was 65%. CONCLUSION: Partial left ventriculectomy can be performed in patients with idiopathic cardiomyopathy with acceptable operative and 12 month survival rates. Significant improvements are seen in ejection fraction, LVEDD, and NYHA class at 12 month follow up. Late failures do occur and some patients have required relisting for transplant after partial left ventriculectomy.     

Prediction of left ventricular mass changes after renal transplantation by polymorphism of the angiotensin-converting-enzyme gene

Cardiac complications are the main cause of death in renal transplant patients and left ventricular hypertrophy (LVH) may play a determinant role. An association between the insertion-deletion polymorphism of the angiotensin-converting enzyme (ACE) gene and LVH has been reported in adults. However, little is known about the genetic influence on left ventricular mass changes after renal transplantation, where unique environmental factors, such as cyclosporine A (CsA) and prednisone treatment concur. In fact, CsA treatment has recently been associated with the development of LVH. We prospectively determined the changes on cardiac structure and function, assessed by echocardiographic criteria, in 38 consecutive nondiabetic adults who received a cadaveric renal allograft. They were treated with cyclosporine and prednisone and maintained a good renal function during the follow-up. Echocardiographic studies (M-mode, 2-B and color flow Doppler) were performed without previous knowledge of the genetic typing, at the time of transplantation, and 6 and 12 months later. ACE alleles were typed using a PCR-based assay developed to ascertain the presence of an insertion (I)-deletion (D) polymorphism in intron 16 of the ACE gene. Patients with the so-called "unfavorable" DD genotype (N = 16) were compared with the ID or II genotypes (N = 22). The baseline left ventricular mass index was similar in patients with or without the unfavorable DD genotype (X +/- SE; 166.6 +/- 10.4 vs. 181.3 +/- 9 g/m2, respectively) and a similar proportion fulfilled the criteria of LVH (88% vs. 82%, respectively). The mean percent increase of the left ventricular mass index 12 months after renal transplantation was significantly higher in patients with the DD genotype compared to those with other genotypes (21.3 +/- 7.9 vs. -0.08 +/- 4.9%, respectively; P < 0.05). As a result, 94% of DD patients showed LVH at the end of the follow-up, while 68% of the ID or II patients had LVH (P < 0.05). In addition, the left ventricular ejection fraction significantly increased only in ID or II patients 12 months after transplantation with respect to baseline (ID/II patients, 70.4 +/- 1.5 vs. 63.7 +/- 1.8%; P < 0.05; DD patients, 68.3 +/- 2.1 vs. 63.3 +/- 2.9%). The deleterious effect of the DD genotype was independent of blood pressure, biochemical parameters, weight gain, and cumulative steroids dosages or cyclosporine levels. In conclusion, genetic factors determine the changes on cardiac structure and function after renal transplantation. The presence of the DD genotype of the ACE gene is a marker associated with an elevated risk of LVH in this population.     

Paradoxical hypertension after reversal of heart failure in patients treated with intensive vasodilator therapy

Hypertension is a major cause of heart failure, evolving from left ventricular hypertrophy to systolic and diastolic dysfunction. Although effective heart failure therapy has been associated with a lowering or no change in systemic arterial blood pressure in long-term follow-up, this study describes the symptomatic, clinical, and left ventricular functional response of a subgroup of heart failure patients with a prior history of hypertension who demonstrated a paradoxical hypertensive response despite high-dose vasodilator therapy. We prospectively identified 45 patients with a past history of hypertension who had become normotensive with symptomatic heart failure. Of these 45 heart failure patients, 12 became hypertensive while receiving therapy in follow-up, with systolic blood pressure > or = 140 mm Hg (Group A). The remaining 33 patients did not have a hypertensive response to therapy (Group B). In the 12 Group A patients, 60+/-10 years old, with symptomatic heart failure for 6.3+/-4.3 years, vasodilator therapy was intensified in the 2.0+/-0.5 years of follow-up, achieving final doses of enalapril 78+/-19 mg and isosorbide dinitrate 293 +/-106 mg per day. New York Heart Association classification improved from 2.9+/-0.8 to 1.3+/-0.5 (P < or = .0001), with a reduction in heart-failure-related hospitalizations. Left ventricular ejection fraction increased from 17+/-6% to 40+/-10% (P < .0001). Follow-up blood pressure at 1 to 3 months was unchanged. However, both systolic and diastolic blood pressure increased at final follow-up, rising from 116+/-14 to 154+/-13 mm Hg (P = .0001) and from 71+/-9 to 85+/-14 mm Hg (P = .004), respectively. Renal function remained unchanged. Although both groups had similar clinical responses, there were more blacks and women in the hypertensive Group A. Effectively, 12 of 45 (27%) heart failure patients with an antecedent history of hypertension demonstrated a paradoxical hypertensive response to vasodilator therapy. The recurrence of hypertension in a significant portion of patients successfully treated for heart failure has important clinical implications.     

Dynamic cardiomyoplasty: clinical follow-up at 12 years

OBJECTIVE: The purpose of this study is to evaluate the long-term outcome of dynamic cardiomyoplasty. This surgical technique was conceived to assist the failing heart. The many proposed mechanisms of action of cardiomyoplasty are: (1) systolic assist; (2) limitation of ventricular dilation; (3) reduction of ventricular wall stress (sparing effect); (4) ventricular remodeling with an active girdling effect; (5) angiogenesis; and (6) a neurohumoral effect. METHODS: We investigated 95 patients in our hospital undergoing this procedure due to severe chronic heart failure, refractory to optimal medical treatment. Patients had a mean age of 51 +/- 12 years. The etiology of heart failure was ischemic 55%, idiopathic 34%, ventricular tumor 6%, and other 5%. The mean follow-up was 44 months. RESULTS: The mean New York Heart Association (NYHA) functional class improved postoperatively from 3.2 to 1.8. Average radioisotopic left ventricular (LV) ejection fraction increased from 17 +/- 5 to 27 +/- 4% (P < 0.05). Stroke volume index increased from 32 +/- 7 to 43 +/- 8 ml/beat per m2 (P < 0.05). The heart size remained stable over the long term. Following cardiomyoplasty, the number of hospitalizations due to congestive heart failure was reduced to 0.4 hospitalizations/patient per year (preoperative: 2.5, P < 0.05). Computed tomography scans showed at long term a preserved latissimus dorsi muscle structure in 84% of patients. Survival probability at 7 years is 54%. Six patients underwent heart transplant after cardiomyoplasty (mean delay: 25 months), due to the natural evolution of their underlying heart disease. There were no specific technical difficulties. CONCLUSIONS: Clinically, this procedure reverses heart failure, improves functional class and ameliorates quality of life. The latissimus dorsi muscle histological structure is maintained at long-term, when postoperative electrostimulation is performed, avoiding excessive stimulation. Cardiomyoplasty may delay or prevent the progression of heart failure and the indication of cardiac transplantation.