Effects of carvedilol on oxidative stress and chronotropic response to exercise in patients with chronic heart failure.

BACKGROUND: Our previous studies suggest that the increase in heart rate from rest to peak exercise is reduced in patients with chronic heart failure (CHF) and this is associated with increased oxidative stress, as determined by malondialdehyde (MDA) plasma levels. AIM: To investigate the effects of carvedilol on the heart rate response to exercise and oxidative stress in patients with CHF. METHODS AND RESULTS: Thirty stable NYHA classes II-III CHF patients received carvedilol therapy for 6 months, at a mean maintenance dose of 25 mg (range 6.25-50 mg/day). After treatment, the patients showed a significant improvement in their functional NYHA class (p=0.013), increased left ventricular ejection fraction (LVEF) (24+/-1.4% to 31+/-2.3%, p=0.003) and 6-min walk distance (499+/-18 to 534+/-18 m, p=0.03), without changes in the peak VO2. At baseline, norepinephrine (NE) plasma levels increased with exercise (510+/-51 to 2513+/-230 pg/mL, p<0.001), and these levels were not affected by carvedilol. Chronotropic responsiveness index (increase in heart rate divided by the increase in NE from rest to peak exercise) was not changed by carvedilol (0.049+/-0.001 to 0.042+/-0.001, p=0.6). MDA levels of CHF patients decreased after treatment with carvedilol (2.4+/-0.2 to 1.1+/-0.2 microM, p<0.001), without changes in antioxidant enzyme activities. CONCLUSIONS: Carvedilol treatment in patients with CHF results in reduced oxidative stress without restoration of the chronotropic responsiveness index.

Dobutamine stress radionuclide ventriculography reveals silent myocardial dysfunction in Kawasaki disease.

Dobutamine (DOB) stress radionuclide ventriculography (RVG) is proposed for evaluating left ventricular performance in patients with Kawasaki disease (KD). Dobutamine stress RVG, up to 15 microg x kg(-1) x min(-1), was performed in 40 patients with a history of KD, some of whom had a perfusion defect (PD group) on dipyridamole stress thallium-201 myocardial imaging, some of whom had no perfusion defects (NPD group), and some of whom had no coronary artery lesions (C group). No significant differences in either systolic or diastolic indices of the left ventricle at rest were observed between the 3 groups. Although hemodynamic responses were similar in all patients after DOB stress, early diastolic index of the first third filling fraction decreased only in the PD group and was significantly lower in this group compared with the C group (p<0.01). The asynchrony index increased significantly in those patients with coronary stenosis after DOB stress (p<0.05). No serious side-effects were observed during the study. Even late after onset, patients with myocardial ischemia as a result of KD still had impaired early diastolic filling and asynchronous relaxation of the left ventricle. As an alternative to exercise testing, DOB stress RVG is a safe and promising means for serially evaluating left ventricular performance in patients with KD.

Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure.

Cardiomyocyte apoptosis or programmed cell death has been shown to occur in end-stage explanted failed human hearts and in dogs with chronic heart failure (HF). We tested the hypothesis that early long-term monotherapy with an angiotensin-converting enzyme (ACE) inhibitor attenuates cardiomyocyte apoptosis in dogs with moderate HF. Left ventricular (LV) dysfunction (ejection fraction 30-40%) was produced in dogs by multiple sequential intracoronary microembolizations. Dogs were randomized to 3 mo of therapy with enalapril (Ena, 10 mg twice daily, n = 7) or to no therapy at all (control, n = 7). After 3 mo of therapy, dogs were euthanized and the hearts removed. Presence of nuclear DNA fragmentation (nDNAf), a marker of apoptosis, was assessed in frozen LV sections using the immunohistochemical deoxynucleotidal transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method. Sections were also stained with ventricular anti-myosin antibody to identify cells of cardiocyte origin. From each dog, 80 fields (x40) were selected at random, 40 from LV regions bordering old infarcts and 40 from LV regions remote from any infarcts, for quantifying the number of cardiomyocyte nDNAf events per 1,000 cardiomyocytes. The average number of cardiomyocyte nDNAf events per 1,000 cardiomyocytes was significantly lower in Ena-treated dogs compared with controls (0.81 +/- 0.13 vs. 2.65 +/- 0.81, P < 0.029). This difference was due to a significantly lower incidence of cardiomyocyte nDNAf events in LV regions bordering scarred tissue (infarcts) in Ena-treated dogs compared with controls. We conclude that early long-term Ena therapy attenuates cardiomyocyte apoptosis in dogs with moderate HF. Attenuation of cardiomyocyte apoptosis may be one mechanism by which ACE inhibitors preserve global LV function in HF.

Quinapril therapy in patients with chronic mitral regurgitation.

Pre- and afterload reduction is known to have beneficial effects in patients with chronic mitral regurgitation. To date, no controlled study has been reported analyzing the long term influence of angiotensin-converting enzyme inhibitor treatment on patients with chronic mitral regurgitation. Therefore the aim of this study was to assess the effects of one year angiotensin-converting enzyme inhibition with quinapril on myocardial performance in patients with chronic mitral regurgitation. Twelve patients with moderate to severe isolated chronic mitral regurgitation and no coronary disease on coronary angiography were studied under control conditions and followed up until one year of quinapril therapy (10-20mg/day) using echocardiography and simultaneous right heart catheterization, and radionuclide ventriculography at rest and exercise. As the result of a significant pre- and afterload reduction after one year quinapril treatment regurgitant fraction fell from 0.43 +/- 0.10 at control before therapy to 0.25 +/- 0.08 (p = 0.0001), left ventricular end-diastolic volume was reduced from 146 +/- 26 to 109 +/- 24 ml/m2 (p = 0.0001) and end-systolic volume decreased from 63 +/- 43 to 47 +/- 29 ml/m2 (p = 0.02). Left ventricular ejection fraction at control averaged 0.59 +/- 0.20 at rest, increased to 0.65 +/- 0.21 with maximum exercise and was unchanged after one year quinapril therapy. After one year treatment left ventricular mass was reduced by 15% (p = 0.0004) and septal wall thickness decreased from 11.8 +/- 0.7 to 10.8 +/- 0.8 mm (p = 0.0006). Moreover, there was significant functional improvement of nearly one NYHA class after one year quinapril therapy. In conclusion, in patients with chronic mitral regurgitation long term angiotensin-converting enzyme inhibition with quinapril reduces regurgitation and decreases left ventricular size and mass thereby demonstrating functional improvement. In addition, these data suggest that angiotensin-converting enzyme inhibition might have the potential of delaying mitral valve surgery.

[Left ventricular relaxation and hypertension. Effect of captopril on gamma-angiographic parameters]. / Relaxation ventriculaire gauche et hypertension artérielle effet du captopril sur les paramètres gamma-angiographiques.

In order to evaluate the action of captopril on left ventricular filling in hypertension, 14 hypertension (158 +/- 10/101 +/- 5 mmHg) patients aged 51 +/- 6 years were investigated by Technetium 99m gamma-angiography. The time/activity curve was used to determine the maximum filling rate (MFR) and maximum filling time (MFT) of the ventricle before and after treatment with captopril (mean dose : 44 +/- 26 mg/day for 7 months). Blood pressure was significantly lowered by treatment and there was a decrease in left ventricular mass from 128 +/- 17 to 118 +/- 15 g/m2 (p = 0.07). Maximum filling rate was accelerated by treatment from 2.27 +/- 0.57 to 2.57 +/- 0.43 VTD . s-1, p = 0.005). This variation was due essentially to half of the patients, suggesting an "all or nothing" type response. Maximum filling time did not vary. The basic question raised by this type of study is to know whether the improvement in the available relaxation parameter, MFR, was associated with actual improvement in filling, which is the true aim. Although the explanations offered for the observed findings are hypothetical, taking into account of all the trial data together with the morphological data provided by echocardiography suggests that captopril does have an actual and hemodynamically significant action on filling.

Effect of propranolol and disopyramide on left ventricular function at rest and during exercise in hypertrophic cardiomyopathy.

In 19 patients with hypertrophic cardiomyopathy (15 males, 4 females, mean age 49.2 +/- 10.8 years) left ventricular function was studied with radionuclide ventriculography at rest and during exercise in a crossover design without intervention and after disopyramide and propranolol treatment. 15 of the 19 patients had a resting or latent intraventricular gradient of more than 30 mm Hg. Left ventricular function at rest and during exercise was evaluated before medication, 90 min after oral administration of 200 mg disopyramide or 160 mg propranolol and after 3 weeks of oral therapy with disopyramide 200 mg 2 times a day or propranolol 80 mg 4 times a day. After long-term treatment with disopyramide, resting ejection fraction decreased from 72 +/- 12 to 69 +/- 14% (p less than 0.01) and peak ejection rate (PER) decreased from 3.46 +/- 135 to 3.24 +/- 65 end-diastolic volume (EDV).s-1 (p less than 0.01). Peak filling rate (PFR) at rest decreased from 3.01 +/- 0.8 to 2.77 +/- 0.63 EDV.s-1 (p less than 0.05). Time to peak filling rate (TPFR) at rest and during exercise after acute and chronic therapy did not change compared to control values. Acute and long-term administration of propranolol lead to a significant reduction in heart rate at rest and during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of barucainide on left ventricular ejection fraction in patients with ventricular cardiac arrhythmias]. / Einfluss von Barucainid auf die linksventrikuläre Auswurffraktion bei Patienten mit ventrikulären Herzrhythmusstörungen.

We studied the effect of barucainide, an investigational class lb antiarrhythmic drug, on ventricular arrhythmias and left-ventricular ejection fraction in 10 patients with frequent and complex ventricular arrhythmias (Lown grade 4a/4b). The study was conducted as a single-blind and placebo-controlled trial. With placebo, mean frequency of ventricular arrhythmias was 6238 VPB/24 h, 510 couplets/24 h, and 24 salvos/24 h. Mean left-ventricular ejection fraction was 37.6%, ranging from 18% to 58%. Therapy with barucainide (300-400 mg/day) resulted in a significant reduction of ventricular arrhythmias in 7 of 10 patients; in one patient barucainide had a clear proarrhythmic effect. Over all, left-ventricular ejection fraction (37.6% +/- 12% with placebo vs 36.1% +/- 11% with barucainide) was not significantly altered. In one patient, however, it was depressed by more than 5%; one patient complained of shortness of breath during exercise. None of the four patients with an initial ejection fraction below 35% showed a drop of ejection fraction during therapy with barucainide. The only main adverse effect was a small, but significant (p less than 0.005) rise of serum-kreatinine (1.13 +/- 0.26 vs 1.39 +/- 0.38 mg%) in all patients. We conclude that barucainide has a good antiarrhythmic effect and is usually well tolerated in patients with markedly depressed left-ventricular function. The mechanism causing the rise of serum-kreatinin, however, needs to be clarified in further studies.

Effect of captopril, an angiotensin-converting enzyme inhibitor, in patients with angina pectoris and heart failure.

The effects of captopril and placebo were compared in 18 patients with chronic heart failure and angina pectoris with use of a double-blind crossover trial design. Symptoms were assessed by patient treatment preference, visual analogue scores and nitroglycerin consumption. Exercise performance was assessed using two different treadmill protocols of different work intensity with simultaneous measurement of oxygen consumption and by supine bicycle exercise and simultaneous radionuclide ventriculography. Arrhythmias were assessed by 48 h ambulatory electrocardiographic monitoring. Patients generally preferred placebo to captopril, and this appeared to be due to an increase in symptoms of angina with captopril. Treadmill exercise time on a high intensity protocol was shorter with captopril than with placebo; on a low intensity protocol, angina became a more frequent limiting symptom even though overall exercise performance was not changed. The heart rate-blood pressure product was reduced, but largely because of a reduction in blood pressure rather than in heart rate. During supine bicycle exercise, no differences in symptoms, exercise performance, ejection fraction or changes in blood pressure were noted and ventricular arrhythmias were reduced. Captopril does not appear to be clinically useful in alleviating angina pectoris in patients with heart failure, and this effect may be related to a decrease in coronary perfusion pressure. Nonetheless, desirable metabolic effects, a reduction in arrhythmias and potential effects on survival require further study of captopril in patients with both angina and heart failure.

Antitumor activity of liposome-encapsulated doxorubicin in advanced breast cancer: phase II study.

Previous studies in animals have demonstrated liposome-encapsulated doxorubicin (LED) has substantially less cardiac toxicity than free doxorubicin but retains antitumor activity. In a phase I clinical study of LED, the maximum tolerated dose was 90 mg/m2 and dose-limiting toxicity was considered to have been reached when granulocytopenia was produced. We used LED to treat 20 patients with advanced, measurable breast cancer. LED was given at doses of 60-75 mg/m2 every 3 weeks as an intravenous infusion. Regression of disease was objectively measured in nine patients; in five of these patients, complete regression of the index lesion occurred. The mean duration of the responses was 7 months. Hematologic toxicity consisted of grade 1-2 leukopenia in some patients. Gastrointestinal toxicity and mucositis were generally mild and tolerable. Alopecia occurred in all patients and usually was complete. Twelve patients received cumulative doses of LED of greater than 400 mg/m2 and were evaluated with radionuclide ventriculograms. In eight patients, the cumulative dose was greater than 500 mg/m2, and five had endomyocardial biopsies. Four of these biopsy results were Billingham grade 0, while one (cumulative LED dose, 750 mg/m2) showed grade 1 changes with mild myofibrillar loss and dilatation of the sarcoplasmic reticulum involving less than 5% of cardiac myocytes. Two patients had decreases in left ventricular ejection fraction. One of these patients had received a total dose of LED of 630 mg/m2 and had a decline of 13% in left ventricular ejection fraction, but had no clinical evidence of congestive heart failure and had a Billingham grade 0 endomyocardial biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of tolerance after chronic administration of controlled-release isosorbide-5-mononitrate. Interaction of nitrate and gallopamil.

The effect of a controlled-release formulation of isosorbide-5-mononitrate (IS-5-MN) was studied in patients with coronary heart disease (CHD), with the aim of comparing the acute effect with that after chronic administration on parameters of ischemia. To determine whether any tolerance developed, several aspects of ischemia were observed: ECG signs, clinical parameters, and left ventricular function. Fifteen patients with angiographically proven CHD were examined with 12-lead exercise ECG before, 2 h and 4 h after the first dose and after 10 days of therapy with 60 mg IS-5-MN (Coleb-Duriles) once daily. After 7 days, three radionuclide ventriculographies were performed: control, 2 h after nitrate and 2 h after 75 mg gallopamil. Plasma concentrations of IS-5-MN were measured before every exercise test. The results showed a reduction of total ST-segment depression from 0.59 mV to 0.29 mV after 2 h (NS) and 4 h (P less than 0.05) on the 1st day and from 0.48 mV to 0.32 mV (P less than 0.05) and 0.31 mV (NS) after 10 days. The severity of angina pectoris was diminished by about 50%. The effect on exercise duration and time to ST-segment depression by more than 0.1 mV remained unchanged after 10 days, whereas the effect on blood pressure, heart rate and time to onset of angina was attenuated. The mean decrease in ejection fraction (EF) from rest to exercise was reduced from--5.9% to -1.9% (P less than 0.05) after nitrate, while an increase of +1.4% was seen after gallopamil (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

[Diastolic ventricular function in hypertrophic, obstructive and non-obstructive cardiomyopathy--effect of gallopamil]. / Diastolische Ventrikelfunktion bei hypertrophischer, obstruktiver und nichtobstruktiver Kardiomyopathie--Wirkung von Gallopamil.

Left ventricular function was investigated by radionuclide ventriculography in 13 patients (11 male, two female) with hypertrophic cardiomyopathy, aged from 22-57 years (mean 45.5 years) at rest and during exercise. Ten patients had hypertrophic obstructive cardiomyopathy with maximal left ventricular outflow tract gradients of 64-290 mmHg (mean 147 mmHg). Left ventricular enddiastolic pressure of all patients ranged from 8-35 mmHg (mean 21 mmHg). Radionuclide ventriculography was performed without therapy, after acute application of a single oral dose of gallopamil (50 mg), and after longterm treatment for 3 weeks (50 mg tid). Ejection fraction at rest after single dose increased from 69.2% to 72.9% (p less than 0.02), peak ejection rate (PER) increased from 333.5 to 362.0/s (p less than 0.01) and peak filling rate (PFR) from 284.5 to 316.5/s (p less than 0.02). Under exercise single dose as well as longterm treatment led to a slight but significant shift in the ratio of PFR/PER (from 1.02 to 1.12 after single dose [p less than 0.04], and to 1.18 with longterm treatment [p less than 0.03]). There was no correlation between the individual response to gallopamil treatment and histopathological parameters such as hypertrophy or fibrosis. These data demonstrate that gallopamil in patients with hypertrophic cardiomyopathy leads to an improvement mainly in left ventricular diastolic function which appears to be most effective under exercise.