Predicting response to carvedilol for the treatment of heart failure: a multivariate retrospective analysis.

BACKGROUND: Carvedilol has been shown to decrease the progression of heart failure and improve left ventricular function and survival in patients with a left ventricular ejection fraction (LVEF) less than 35%. However, not all patients respond uniformly to this therapy. We proposed to identify variables that could, potentially, be used to predict response to carvedilol therapy as measured by the change in LVEF after treatment (Delta LVEF), and to identify pretreatment variables associated with hospitalization for heart failure after carvedilol therapy. METHODS AND RESULTS: A retrospective analysis of 98 patients treated with open-label carvedilol for a mean period of 16 months was performed by using bivariate and step-wise multivariate analyses. Bivariate analysis showed a positive correlation of Delta LVEF with heart rate at baseline (P =.001). There was a negative correlation of Delta LVEF with baseline LVEF (P <.01), diabetes mellitus (P =.04), and ischemic cardiomyopathy (P =.0002). Multivariate analysis showed a positive correlation of Delta LVEF with heart rate at baseline (P =.01) and a negative correlation with initial LVEF (P =.02) and ischemic cardiomyopathy (P =.006). Variables associated with hospitalization after initiation of carvedilol therapy were New York Heart Association (NYHA) classification (P =.001), lower extremity edema (P =.001), presence of an S3 (P =.02), hyponatremia (P =.02), elevated blood urea nitrogen (BUN) (P =.002), atrial fibrillation (P =.001), diabetes mellitus (P =.02), and obstructive sleep apnea (P =.009). CONCLUSIONS: Heart failure patients with the lowest LVEF or the highest heart rate at baseline had the greatest gain in LVEF after treatment with carvedilol. Patients with ischemic cardiomyopathy derived less benefit. Patients with clinical evidence of decompensated heart failure were at greater risk for hospitalization after initiation of carvedilol therapy.

[Nuclear cardiology study on effective ingredients of Astragalus membranaceus in treating heart failure].

UNLABELLED: The experimental study has testified that among the various effective constituents gained from Astragalus membranaceus (AM) is the main component. Nineteen patients with heart congestive failure were treated with effective ingredient of AM, the astragaloside IV (XGA) injection. RESULTS: After 2 weeks of treatment the symptoms of chest distress, dispnea in 15 patients was alleviated, their capability of exercise reinforced. Radionuclide ventriculography showed that left ventricular modelling improved, left ventricular end-diastolic volume diminished by 11.74 +/- 18.39 ml, left ventricular end-systolic volume by 9.35 +/- 18.01 ml, with statistical significance. HR slowed from 88.21 +/- 17.19 to 64.55 +/- 13.06 beats/min, P < 0.05; PER increased from 1.80 +/- 0.86 to 1.95 +/- 0.85 u/second, P < 0.05. Left ventricular EF, PFR increased also at some extent without statistical significance. CONCLUSION: Effective ingredient of AM, XGA injection is efficient positive inotropic drug, and could improve the left ventricular modelling and ejection function in patients with congestive heart failure after continuous administration of XGA injection for two weeks.

Vasodilating beta-blockers in heart failure.

Carvedilol is a non-selective beta-adrenoceptor antagonist with vasodilating properties which has been shown to be effective in the management both of hypertension and of stable angina pectoris. In order to explore its wider efficacy in patients with manifest heart failure, a preliminary study was performed in patients with chronic stable angina pectoris accompanied by abnormal left ventricular wall motion, but without overt heart failure (mean ejection fraction < 40%). Six patients were given carvedilol 25 mg b.i.d. for 2 weeks followed by 50 mg b.i.d. for a further 2 weeks according to a single-blind placebo-controlled protocol. At the end of the 4 week period of treatment, in four patients left ventricular wall motion was improved, in two it was unchanged, and in none was there any deterioration; mean ejection fraction increased from 40 to 48%. These results prompted a further study in 17 patients with chronic ischaemic heart failure. The haemodynamic and clinical responses to intravenous carvedilol followed by the oral drug (50 mg b.i.d.) for 8 weeks were studied. There was an improvement in all haemodynamic variables, although postural hypotension necessitated withdrawing two patients, and clinical deterioration was evident in two others. The beneficial effects of carvedilol were considered to be related to the combined reduction in afterload and inhibition of neurohumeral activation. These results have been confirmed in placebo-controlled, double-blind studies.

The link between acute haemodynamic adrenergic beta-blockade and long-term effects in patients with heart failure. A study on diastolic function, heart rate and myocardial metabolism following intravenous metoprolol.

The present study was performed to find possible mechanisms linking the early effects of beta-blockade with the observed long-term effects in patients with heart failure. In 57 patients with heart failure, 13 +/- 3.1 mg of metoprolol was given intravenously. The patients were investigated by invasive haemodynamics (n = 34), including collection of myocardial metabolic data during atrial pacing stress (n = 16), by radionuclide angiography during physiological atrial pacing (n = 13), and by a bedside evaluation (n = 10). Diastolic function, measured by early peak filling rate, followed changes in heart rate, but was similar when heart rate was held constant by atrial pacing before and after beta-blockade. Following beta-blockade and slower heart rates, diastolic filling volumes were redistributed to late diastole. Metoprolol induced a parallel decrease in coronary sinus flow and myocardial oxygen consumption. Myocardial oxygen consumption following beta-blockade decreased both during spontaneous rhythm (25 +/- 15 to 16 +/- 8.8 ml min-1; P = 0.006), and during atrial pacing stress (30 +/- 13 to 23 +/- 11 ml.min-1; P = 0.004). Cardiac index decreased owing to reduction of heart rate (2.3 +/- 1.0 to 1.9 +/- 0.64 l.min-1.m2; P = 0.0003), while left ventricular filling pressure was unchanged. Ejection fraction and ventricular volumes were unaltered following atrial pacing or beta-blockade. There was a reflex increase in noradrenaline concentration after beta-blockade injection (0.96 +/- 0.66 to 1.20 +/- 0.91 nmol.l-1; P = 0.002), whereas myocardial noradrenaline overflow was unchanged. There was a trend towards an increase in myocardial lactate consumption after beta-blockade administration during atrial pacing stress. It is suggested that the surprisingly good tolerability seen after acute administration of beta-blockers to patients with severe heart failure may be explained by prolongation of the diastolic filling phase, which outweighs the negative inotropic effects. The reduced myocardial metabolic demand may allow the failing myocardium to recover and explain the excellent long-term effect on heart function following beta-blockade treatment.

Angiogenic effects of low molecular weight heparin in patients with stable coronary artery disease: a pilot study.

OBJECTIVES: The study was designed to assess the feasibility of conducting a trial to investigate whether exercise and low molecular weight heparin therapy with dalteparin sodium (Fragmin) would improve collateral function to the ischemic myocardium in patients with coronary artery disease. BACKGROUND: The severity of myocardial ischemia in patients with coronary artery disease is at least partly dependent on the status of the collateral circulation. Therefore, improvement in collateral function would potentially provide a unique way of alleviating myocardial ischemia. Because the combination of ischemia and heparin has previously been demonstrated to enhance collateral growth, we studied the anti-ischemic effects of combined treatment with dalteparin sodium and exercise-induced ischemia in patients with coronary artery disease. METHODS: Twenty-three patients with stable coronary artery disease were randomized to receive either subcutaneous dalteparin sodium or placebo for a 4-week period. Patients received either placebo or 10,000 IU of dalteparin sodium by subcutaneous injection once daily for weeks 1 and 2 and 5,000 IU daily for weeks 3 and 4. During the 1st 2 weeks, patients were exercised to ischemia three times a day. At baseline and 4 weeks after treatment, treadmill exercise testing, exercise radionuclide ventriculography and 48-h ambulatory ST segment monitoring were performed. RESULTS: Eight (80%) of the 10 dalteparin sodium-treated patients compared with 4 (31%) of 13 placebo-treated patients (p < 0.02) had an increased rate-pressure product at the onset of 1 mm of ST segment depression. The duration of exercise to ischemia increased in all patients treated with low molecular weight heparin and in 62% of placebo-treated patients (p < 0.03). The number and duration of episodes of ST segment depression during ambulatory monitoring decreased by 30% and 35%, respectively (p < 0.05), in the dalteparin sodium group but were unchanged in the placebo group. The decrease in left ventricular ejection fraction with exercise was lower in 80% of dalteparin sodium-treated patients compared with 54% of placebo-treated patients (p = 0.06). When all five factors reflecting collateral function were considered together in a multivariate analysis of variance, there was a significant improvement in low molecular weight heparin-treated patients compared with placebo-treated patients (p = 0.014). CONCLUSIONS: This study provides preliminary evidence suggesting that exercise and low molecular weight heparin therapy with dalteparin sodium lessen myocardial ischemia and that the improvement is likely to be mediated by enhanced collateral function.

Atenolol or nicardipine alone is as efficacious in stable angina as their combination: a double blind randomised trial.

BACKGROUND: Beta blockers and calcium antagonists are widely used in the management of angina pectoris in the belief that the combination is more efficacious than either drug alone. METHODS: This double blind randomised crossover placebo controlled study compares the effects of nicardipine, atenolol and their combination in 30 patients with chronic stable angina. Each treatment period lasted 6 weeks with dose titration after 3 weeks. Symptom limited treadmill exercise testing and radionuclide ventriculography at rest was carried out at the end of each treatment period. RESULTS: Total exercise duration and time to 1-mm ST-segment depression was significantly prolonged by nicardipine and atenolol when compared to placebo, the combination offered no additional benefit. Time to onset of angina was significantly prolonged by nicardipine and the combination but not by atenolol. Indices of left ventricular function were not significantly affected by any treatment other than an increase in left ventricular end diastolic volume on atenolol and the combination. CONCLUSIONS: Nicardipine and atenolol are equally effective in prolonging exercise duration and time to onset of ischemia in patients with chronic stable angina while the combination appeared to offer no additional benefit. Nicardipine prolonged the time to onset of angina significantly; again there was no further improvement with the combination. Neither drug appears to have an important effect on the parameters of diastolic function studied in patients with chronic stable angina.

Nuclear imaging study of nifedipine induced modulations of central haemodynamics in severe hypertension with and without coronary artery disease.

Acute effects of Nifedipine, a calcium channel blocking agent (CCBA), on central haemodynamics in patients with severe hypertension and angiographically proved coronary artery disease (CAD) has been studied using Nuclear Ventriculography (MUGA). While peripheral vasodilatation leads to significant reduction of systemic blood pressure in all severe hypertensive patients (p < 0.0005 and p < 0.0001), the central haemodynamics did not improve significantly in patients without CAD (p = NS). However, in hypertensive subset of CAD, central haemodynamics significantly improves with rise of global ejection fraction (p < 0.001) and improvement of wall motion abnormalities (p < 0.001).

The effects of thrombolytic therapy on the high-resolution electrocardiogram after myocardial infarction.

The effects of thrombolytic treatment was studied in 109 consecutive patients 9-11 days after their first acute myocardial infarction by high-resolution electrocardiography (ECG), 24 h Holter monitoring, exercise test and radionuclide ventriculography. Thirty-seven patients were treated with intravenous thrombolytic agents. Thrombolytic treatment was assessed by clinical criteria to be successful in 22 patients and probably successful in 12 patients. Thrombolysis failed in three patients and 72 patients did not receive thrombolytic treatment (control group). Measurements made on the high-resolution and filtered (60 Hz high-pass) vectormagnitude complex included the total duration, the duration of the potential less than 40 microV, the root mean square (RMS) voltage in 10 ms intervals over the first 50 ms and RMS voltage of the last 40, 50 and 60 ms. The filtered QRS duration was significantly shorter in reperfused patients compared with the control group (83 +/- 10 vs 89 +/- 12 ms; P = 0.017). In inferior infarcts (n = 57) the filtered QRS duration was 83 +/- 11 ms in reperfused and 89 +/- 10 ms in non-reperfused patients (P = 0.044), but in anterior infarcts (n = 52) there was no difference. The RMS voltage of the initial 50 ms of the QRS was higher in the reperfused than in non-reperfused anteroseptal infarcts (38 +/- 14 v 23 +/- 10 microV; P = 0.022). Patients successfully treated with thrombolytic agents within the first 2 h had higher RMS voltage of the terminal 40 ms of the QRS than patients treated within 2-4 h (38 +/- 17 vs 27 +/- 17 microV; P = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in blood pressure regulation of congestive heart failure, before and after treatment, correlate with changes in the circulating pattern of atrial natriuretic peptide.

The mechanisms underlying altered BP regulation in congestive heart failure are unknown. This study examines the possibility that differences in circadian blood pressure (BP) regulation between the normal and the failing heart correlate with changes in the circulating pattern of atrial natriuretic peptide (ANP). Twelve normotensive patients with coronary artery disease were studied over two separate 24-h periods, the first during acute exacerbation of congestive heart failure (radionuclide-determined ejection fraction at rest was less than 30%) and the second after therapy-induced functional recovery (ejection fraction was more than 40%). BP monitoring at 10-min intervals and intra-atrial blood samples for ANP assays at hourly intervals were obtained. Significant correlation between ejection fraction and the indexes of circadian BP variability (standard deviation of the 24-h pressure mean and day-night pressure difference) were found both before and after treatment. Ejection fraction was independent of the BP means (24-h, daytime and night-time). BP variability, 24-h mean and daytime mean were higher after treatment. ANP means were lower after treatment, whereas ANP variability was higher. The indexes of BP and ANP variability correlated both before and after treatment, whereas the BP and the ANP means were independent. These findings demonstrate that differences in BP regulation of CHF before and after effective treatment correlate with changes in the circulating pattern of ANP. We speculate that by modulating ANP release, the heart could be actively involved in BP regulation as part of the compensatory mechanisms aimed at protecting against circulatory overload.

Verapamil but not nifedipine impairs left ventricular function during exercise in hypertensive patients.

Calcium antagonists are popular therapeutic agents in the treatment of systemic hypertension. Although these agents have similar antihypertensive efficacy, they have varied effects on left ventricular function at rest in hypertensive patients. The effect of different calcium antagonists on left ventricular function during exercise and on exercise performance in patients with hypertension, however, is less clear. Fifteen patients with essential hypertension (diastolic blood pressure = 95 to 110 mm Hg) were enrolled in a placebo-controlled, single-blinded crossover study comparing nifedipine with verapamil for rest/exercise heart rate and blood pressure, exercise performance, and rest/exercise left ventricular function. Each drug was titrated to achieve resting diastolic pressures less than 90 mm Hg. All patients underwent maximal exercise testing and rest/exercise gated radionuclide ventriculography at the end of 3-week placebo, nifedipine, and verapamil treatment periods. Both calcium antagonists significantly reduced blood pressure at rest and during exercise compared with placebo. Neither calcium antagonist altered resting heart rate; however, both verapamil and nifedipine significantly reduced heart rate at maximal exercise. Verapamil but not nifedipine impaired left ventricular peak emptying rate and left ventricular peak filling rate during exercise but not at rest. Neither verapamil nor nifedipine, however, significantly altered rest or exercise global left ventricular ejection fraction (LVEF) compared with placebo. There was a trend, however, for impairment in the LVEF response to exercise (delta LVEF) in the verapamil treatment group. Exercise capacity was not significantly altered by either calcium antagonist compared with placebo. Thus verapamil but not nifedipine impairs left ventricular function during exercise in hypertensive patients.(ABSTRACT TRUNCATED AT 250 WORDS)