Value of carvedilol in congestive heart failure secondary to coronary artery disease

Despite considerable interest in the use of beta-blocking agents in congestive heart failure (CHF), their clinical application is limited because of their negative inotropic effects. Beta blockers with vasodilating properties may have the advantage of overcoming this, however. Carvedilol, a beta-blocking agent with vasodilating properties, was evaluated in 17 patients with chronic CHF secondary to ischemic heart disease with a resting left ventricular ejection fraction less than or equal to 45%, who were being maintained on diuretics. Exercise testing, radionuclide ventriculography, and right-sided cardiac catheterization were performed and intraarterial blood pressure measured before and after 8 weeks of carvedilol therapy in a dosage of 12.5 to 50.0 mg twice a day. Twelve patients completed the study and 5 withdrew. Symptomatic and hemodynamic improvement was demonstrated in 11 of the 12 patients. Heart rate and intraarterial blood pressure were both reduced by chronic therapy. Mean +/- standard deviation exercise time improved from 4.3 +/- 1.6 to 7.1 +/- 2.7 minutes (p less than 0.0001), as did resting left ventricular ejection fraction, from 27 +/- 9 to 31 +/- 11% (p less than 0.02). Pulmonary arterial wedge pressure fell from 19 +/- 7 mm Hg to 12 +/- 5 mm Hg (p less than 0.001) and total systemic vascular resistance from 1,752 +/- 403 to 1,497 +/- 310 dynes/s/cm-5/m2 (p less than 0.02). Stroke volume index improved also, from 31 +/- 6 ml to 40 +/- 6 ml (p less than 0.0005). These hemodynamic changes were mediated partly by vasodilation, diminished myocardial oxygen demand and reduction of sympathetic overactivity in the failing heart. These data suggest that carvedilol may have beneficial effects in patients with chronic CHF secondary to coronary artery disease.     

Enhanced metabolic vasodilation secondary to diuretic therapy in decompensated congestive heart failure secondary to coronary artery disease

Since sodium and water retention have been implicated as major factors limiting maximal metabolic vasodilation in congestive heart failure (CHF), the effect of rigorous diuresis on maximal vasodilatory capacity was studied systematically in 9 subjects hospitalized with decompensated CHF. Peak reactive hyperemic blood flow, measured by straingauge plethysmography, was used as an index of maximal vasodilatory capacity. After 24 hours of diuresis and a 2.2-kg weight loss, maximal flow increased from 19.9 to 26.1 ml/min · 100 ml (p < 0.05). Despite a further 1.4-kg weight loss between 24 and 48 hours, maximal blood flow increased no more (26.1 to 25.8 ml/min · 100 ml). Since blood pressure did not change significantly, minimal forearm resistance and maximal conductance showed similar improvements. It is unlikely that vasoconstrictor hormone changes could account for this effect since a marked decrease in plasma norepinephrine occurred in only 2 of 8 subjects and plasma renin activity decreased in only 1 subject. As a group there was no significant change in norepinephrine level, which remained substantially above normal (1,525 to 1,148 pg/ml), or in plasma renin activity (12.3 to 18.9 ng/ml/hour). Because the improvement in vasodilator capacity reached a plateau by 24 hours despite continued diuresis, and because peak reactive hyperemic blood flow was still 32% below normal, it is suggested that a second mechanism besides sodium and water retention is responsible for a significant portion of the impaired peripheral vasodilation in CHF.     

高位硬膜外阻滞治疗充血性心力衰竭的机制探讨

充血性心力衰竭(congestive heartfailure,CHF)是各种病因所致的心脏病的终末阶段。Packer在1988年首先提出了神经内分泌系统对CHF的作用,现在已经公认CHF的发生、发展是神经内分泌系统被过度激活,长期发展作用的结果。一些学者根据冠状动脉循环的神经内分泌体液调节机制,把麻醉学上常用的技术——高位硬膜外阻滞(thoracic epidural anesthesia,TEA)应用于心脏病的治疗,并取得了令人鼓舞的效果。本文就目前资料来探讨TEA在CHF治疗方面的机制。     

Failure of captopril to prevent nitrate tolerance in congestive heart failure secondary to coronary artery disease

The possible role of angiotensin-converting enzyme inhibition in preventing or minimizing tolerance to intravenous nitroglycerin in severe congestive heart failure (CHF) was studied by quantitating the degree of tolerance in 12 patients receiving nitroglycerin (group 1) and in 9 patients (group 2) receiving nitroglycerin and concurrent treatment with captopril (60 +/- 29 mg/day). At peak effect, nitroglycerin produced almost identical hemodynamic changes in both groups, with significant decreases in right atrial and pulmonary arterial wedge pressure, systolic blood pressure and systemic and pulmonary vascular resistances. Cardiac index increased. The extent of nitrate tolerance was calculated for each hemodynamic parameter as the percentage loss of the peak effect achieved by the drug. At 24 hours, 98 +/- 80% of the benefit achieved with respect to right atrial pressure was lost in group 1 and 61 +/- 74% in group 2 (group 1 vs 2, difference not significant). For pulmonary arterial wedge pressure, 51 +/- 31% (group 1) and 85 +/- 53% (group 2) (difference not significant) of the effect was lost, and for cardiac index, 53 +/- 58% (group 1) and 54 +/- 44% (group 2) (difference not significant). Tolerance was also almost identical regarding systolic blood pressure and systemic and pulmonary vascular resistance. Thus, the extent of tolerance to high-dose intravenous nitroglycerin in CHF was unaltered by administration of captopril, indicating that in clinical dosage, counter-regulatory neurohumoral mechanisms involving the renin-angiotensin system appear to be unimportant in its development.     

Comparison of different methods for assessing sympathovagal balance in chronic congestive heart failure secondary to coronary artery disease.

Twenty-five patients (aged 62 +/- 2 years) with stable, moderate to severe ischemic congestive heart failure (CHF) (New York Heart Association class II/III: 15/10; ejection fraction 21.6 +/- 2%; and peak oxygen uptake 13.6 +/- 0.7 ml/kg/min) were studied to evaluate the ability of different methods to characterize autonomic tone in chronic CHF. Sympathovagal balance was assessed by: (1) heart rate variability in the time domain, assessed by the SD of RR intervals; (2) heart rate variability in the frequency domain, assessed by low- (0.03 to 0.14 Hz) and high- (0.18 to 0.40 Hz) frequency components of heart rate variability by autoregressive power spectral analysis; (3) 24-hour, daytime and nighttime heart rate; (4) submaximal heart rate during upright bicycle exercise, with respiratory gas analysis to obtain peak oxygen uptake; and (5) radiolabeled norepinephrine spillover. These methods did not correlate, with the exception of day and nighttime heart rate (r = 0.74; p < 0.001) and the expected inverse correlation between low and high frequency (r = -0.92; p < 0.001). No method correlated significantly with peak oxygen uptake, exercise tolerance or ejection fraction. After 8 weeks of physical training at home, all methods showed improvement in autonomic balance: increases in SD of RR intervals (+21%; p < 0.02) and high frequency (+41%; p < 0.007), and decreases in low frequency (-19%; p < 0.002), low-/high-frequency ratio (-48%; p < 0.03), norepinephrine spillover (-28.9%; p < 0.03), 24-hour heart rate (-2.7%; p < 0.005) and submaximal heart rate (-10.8%; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term predictors of sudden and low output death in chronic congestive heart failure secondary to coronary artery disease

Clinical, hemodynamic and neurohumoral variables in 238 patients with chronic congestive heart failure (CHF) secondary to coronary artery disease were analyzed to determine potential predictors of mortality in a large population and to allow analysis according to mode of death (sudden or low output death). All variables were assessed before initiation of treatment with vasodilators (converting enzyme inhibitors, direct acting vasodilators) or with the nonglycoside, noncatecholamine class of inotropic agents. Survival outcome was determined as alive, sudden death or low output death. When all variables except ejection fraction were analyzed by Cox multiple regression analysis, the most important independent predictor of all deaths was the baseline plasma renin activity (p less than 0.001). When subdivided by cause of cardiovascular death, baseline plasma renin activity was retained as the most important determinant of low output death (p less than 0.001), whereas baseline left ventricular stroke work index (p less than 0.001), pulmonary capillary wedge pressure (p less than 0.002) and absence of sinus rhythm (p less than 0.006) were the most powerful independent predictors of sudden death. Plasma norepinephrine was markedly elevated in the group dying of low output, but only modestly elevated in the group of survivors and the group dying suddenly. However, baseline norepinephrine was not found to be an important independent predictor of mortality in any of the subgroups. Plasma renin activity, but not plasma norepinephrine, is a powerful independent prognostic determinant of mortality in this group of patients with CHF.     

Dissociation of the prostaglandin and renin angiotensin systems during captopril therapy for chronic congestive heart failure secondary to coronary artery disease

Neurohumoral systems are activated as compensatory mechanisms in congestive heart failure (CHF). A close correlation has been reported between the renin angiotensin and prostaglandin systems in CHF. Furthermore, serum sodium concentration provided an excellent index of hormonal status. In this study, these relations were examined after acute and chronic blockade of renin angiotensin system with captopril. Eight patients with advanced CHF (New York Heart Association III or IV) were studied. Before captopril treatment, all hormone levels were elevated. Mean plasma renin activity was 24 +/- 7 ng Al/ml/hour, angiotensin concentration was 221 +/- 11 pg/ml and aldosterone concentration was 82 +/- 17 pg/ml. Plasma PGE2 metabolite was 1,425 +/- 321 pg/ml. A close correlation was observed between plasma angiotensin II and PGE2 metabolite levels (r = 0.7); inverse correlations existed between serum sodium concentration and PGE2 metabolite levels (r = -0.9) and with plasma renin activity (r = -0.6). Captopril therapy reduced the plasma angiotensin II level to 38 +/- 6 pg/ml and aldosterone concentration to 15 +/- 3 pg/ml, but did not affect plasma renin activity (31 +/- 10 ng Al/ml/hour) when measured in 1 week. Paradoxically, PGE2-metabolite levels increased further (to 3,031 +/- 346 pg/ml) despite blockade of the renin angiotensin system. Serum sodium concentration no longer correlated with hormone levels. These effects were sustained at 2 months of follow-up. Thus, captopril caused a dissociation between the renin angiotensin system and prostaglandin. The activation of prostaglandin is probably due to captopril's effect on prostaglandin biosynthesis and may contribute to captopril's sustained efficacy in CHF.     

Incremental prognostic value of exercise hemodynamic variables in chronic congestive heart failure secondary to coronary artery disease or to dilated cardiomyopathy

To determine the prognostic value of hemodynamic variables at rest and during exercise, 49 patients with chronic congestive heart failure undergoing hemodynamic evaluation at rest and during symptom-limited exercise were followed for 1 year. One-year mortality rate was 33%. On univariate analysis, nonsurvivors differed significantly from survivors in pulmonary arterial wedge pressure at rest (22 +/- 10 vs 15 +/- 10 mm Hg; p = 0.01) and during exercise (32 +/- 9 vs 24 +/- 9 mm Hg; p = 0.003), stroke work index at rest (19 +/- 6 vs 25 +/- 9 g-m/m2; p = 0.03) and during exercise (20 +/- 7 vs 32 +/- 14 g-m/m2; p = 0.001) and exercise-induced increment in stroke work index (0.5 +/- 0.4 vs 7 +/- 8 g-m/m2; p = 0.004), but not with respect to left ventricular ejection fraction, exercise duration, peak oxygen consumption or peak left ventricular hydraulic power. Patients with a peak exercise stroke work index less than 20 g-m/m2 had a 66% mortality rate compared with a mortality rate of 13% in patients with a peak exercise stroke work index greater than 20 g-m/m2 (p = 0.0001). Multiple logistic regression analysis identified pulmonary arterial wedge pressure at rest and peak exercise stroke work index as the only independent predictors of mortality. A receiver-operating characteristic curve analysis revealed that peak exercise stroke work index provided significant incremental prognostic information over the resting hemodynamic variables.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease

In chronic heart failure, a diuretic plus an angiotensin-converting enzyme (ACE) inhibitor only partially suppresses aldosterone despite the fact that aldosterone has many harmful effects independent of angiotensin II. These possible harmful effects of aldosterone are magnesium loss, increased cardiac sympathetic activity, and increased ventricular arrhythmias. We have therefore assessed whether adding the aldosterone antagonist, spironolactone, to a loop diuretic and ACE inhibitor reverses any of these potentially harmful effects of residual aldosterone. In a preliminary animal study, we found that exogenous aldosterone reduced myocardial norepinephrine uptake by 24% in anesthetized rats in vivo. In our main study, 42 patients with New York Heart Association II to III congestive heart failure were randomized to spironolactone (50 to 100 mg/ day, titrated to blood pressure and plasma potassium) or placebo in a double-blind fashion. Our principal finding is that cardiac norepinephrine uptake as assessed by ¹²³I-metaiodobenzylguanidine scintigraphy increased with spironolactone (p < 0.01). Spironolactone also elevated plasma magnesium (p < 0.05), reduced urinary magnesium excretion (p < 0.05), and caused a reduction in ventricular arrhythmias on 24-hour ambulatory electrocardiography (p < 0.05). Spironolactone increased plasma renin activity, plasma aldosterone (p < 0.01), 24-hour urinary sodium excretion (p < 0.05), and urinary sodium/potassium ratio (p < 0.01). Echocardiographic-determined measurements of left ventricular systolic and diastolic function were unaltered by spironolactone. Therefore, spironolactone has potentially beneficial effects on cardiac adrenergic tone, divalent cation balance, and ventricular arrhythmias in patients with chronic heart failure who are already receiving standard doses of ACE inhibitors. All of these factors could be significant in the prevention of sudden cardiac death in this population.     

Reproducibility and relation to mean heart rate of heart rate variability in normal subjects and in patients with congestive heart failure secondary to coronary artery disease

Before heart rate (HR) variability can be used for predictive purposes in the clinical setting, day-to-day variation and reproducibility need to be defined as do relations to mean HR. HR variability and mean HR were therefore determined in 2 successive 24-hour ambulatory electrocardiograms obtained from 33 normal subjects (age 34 ± 7 years, group I), and 22 patients with coronary disease and stable congestive heart failure (CHF) (age 59 ± 7 years, group II). Three measures were used: (1) SDANN (standard deviation of all mean 5-minute normal sinus RR intervals in successive 5-minute recording periods over 24 hours); (2) SD (the mean of the standard deviation of all normal sinus RR intervals in successive 5-minute recording periods over 24 hours); and (3) CV (coefficient of variation of the SD measure), a new measure that compensates for HR effects. Group mean HR was higher and HR variability lower in group II than in group I (80 ±10 vs 74 ± 9 beats/min, p < 0.04). Mean group values for HR and HR variability showed good correlations between days 1 and 2 (mean RR, R = 0.89, 0.97; SDANN, R = 0.87, 0.87; SD, R = 0.93, 0.97; CV, R = 0.95, 0.97 in groups I and II, respectively). In contrast, considerable individual day-to-day variation occurred (group I, 0 to 46%; group II, 0 to 51%). Low HR variability values were more consistent than high values. SDANN and SD correlated moderately with HR in both groups (r = 0.50 to 0.64). The CV measure minimizes HR effects on HR variability. In conclusion (1) mean group differences in HR variability between normal subjects and patients with CHF are highly reproducible, but considerable day-to-day variations may occur in some subjects, particularly normal persons with high HR variability; (2) mean HR is higher and HR variability lower in patients with CHF; and (3) mean HR must be considered when interpreting changes in HR variability. The CV measure minimizes this problem.     

Noninvasive evaluation of systolic and diastolic function in severe congestive heart failure secondary to coronary artery disease or idiopathic dilated cardiomyopathy

The usefulness of systolic time intervals, diastolic time intervals and echocardiography in evaluating left ventricular (LV) function was determined in 69 patients with severe congestive heart failure. All systolic time intervals were markedly abnormal (preejection period/LV ejection time 0.59 +/- 0.18 vs 0.30 +/- 0.04, preejection period index 170 +/- 37 vs 117 +/- 11, LV ejection time index 372 +/- 26 vs 410 +/- 17; patients vs control subjects, p less than 0.05). Diastolic time intervals in patients were not different from those in control subjects. Echocardiographic measurements were all markedly abnormal (LV end-diastolic dimension 6.9 +/- 1.0 vs 4.8 +/- 0.4 cm, patients vs control subjects, p less than 0.05). No pattern of abnormalities distinguished ischemic cardiomyopathies from idiopathic dilated cardiomyopathies. The presence of LV conduction delay did not substantially alter results, except that exclusion of patients with LV conduction delay normalized the total time of systole (QA2) index (from 542 +/- 40 to 531 +/- 31 ms) and reduced but did not normalize prolongation in the preejection period index (from 170 +/- 37 to 162 +/- 29 ms). No systolic or diastolic interval strongly correlated with any hemodynamic or other independent measure of LV performance. Twenty-four patients were given inotropic or unloading agents, which significantly improved hemodynamic values. Systolic and diastolic intervals were measured at baseline and at maximal hemodynamic effect. The correlation of changes in hemodynamics with changes in systolic and diastolic intervals was only modest. Thus, although systolic time intervals and associated echocardiographic measurements can detect abnormal LV function, they cannot reliably detect a change in LV function or distinguish gradations of abnormality.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative hemodynamic and clinical effects of long-term treatment with prazosin and captopril for severe chronic congestive heart failure secondary to coronary artery disease or idiopathic dilated cardiomyopathy

Short- and long-term hemodynamic and clinical responses to sequential therapy with prazosin (15 mg/day for 3 to 12 weeks) and captopril (75 to 300 mg/day for 2 to 15 weeks) were compared in 22 patients with severe chronic congestive heart failure. First doses of prazosin produced marked increases in cardiac index and stroke volume index (p less than 0.01), but these effects were lost during long-term treatment. First doses of captopril produced only modest increases in both variables, but these persisted without attenuation during prolonged therapy. Both drugs produced immediate decreases in left ventricular filling pressure, mean arterial pressure, mean right atrial pressure and systemic vascular resistance; these changes became significantly attenuated (p less than 0.01) with prazosin but not with captopril. At the end of treatment, stroke volume index was significantly higher and right and left ventricular filling pressures were significantly lower with captopril than with prazosin (p less than 0.05 to 0.01). Only 8 of the 22 patients (36%) treated with prazosin benefited clinically, whereas 14 of 19 patients (74%) treated with captopril felt that they had improved (p less than 0.05). These differences could not have been predicted by comparing responses to first doses of the 2 drugs. These findings indicate that the choice of 1 vasodilator drug over another in patients with congestive heart failure should be based on studies that compare their long-term rather than short-term hemodynamic and clinical effects.     

Effects of CI-914 in congestive heart failure due to coronary artery disease or idiopathic cardiomyopathy

The hemodynamic effects of CI-914, a phosphodiesterase inhibitor, were studied in 12 patients with left ventricular (LV) dysfunction who were undergoing diagnostic cardiac catheterization. CI-914 was infused intravenously at a rate of 0.8 to 7.0 micrograms/kg/min for 30 to 60 minutes; hemodynamic values were measured every 10 minutes. No effect was seen in the patient receiving 0.8 microgram/kg/min. At infusion rates of 1.2 to 2.4 micrograms/kg/min, cardiac index increased by 14% (p less than 0.025). At infusion rates of 4.5 to 7.0 micrograms/kg/min, cardiac index increased by 21% (n = 8, difference not significant [NS]). Among 4 patients (group B) with an initial pulmonary artery wedge pressure greater than 20 mm Hg and cardiac index less than 2.5 liters/min/m2, cardiac index increased by 50% (p less than 0.001); it did not change among the 4 patients with an initial pulmonary artery wedge pressure of less than 20 mm Hg and cardiac index of more than 2.5 liters/min/m2 (group A). Although systemic vascular resistance decreased in all 8 patients by 26% (p less than 0.01), the reduction was greater in group B (33%, p less than 0.01) than in group A (16%, NS). Peak +dP/dt increased in all 8 patients by 13% (p less than 0.01). Mean stroke work index increased from 29 +/- 15 to 34 +/- 13 g-m/m2; the double product fell from 101 +/- 31 to 91 +/- 23 (NS). In all 12 patients, a linear correlation between peak venous blood concentration and peak effect on cardiac index, systemic vascular resistance and pulmonary artery wedge pressure was observed.(ABSTRACT TRUNCATED AT 250 WORDS)