Rochelle L. Goldsmith

Double-Blind, Placebo-Controlled Study of the Long-term Efficacy of Carvedilol in Patients With Severe Chronic Heart Failure

BACKGROUND Clinical trials have shown that beta-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure, but the utility and safety of these drugs in patients with advanced disease have not been evaluated. METHODS AND RESULTS We enrolled 56 patients with severe chronic heart failure into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had advanced heart failure, as evidenced by a mean left ventricular ejection fraction of 0.16 +/- 0.01 and a mean maximal oxygen consumption of 13.6 +/- 0.6 mL.kg-1.min-1 despite digitalis, diuretics, and an angiotensin-converting enzyme inhibitor (if tolerated). After a 3-week, open-label, up-titration period, 49 of the 56 patients were assigned (in a double-blind fashion using a 2:1 randomization) to receive either carvedilol (25 mg BID, n = 33) or matching placebo (n = 16) for 14 weeks, while background therapy remained constant. Hemodynamic and functional variables were measured at the start and end of the study. Compared with the placebo group, patients in the carvedilol group showed improved cardiac performance, as reflected by an increase in left ventricular ejection fraction (P = .005) and stroke volume index (P = .010) and a decrease in pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance (P = .003, .002, and .017, respectively). In addition, compared with placebo, patients treated with carvedilol benefited clinically, as shown by an improvement in symptom scores (P = .002), functional class (P = .013), and submaximal exercise tolerance (P = .006). The combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group (P = .028), but carvedilol-treated patients had more dizziness and advanced heart block. CONCLUSIONS Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors.

Comparison of 24-hour parasympathetic activity in endurance-trained and untrained young men

OBJECTIVES This study compares 24-h parasympathetic activity in aerobically trained and untrained healthy young men. BACKGROUND Higher values of parasympathetic nervous system activity are associated with a low mortality rate in patients after myocardial infarction, but it remains uncertain what therapeutic interventions can be used to increase parasympathetic activity. Although it is thought that exercise training can increase parasympathetic activity, studies have reported conflicting results, perhaps because this variable was measured for only brief intervals and usually inferred from changes in reflex responses induced by pharmacologic blockade. METHODS Parasympathetic activity was assessed noninvasively from 24-h ECG recordings by calculating high frequency (0.15 to 0.40 Hz) beat to beat heart period variability in eight endurance-trained men (maximal oxygen consumption greater than or equal to 55 ml/kg per min) and eight age-matched (mean = 29 yr) untrained men (maximal oxygen consumption less than or equal to 40 ml/kg per min). The data were analyzed separately for sleeping hours when parasympathetic activity is dominant and also for waking hours. RESULTS The geometric mean of high frequency power was greater in the trained than in the untrained men during the day (852 vs. 177 ms2, p less than 0.005), during the night (1,874 vs. 427 ms2, p less than 0.005) and over the entire 24 h (1,165 vs. 276 ms2, p less than 0.001). CONCLUSIONS Parasympathetic activity is substantially greater in trained than in untrained men, and this effect is present during both waking and sleeping hours. These data suggest that exercise training may increase parasympathetic activity over the entire day and may therefore prove to be a useful adjunct or alternative to drug therapy in lessening the derangements of autonomic balance found in many cardiovascular diseases.

Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure

OBJECTIVES This study was conducted to determine the effect of long-term digoxin therapy on autonomic function in patients with mild to moderate chronic heart failure. BACKGROUND Chronic heart failure is characterized by increased sympathetic activity and decreased parasympathetic activity. Intravenous digitalis has been found to reduce sympathetic activity immediately in these patients, but whether short-term neurohormonal effects are sustained during long-term oral therapy has not been assessed. METHODS We determined sympathetic activity in 26 patients with heart failure by measuring plasma norepinephrine levels and parasympathetic activity from variables of heart period variability derived from 24-h ambulatory electrocardiographic Holter recordings obtained before and after 4 to 8 weeks of digoxin therapy. RESULTS After digoxin therapy, plasma norepinephrine decreased significantly from a mean +/- SEM of 552 +/- 80 to 390 +/- 37 ng/ml. In addition, the RR interval increased significantly from 719 +/- 19 to 771 +/- 20 ms. High frequency power increased from 84 +/- 24 to 212 +/- 72 ms2, and the root mean square of successive differences in RR interval increased from 20.3 +/- 1.8 to 27.0 +/- 3.4 ms, indicating a substantial increase in parasympathetic activity. Low frequency power, an index of baroreflex activity, was also significantly increased (239 +/- 80 to 483 +/- 144 ms2) by digoxin therapy. CONCLUSIONS These results indicate 1) that long-term therapy with digoxin acts to ameliorate the autonomic dysfunction of patients with heart failure, and 2) that the short-term neurohormonal effects of digoxin are sustained during prolonged treatment with the drug.

EXERCISE AND AUTONOMIC FUNCTION IN HEALTH AND CARDIOVASCULAR DISEASE

Autonomic nervous system activity contributes to the regulation of cardiac output during rest, exercise, and cardiovascular disease. Measurement of HRV has been particularly useful in assessing parasympathetic activity, while its utility for assessing sympathetic function and overall sympathovagal balance remains controversial. Studies have revealed that parasympathetic tone dominates the resting state, while exercise is associated with prompt withdrawal of vagal tone and subsequent sympathetic activation. Conversely, recovery is characterized by parasympathetic activation followed by sympathetic withdrawal, although clarification of the normal trajectory and autonomic basis of heart rate decay following exercise is needed. Abnormalities in autonomic physiology--especially increased sympathetic activity, attenuated vagal tone, and delayed heart rate recovery--have been associated with increased mortality. Exercise training is associated with a relative enhancement of vagal tone, improved heart rate recovery after exercise, and reduced morbidity in patients with cardiovascular disease. However, whether exercise training leads to reduced mortality in this population because of its ability to specifically modulate autonomic function is unknown at the present time. Although the results of a recent randomized study in patients with CHF and a meta-analysis in the setting of a recent myocardial infarction determined that exercise training leads to improved outcomes in these populations, neither study measured autonomic function. Improved autonomic function due to exercise training is a promising rationale for explaining improvements in outcome, although more research is needed to confirm this hypothesis.

Exercise and autonomic function.

The complex interplay between the dichotomous subdivisions of the autonomic nervous system establishes and maintains a delicately tuned homeostasis in spite of an ever‐changing environment. Aerobic exercise training can increase activity of the parasympathetic nervous system and decrease sympathetic activity. Conversely, it is well‐documented that cardiac disease is often characterized by attenuated parasympathetic activity and heightened sympathetic tone. A correlation between autonomic disequilibrium and disease has led to the hypothesis that exercise training, as a therapy that restores the autonomic nervous system towards normal function, may be associated with, and possibly responsible for, outcome improvements in various populations. This is merely one of the many benefits that is conferred by chronic exercise training and reviewed in this issue.

Role of Endothelin in the Exercise Intolerance of Chronic Heart Failure

In conclusion, plasma levels of the endothelial-derived vasoconstrictor endothelin-1 (but not those of other neurohormonal vasoconstrictor factors), measured during exercise correlated closely with objective variables of exercise capacity in patients with heart failure. These findings suggest that endothelin-1 may contribute to exercise intolerance in patients with heart failure, perhaps by limiting the ability of the peripheral vasculature to dilate during exercise.

Potential of left ventricular assist devices as outpatient therapy while awaiting transplantation

Left ventricular assist devices (LVADs) increasingly are being used as a bridge to transplantation. We studied changes in New York Heart Association class, mean arterial pressure, resting cardiac output, end-organ function, exercise oxygen consumption, and exercise cardiac output in 12 LVAD recipients. In addition, resting levels of neurohormonal factors were evaluated 4 to 16 weeks after implantation. Two of the 12 patients died of right heart failure and 1 of aspiration; all deaths occurred in the first 2 weeks after LVAD implantation. Of the other 9 patients, 8 improved to New York Heart Association class I and 1 to class II, all of whom were in class IV preoperatively. The 4 patients who underwent exercise testing achieved an exercise oxygen consumption of 15.0 +/- 2.7 mL.kg-1.min-1, which was paralleled by an increase in resting cardiac output from 3.07 +/- 0.9 L.min-1 preoperatively to 5.66 +/- 1.1 L.min-1 at 2 months, and mean arterial pressure from 60 +/- 8 to 91 +/- 10 mm Hg at 2 months, a benefit that was maintained for up to 10 months. End-organ function revealed comparable improvement at 2 months for both creatinine (1.68 +/- 0.7 to 1.0 +/- 0.19 mg.dL-1) and total bilirubin (1.37 +/- 1.17 to 0.54 +/- 0.26 mg.dL-1) levels. Levels of neurohormones were within normal limits. Adverse clinical events after the perioperative period were minimal, and no thromboembolic complications occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term carvedilol therapy increases parasympathetic nervous system activity in chronic congestive heart failure

To determine the effect of beta blockade on parasympathetic nervous system activity, we assessed RR variability during 24-hour Holter monitoring in 10 patients with congestive heart failure before and after 3 to 4 months of treatment with the beta blocker carvedilol. High-frequency power increased from 26 to 64 ms2, root-mean-square of successive differences in RR interval increased from 14.3 to 23.7 ms2, and percentage of absolute differences >50 ms between successive normal RR intervals increased from 0.8% to 4.7%, all p <0.01, indicating a substantial increase in parasympathetic modulation of RR intervals.

A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure.

BACKGROUND Cardiac contractility modulation (CCM) delivers nonexcitatory electrical signals to the heart during the absolute refractory period intended to improve contraction. METHODS We tested CCM in 428 New York Heart Association class III or IV, narrow QRS heart failure patients with ejection fraction (EF) ≤ 35% randomized to optimal medical therapy (OMT) plus CCM (n = 215) versus OMT alone (n = 213). Efficacy was assessed by ventilatory anaerobic threshold (VAT), primary end point, peak Vo₂ (pVo₂), and Minnesota Living with Heart Failure Questionnaire (MLWFQ) at 6 months. The primary safety end point was a test of noninferiority between groups at 12 months for the composite of all-cause mortality and hospitalizations (12.5% allowable delta). RESULTS The groups were comparable for age (58 ± 13 vs 59 ± 12 years), EF (26% ± 7% vs 26% ± 7%), pVo₂ (14.7 ± 2.9 vs 14.8 ± 3.2 mL kg⁻¹ min⁻¹), and other characteristics. While VAT did not improve at 6 months, CCM significantly improved pVo₂ and MLWHFQ (by 0.65 mL kg⁻¹ min⁻¹ [P = .024] and -9.7 points [P < .0001], respectively) over OMT. Forty-eight percent of OMT and 52% of CCM patients experienced a safety end point, which satisfied the noniferiority criterion (P = .03). Post hoc, hypothesis-generating analysis identified a subgroup (characterized by baseline EF ≥ 25% and New York Heart Association class III symptoms) in which all parameters were improved by CCM. CONCLUSIONS In the overall target population, CCM did not improve VAT (the primary end point) but did improve pVo₂ and MLWHFQ. Cardiac contractility modulation did not have an adverse affect on hospitalizations or mortality within the prespecified boundaries. Further study is required to clarify the role of CCM as a treatment for medically refractory heart failure.

Comparison of functional capacity in patients with end-stage heart failure following implantation of a left ventricular assist device versus heart transplantation: results of the experience with left ventricular assist device with exercise trial.

BACKGROUND Use of a permanent left ventricular assist device (LVAD) has been proposed as an alternate treatment of patients with end-stage heart failure. The purpose of this study was to compare the functional capacity of patients following implantation of a LVAD vs heart transplant (HTx). METHODS Eighteen patients from 6 centers who received an intracorporeal LVAD as a bridge to HTx underwent treadmill testing 1 to 3 months post-LVAD and again post-HTx. Baseline and peak measurements, including oxygen consumption, blood pressures, and respiratory rate were made during each treadmill test. RESULTS Peak oxygen consumption was 14.5+/-3.9 ml/kg/minute post-LVAD and 17.5+/-5.0 ml/kg/minute post-HTx (p < .005). The percentage of the predicted peak oxygen consumption based on gender, weight, and age was 39.5%+/-5.5% post-LVAD and 47.7%+/-10.9% post-HTx (p < .005). Exercise duration was lower post-LVAD than post-HTx (10.3+/-4.2 minute vs 12.5+/-5.4 minute, p < .05). After LVAD implantation, peak total oxygen consumption correlated with peak LVAD rate and output. Eight patients reached an LVAD rate of 120 beats per minute (bpm) before the conclusion of exercise, the maximum rate for the outpatient electric device. The peak respiratory exchange ratio post-LVAD was 1.15+/-0.22 and post-HTx was 1.15+/-0.18, consistent with a good effort in both groups. CONCLUSIONS Patients demonstrated a lower functional capacity post-LVAD than post-HTx. For some patients functional capacity post-LVAD may be improved by a higher maximum LVAD rate and output.