Michael L. Fisher

Dual-chamber pacing with a short atrioventricular delay in congestive heart failure: A randomized study

OBJECTIVES This prospective study assessed the initial hemodynamic effects and long-term clinical benefits of dual-chamber pacing with a short atrioventricular (AV) delay in patients with chronic heart failure who had no traditional indication for pacemaker implantation. BACKGROUND Dual-chamber pacing with a short AV delay has been proposed as a nonpharmacologic treatment for drug-refractory heart failure. Both initial and long-term hemodynamic as well as functional benefits have been reported. All previous studies have used an AV delay of 100 ms. Despite encouraging results, these previous studies have been anecdotal and uncontrolled. METHODS This double-blind, randomized, crossover trial included 12 subjects with chronic congestive heart failure despite optimal medical therapy. Patients were required to be in sinus rhythm with no evidence of significant bradyarrhythmias. On the day after implantation of a dual-chamber pacemaker, invasive hemodynamic measurements were made at varying AV delays between 100 and 200 ms. Patients were then randomized to either dual-chamber pacing with a 100-ms AV delay or backup mode (VVI at 40 beats/min). After 4 to 6 weeks, crossover to the other pacing mode was programmed. RESULTS Hemodynamic measurements on the day after pacemaker implantation demonstrated no benefit of pacing with any AV delay compared with intrinsic conduction. At the optimal AV interval for each patient, neither cardiac output (4.5 +/- 1.5 vs 4.7 +/- 1.6 liters/min [mean +/- SD]) nor wedge pressure (16 +/- 10 vs 17 +/- 8 mm Hg) improved significantly from baseline measurements during intrinsic conduction. The long-term pacing protocol was completed in nine patients. Ejection fraction was 16 +/- 6% with dual-chamber (VDD mode) pacing and 18 +/- 4% in backup mode (p = NS). No patient had an increase in ejection fraction by > or = 5% with VDD pacing, nor did any patient improve in New York Heart Association functional class with short AV delay dual-chamber pacing. Also, there were no significant reductions in body weight or diuretic requirements during this pacing period. CONCLUSIONS Dual-chamber pacing with a short AV delay does not improve hemodynamic and clinical status or ejection fraction measured on the day after pacemaker implantation in patients with chronic congestive heart failure. Routine use of pacemaker therapy with a short AV delay aas a primary treatment of heart failure in patients without standard arrhythmic indications is unwarranted.

Nesiritide does not improve renal function in patients with chronic heart failure and worsening serum creatinine

Background—Nesiritide (synthetic human brain natriuretic peptide) is approved for the treatment of symptomatic heart failure. However, studies of brain natriuretic peptide in patients with heart failure have come to conflicting conclusions about effects on glomerular filtration rate (GFR), effective renal plasma flow, natriuresis, and diuresis. Methods and Results—To identify a population at high risk of renal dysfunction with conventional treatment, we selected patients with a creatinine level increased from baseline (within 6 months). We examined the effects of nesiritide on GFR (measured by iothalamate clearance), renal plasma flow (measured by para-amino hippurate clearance), urinary sodium excretion, and urine output in a double-blind, placebo-controlled, crossover study. Patients received nesiritide (2 &mgr;g/kg IV bolus followed by an infusion of 0.01 &mgr;g/kg per minute) or placebo for 24 hours on consecutive days. Nesiritide and placebo data were compared by repeated-measures analysis and Student t test. We studied 15 patients with a recent mean baseline creatinine of 1.5±0.4 mg/dL and serum creatinine of 1.8±0.8 mg/dL on admission to the study. There were no differences in GFR, effective renal plasma flow, urine output, or sodium excretion for any time interval or for the entire 24-hour period between the nesiritide and placebo study days. For 24 hours, urine output was 113±51 mL/h with placebo and 110±56 mL/h with nesiritide. GFR during placebo was 40.9±25.9 mL/min and with nesiritide was 40.9±25.8. Conclusions—Nesiritide did not improve renal function in patients with decompensated heart failure, mild chronic renal insufficiency, and renal function that had worsened compared with baseline. The lack of effect may be related to renal insufficiency, hemodynamic alterations, sodium balance, severity of heart failure, or drug dose. Understanding the importance of these issues will permit effective and appropriate use of nesiritide.

Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial.

OBJECTIVES This clinical trial was performed to determine the safety and clinical impact of titrated metoprolol therapy in patients with heart failure, documented coronary artery disease and a low ejection fraction. BACKGROUND Despite known cardiodepressant effects, long-term use of beta-adrenergic antagonists appears to be beneficial in patients with idiopathic dilated cardiomyopathy. However, this therapy has not been critically evaluated in patients with heart failure and coronary artery disease. METHODS In 50 patients with heart failure, known coronary artery disease and an ejection fraction < or = 0.40, we examined the impact of metoprolol therapy in a 6-month double-blind, placebo-controlled randomized trial, assessing the frequency of heart failure exacerbations and changes in symptoms (New York Heart Association functional class), ejection fraction and exercise duration. Placebo-treated patients who completed 6-month follow-up studies then underwent a trial with metoprolol therapy (crossover group). RESULTS Metoprolol was titrated to a mean maximal dose of 87 mg/day (range 25 to 100) without serious adverse reactions. During double-blind therapy, use of a beta-blocker was associated with a significant reduction in the number of hospital admissions (4% vs. 32%, p < 0.05), overall improved functional class (p = 0.02), increased ejection fraction (4 +/- 7% [mean +/- SD] compared with 0 +/- 6%, p < 0.05) and a greater increase in exercise duration (193 +/- 276 vs. 38 +/- 213 s with placebo, p < 0.01). Crossover outcome paralleled the favorable impact seen during randomized metoprolol therapy. CONCLUSIONS Cautious use of titrated metoprolol appears to be safe and beneficial when added to standard heart failure therapy in patients with dilated cardiomyopathy associated with coronary artery disease.

Increased Resting Metabolic Rate in Patients with Congestive Heart Failure

Cardiac cachexia, which is characterized by a negative energy balance and subsequent weight loss and systemic wasting, occurs frequently in patients with end-stage heart failure [1]. It is unclear whether reduction in caloric intake or elevated caloric expenditure causes this condition. We know of no recent studies that have systematically investigated resting metabolic rate and body composition in patients with heart failure and documented systolic dysfunction. Thus, we investigated a cohort of patients with heart failure, using indirect calorimetry to measure resting metabolic rate, dual energy x-ray absorptiometry to measure body composition, and food diaries to measure caloric intake. We then compared the results with those from an age-matched cohort of healthy volunteers. Methods Patients Twenty patients with documented dyspnea and fatigue during ordinary physical activity were recruited by the Heart Failure Service at the Baltimore Veterans Affairs Medical Center. Patients were male (7 were black and 13 were white), and each had a mean left ventricular ejection fraction (SD) by radionuclide ventriculography of 0.24 0.10 (range, 0.06 to 0.40). Mean time (SD) since diagnosis was 45 36 months. Patients were taking two or more of the following medications: diuretics, digoxin, and vasodilators (angiotensin-converting enzyme inhibitors or hydralazine-nitrates). Symptoms were stable, patients were in New York Heart Association functional class II (n = 2), III (n = 14), or IV [n = 4], and no concomitant acute disease was present. Forty healthy, age-matched male volunteers served as controls. Reasons for excluding volunteers from the control cohort included 1) cardiomyopathy or clinical evidence of coronary heart disease, such as ST-segment depression 1 mm at rest or exercise; 2) hypertension with resting blood pressure greater than 140/90 mm Hg; and 3) noncardiac disease that limited exercise performance, such as arthritis, peripheral vascular disease, and cerebral vascular disease. This study was approved by the Committee on Human Research at the University of Maryland, and written informed consent was obtained from each patient and control before the investigation. Timing of Tests Methods for the timing of tests have been previously described [2]. At approximately 8:30 a.m., after patients and controls had completed a 12-hour fast in a darkened, temperature-controlled room, their resting metabolic rates were measured for 45 minutes. Each patient or control was placed in a supine position with a clear plastic hood over his head. Room air was continuously drawn through the hood and the flow rate was measured by a pneumotachograph. Oxygen consumption and carbon dioxide production were continuously measured and analyzed and converted to a caloric equivalent (kcal/d) using the Weir equation [3]. Daily caloric intake and daily macronutrient intake were estimated from a 3-day (2 weekdays and 1 weekend day) food diary. Fat-free mass and fat mass were measured using a total body scan with dual-energy x-ray absorptiometry (Model DPX-L, Lunar Radiation Corp., Madison, Wisconsin). Peak oxygen consumption (Vo 2) was assessed by a progressive, symptom-limited treadmill exercise test in which the speed of the treadmill was constant and the incline was increased by 2% every 2 minutes. Statistical Analysis The physical characteristics of cohorts and patients with heart failure were compared using unpaired t-tests. The relation between variables was measured by linear regression analysis. A one-way analysis of covariance examined whether resting metabolic rate differed between controls and patients with heart failure after we statistically controlled for differences in fat-free mass. Values are expressed as mean SD. Results Because no differences were noted between black and white patients, data for all patients were pooled. No differences in age or body weight existed between controls and patients with heart failure Table 1, but because patients with heart failure were shorter than controls (P = 0.08), the body mass index in patients with heart failure was higher than it was in controls (P < 0.05). Fat-free mass tended to be lower in patients with heart failure (P = 0.09), but no difference in fat mass existed. Predictably, peak Vo 2 was lower (P < 0.01) in patients with heart failure. No difference was noted in daily caloric intake between groups. Table 1. Physical Characteristics in Healthy Men and Patients with Congestive Heart Failure* Measured resting metabolic rate (kcal/d) was 18% higher in patients with heart failure (mean, 1828 275 kcal/d [95% CI, 1289 to 2367 kcal/d]) than in controls (1543 219 kcal/d [95% CI, 1114 to 1972 kcal/d]; P < 0.01). Resting metabolic rate correlated with fat-free mass in both groups (Figure 1). When statistically adjusted for differences in fat-free mass, the mean difference in resting metabolic rate between patients with heart failure (1875 178 kcal/d) and controls (1521 171 kcal/d) was magnified. Figure 1. Relation between resting metabolic rate (kcal/d) and fat-free mass in patients with heart failure and controls. Discussion The higher resting metabolic rate in patients with heart failure probably contributes to weight loss and musculoskeletal wasting. The difference in resting metabolic rate between elderly patients with heart failure and healthy elderly persons is clinically significant (18%; 283 kcal/d). When resting metabolic rate data for each group were compared after being normalized for differences in fat-free mass, the higher resting metabolic rate in patients with heart failure compared with that in healthy elderly persons was even more striking ( 354 kcal/d). These data highlight the importance of factors other than simple reduction in caloric intake that contribute to weight loss, which complicates the course of many patients with late-stage heart failure. It is unlikely that abnormalities in the two other components of daily caloric expenditure contribute substantially to weight loss in patients with heart failure; that is, the caloric expenditure associated with meal consumption constitutes only 10% of daily caloric expenditure [4], and the deconditioned state of patients with heart failure diminishes the possibility that a high level of caloric expenditure associated with physical activity is an important factor. A voluntary reduction in caloric intake is commonly thought to contribute to the weight loss of patients with heart failure [1], but we found no difference in reported daily caloric intake between patients with heart failure and controls. However, it should be acknowledged that difficulties and inaccuracies associated with reporting of food intake exist [5]. Resting metabolic rate is frequently used to establish daily caloric requirements in both healthy and diseased elderly persons [6]. Data from our study suggest that such guidelines, if based on the caloric requirements of healthy persons, would be inappropriate for patients with heart failure. Using recent equations generated from a healthy elderly cohort in our laboratory would underestimate resting metabolic rate in patients with heart failure by 270 kcal per day (measured, 1828 kcal/d; predicted, 1556 kcal/d) [7]. The mechanism for the higher resting metabolic rate in patients with heart failure is unknown. Increased myocardial oxygen requirements and the increased metabolic cost of breathing may contribute [1], but it is probable that systemic factors are also important. Circulating levels of tumor necrosis factor are higher in patients with heart failure [8], but the relation of this to resting metabolic rate is unknown. A more likely explanation is elevated sympathetic nervous system activity, which is typically seen in patients with heart failure, especially heart failure in its advanced stages [9]. We have shown that resting metabolic rate increases in relation to increments in the rate of norepinephrine appearance into circulation [2]. Thus, it is likely that overactivity of the sympathetic nervous system is involved in the pathogenesis of the higher resting metabolic rate in patients with heart failure. Future studies in patients with heart failure should address this important hypothesis. A higher resting metabolic rate in patients with heart failure may at least partially account for otherwise unexplained weight loss. Present caloric guidelines established in healthy elderly persons significantly underestimate the resting caloric needs of elderly patients with heart failure. Proper nutritional and physical activity interventions could reverse or prevent weight loss in patients with heart failure, improve their functional capacity and body composition, and possibly alter the long-term evolution of cardiac dysfunction.

Effects of BG9719 (CVT-124), an A1-Adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure

OBJECTIVES To determine the effects of furosemide and the selective A1 adenosine receptor BG9719 on renal function in patients with congestive heart failure (CHF). BACKGROUND Studies suggest that adenosine may affect renal function by various mechanisms, but the effects of blockade of this system in humans is unknown. In addition, the effects of a therapeutic dose of furosemide on glomerular filtration rate (GFR) and renal plasma flow (RPF) in heart failure patients are controversial. METHODS On different days, 12 patients received placebo, BG9719 and furosemide. Glomerular filtration rate, RPF and sodium and water excretion were assessed immediately following drug administration. RESULTS Glomerular filtration rate was 84 +/- 23 ml/min/1.73m2 after receiving placebo, 82 +/- 24 following BG9719 administration and a decreased (p < 0.005) 63 +/- 18 following furosemide. Renal plasma flow was unchanged at 293 +/- 124 ml/min/1.73m2 on placebo, 334 +/- 155 after receiving BG9719 and 374 +/- 231 after receiving furosemide. Sodium excretion increased from 8 +/- 8 mEq following placebo administration to 37 +/- 26 mEq following BG9719 administration. In the six patients in whom it was measured, sodium excretion was 104 +/- 78 mEq following furosemide administration. CONCLUSIONS Natriuresis is effectively induced by both furosemide and the adenosine A1 antagonist BG9719 in patients with CHF. Doses of the two drugs used in this study did not cause equivalent sodium and water excretion but only furosemide decreased GFR. These data suggest that adenosine is an important determinant of renal function in patients with heart failure.

Routine preoperative exercise testing in patients undergoing major noncardiac surgery

A prospective study of preoperative exercise testing was carried out in 200 patients older than 40 years scheduled for elective major noncardiac surgery under general anesthesia. The exercise test response was electrocardiographically positive in 32 patients (16%) (2 patients had a markedly positive test), equivocal in 11 patients (5.5%) and negative in 157 patients (78.5%). The patients were followed with serial pre- and postoperative electrocardiograms (ECGs) and determinations of serum creatine kinase (CK) and CK-MB. Six patients (3%) had primary endpoints: 3 (1.5%) died postoperatively and 3 (1.5%) had definite postoperative myocardial infarction. Secondary endpoints of suspected postoperative myocardial ischemia/injury diagnosed by ECG or elevation in CK-MB levels occurred in 27 patients (14%). Endpoint events were more common in patients aged 70 years or older. Endpoint events were also more common in patients with an abnormal (positive or equivocal) preoperative exercise test response than in those with a negative response (27% vs 14%); however, preoperative exercise results were not statistically significant independent predictors of cardiac risk. Using multivariate analysis, the only statistically significant independent predictor of risk was the preoperative ECG. Endpoint events were more common in patients with an abnormal than in those with a normal ECG (23% vs 7%, p less than 0.002). Because the results of exercise testing do not appear to add substantially to the risk separation provided by the ECG at rest, exercise testing is not recommended as a routine preoperative method for assessing perioperative risk in older patients who are being evaluated before major elective noncardiac surgery under general anesthesia.

Effects of exercise training on peak performance and quality of life in congestive heart failure patients.

BACKGROUND Exercise programs for patients with heart failure have often enrolled and evaluated relatively healthy, young patients. They also have not measured the impact of exercise performance on daily activities and quality of life. METHODS AND RESULTS We investigated the impact of a 6-month supervised and graded exercise program in 33 elderly patients with moderate to severe heart failure randomized to usual care or an exercise program. Six of 17 patients did not tolerate the exercise program. Of those who did, peak oxygen consumption increased by 2.4 +/- 2.8 mL/kg/min (P < .05) and 6-minute walk increased by 194 ft (P < .05). However, outpatient energy expenditure did not increase, as measured by either the doubly labeled water technique or Caltrac accelerometer. Perceived quality of life also did not improve, as measured by the Medical Outcomes Study, Functional Status Assessment, or Minnesota Living With Heart Failure questionnaires. CONCLUSION Elderly patients with severe heart failure can safely exercise, with an improvement in peak exercise tolerance. However, not all patients will benefit, and daily energy expenditure and quality of life do not improve to the same extent as peak exercise.

Prognostic importance of the serum magnesium concentration in patients with congestive heart failure

Magnesium abnormalities are common in patients with congestive heart failure but the clinical and prognostic significance of an abnormal serum magnesium concentration in this disorder has not been investigated. Therefore, the relation between serum magnesium concentration and the clinical characteristics and long-term outcome of 199 patients with chronic heart failure was evaluated. The serum magnesium concentration was less than 1.6 mEq/liter in 38 patients (19%), within the normal range in 134 patients (67%) and greater than 2.1 mEq/liter in 27 patients (14%). Patients with hypomagnesemia had more frequent ventricular premature complexes and episodes of ventricular tachycardia than did patients with a normal serum magnesium concentration (p less than 0.05). Even though the two groups were similar with respect to severity of heart failure and neurohormonal variables, patients with a low serum magnesium concentration had a significantly worse prognosis during long-term follow-up (45% versus 71% 1 year survival, p less than 0.05). Patients with hypermagnesemia had more severe symptoms, greater neurohormonal activation and worse renal function than did patients with a normal serum magnesium concentration but tended to have fewer ventricular arrhythmias. Hypermagnesemic patients had a worse prognosis than did those with a normal magnesium concentration (37% versus 71% 1 year survival, p less than 0.05). In conclusion, the measurement of serum magnesium concentration provides important clinical and prognostic information in patients with chronic heart failure.

Plasma leptin concentrations and energy expenditure in heart failure patients

Leptin, the protein encoded by the obese gene, is a newly described hormone implicated in the regulation of energy balance. To examine the possible role of leptin in the energy dysregulation that frequently accompanies chronic heart failure, we examined plasma leptin concentrations and energy expenditure in 18 heart failure patients (aged 71 +/- 6 years) and 46 healthy elderly controls (66 +/- 6 years). Plasma leptin concentrations were measured by radioimmunoassay, daily energy expenditure by doubly labeled water, and body composition by dual-energy x-ray absorptiometry. Fat mass was lower (P < .01) in heart failure patients compared with healthy controls, whereas fat-free mass did not differ between groups. Plasma leptin concentrations were not different between heart failure patients and healthy controls (5.1 +/- 4.2 v 6.8 +/- 4.4 pg/mL) and remained similar after statistical control for fat mass (6.0 +/- 3.1 v 7.1 +/- 3.2 pg/mL). Plasma leptin was related to fat mass in heart failure patients (r = .92, P < .01) and healthy controls (r = .69, P < .01). Free-living daily and physical-activity energy expenditures were lower (P < .01) in heart failure patients compared with healthy controls. Plasma leptin concentrations were related to both daily (r = .67, P < .01) and resting (r = .67, P < .01) energy expenditure in heart failure patients, but not in healthy controls (r = .09 and r = .33, respectively). In conclusion, we found an association between plasma leptin concentrations and energy expenditure in heart failure patients, but not in healthy controls. Thus, leptin may participate in the regulation of energy expenditure and body energy stores in heart failure patients.

Skeletal Muscle Atrophy and Peak Oxygen Consumption in Heart Failure

We measured skeletal muscle mass and peak oxygen consumption (VO2) in 13 cachectic heart failure patients, 14 noncachectic patients, and in 52 healthy controls to examine skeletal muscle atrophy and its relation to low peak VO2 in heart failure patients. Our results show that skeletal muscle atrophy is associated with prior weight loss and is related to low peak VO2 in heart failure patients.