An update on nesiritide for treatment of decompensated heart failure.

In the July 1999 issue of this publication, we described the chemical properties, pharmacology and clinical trials involving nesiritide as a therapeutic agent for patients with decompensated heart failure (Exp. Opin. Invest. Drugs) (1999) 8(7):1063--1072). At the time of publication, the US Food and Drug Administration reviewed the clinical experience with the compound and did not approve the drug for clinical use. More data were requested regarding safety issues, comparison with nitroglycerine, onset of effects, need for invasive haemodynamic monitoring and symptomatic improvement. The VMAC Study was designed to address these issues. A dosing regimen, 0.2 microgram/kg bolus followed by 0.01 microg/kg/min continuous infusion, was chosen to provide rapid onset of actions and haemodynamic improvement without a high incidence of symptomatic hypotension. Nesiritide was superior to iv. nitroglycerine in its haemodynamic effects, easier to administer without the need for dose titration and better tolerated overall. The drug could be administered safely without the need for invasive haemodynamic monitoring. Symptomatic hypotension occurred in 4% of patients. Beneficial haemodynamic effects correlated with symptomatic improvement in heart failure patients. Nesiritide appears to be an ideal first-line agent for treatment of patients with acutely decompensated heart failure.

Drug treatment of patients with decompensated heart failure.

Decompensated heart failure (HF) may be defined as sustained deterioration of at least one New York Heart Association functional class, usually with evidence of sodium retention. Episodes of decompensation are most commonly precipitated by sodium retention, often associated with medication noncompliance. Our therapeutic approach to hospitalized patients is based on the documented hemodynamic responses to vasodilator therapy, with redistribution of mitral regurgitant flow to forward cardiac output and decompression of the left atrium. Invasive hemodynamic monitoring is seldom required for the effective management of patients with HF and there are risks associated with pulmonary artery catheterization. The currently available parenteral vasoactive drugs for decompensated heart failure include: (i) vasodilators such as nesiritide, nitroprusside and nitroglycerin (glyceryl trinitrate); (ii) catecholamine inotropes, primarily dobutamine; and (iii) inodilators such as milrinone, a phosphodiesterase inhibitor. Vasodilators are most appropriate for those patients who are primarily volume-overloaded, but with adequate peripheral perfusion. In this class of agents, nesiritide (recombinant human B-type natriuretic peptide) offers advantages over currently available drugs. Nesiritide produces rapid and sustained decreases in right atrial and pulmonary capillary wedge pressures, with reduction in pulmonary and systemic vascular resistance and increases in cardiac index. The hemodynamic effects of nesiritide infusion were sustained over a duration of 1 week and the drug may be used without intensive monitoring in patients with decompensated HF. Treatment with dobutamine is indicated in patients in whom low cardiac output rather than elevated pulmonary pressure is the primary hemodynamic aberration. However, milrinone reduces left atrial congestion more effectively than dobutamine, and is well tolerated and effective when used in patients receiving beta-blockers. In-patient therapy for decompensated HF is a short term exercise for symptom relief and provides an opportunity to re-assess management in the continuum of care.

High dose angiotensin-converting enzyme inhibition prevents fluid volume expansion in heart transplant recipients.

OBJECTIVES: We sought to test the hypothesis that plasma volume (PV) expansion in heart transplant recipients (HTRs) is caused by failure to reflexively suppress the renin-angiotensin-aldosterone (RAA) axis. BACKGROUND: Extracellular fluid volume expansion occurs in clinically stable HTRs who become hypertensive. We have previously demonstrated that the RAA axis is not reflexively suppressed by a hypervolemic stimulus in HTRs. METHODS: Plasma volume and fluid regulatory hormones were measured in eight HTRs (57+/-6 years old) both before and after treatment with captopril (225 mg/day). Antihypertensive and diuretic agents were discontinued 10 days before. The HTRs were admitted to the Clinical Research Center (CRC), and, after three days of a constant diet containing 87 mEq/day of Na+, PV was measured by using the modified Evans blue dye dilution technique. After approximately four months (16+/-5 weeks), the same HTRs again discontinued all antihypertensive and diuretic agents; they were progressed to a captopril dose of 75 mg three times per day over 14 days, and the CRC protocol was repeated. RESULTS: Captopril pharmacologically suppressed (p<0.05) supine rest levels of angiotensin II (-65%) and aldosterone (-75%). The reductions in vasopressin and atrial natriuretic peptide levels after captopril did not reach statistical significance. The PV, normalized for body weight (ml/kg), was significantly reduced by 12% when the HTRs received captopril. CONCLUSIONS: Extracellular fluid volume is expanded (12%) in clinically stable HTRs who become hypertensive. Pharmacologic suppression of the RAA axis with high-dose captopril (225 mg/day) returned HTRs to a normovolemic state. These findings indicate that fluid retention is partly engendered by a failure to reflexively suppress the RAA axis when HTRs become hypervolemic.

Rate-responsive pacing improves exercise tolerance in heart transplant recipients: a pilot study.

BACKGROUND: Chronotropic incompetence is one cause of diminished exercise capacity in heart transplant recipients. If reinnervation occurs, it often is late after transplantation and is not always accompanied by functional improvements in peak heart rate and appropriate tachycardia during exercise. To determine the efficacy of rate-responsive pacing on peak heart rate and exercise capacity, the authors studied eight male heart transplant recipients (age 57 +/- 12 years; 23 +/- 9 months after transplantation) that had either atrial or dual-chambered pacemakers. METHODS: All subjects completed two maximal graded exercise tests (GXT) using the Naughton treadmill protocol. During the first GXT, pacemakers were programmed for bradycardia support only and without rate responsiveness (unpaced). After a 14-day regimen of beta blockade with metoprolol to nullify the influence of circulating catecholamines on heart rate, subjects performed the second GXT with pacemakers programmed to respond optimally in the rate-responsive mode (paced). RESULTS: Peak heart rate (149 versus 129 bpm), peak oxygen uptake (18.9 versus 15.4 mL/kg/min), treadmill time to exhaustion (14.6 versus 12.4 min), and minute ventilation (76.7 versus 66.2 L/min) were significantly increased (P < or = 0.05) during the paced versus unpaced GXT. CONCLUSIONS: The results of this study demonstrate that chronotropic support of the transplanted heart using a rate-responsive pacemaker, with activity-based sensors programmed for maximal sensitivity, improves both peak heart rate and exercise capacity in heart transplant recipients significantly more than circulating catecholamines alone.

Heart failure and sleep-related breathing disorders.

Despite advances in medical and surgical therapy, heart failure (HF) remains a common and serious problem. An association between HF and sleep-related breathing disorders has been recognized since Cheyne's observations in 1818, but only recently have treatment options targeting sleep-related breathing disorders become available. This overview will consider the clinical features, pathophysiology, and treatment options of sleep-related breathing disorders in patients with HF.

Long-term hemodynamic responses to vasodilator therapy in patients with severe left ventricular dysfunction.

Maximal oral vasodilator therapy resulted in long-term reduction of initially elevated pulmonary vascular resistance in 10 of 13 patients with severe heart failure who tolerated inotrope-supported uptitration of afterload reduction. Eleven patients were unable to tolerate vasodilator therapy and required inotropic support for successful cardiac transplantation.

Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. Natrecor Study Group.

OBJECTIVES: The goal of this study was to further define the role of nesiritide (human b-type natriuretic peptide) in the therapy of decompensated heart failure (HF) by assessing the hemodynamic effects of three doses (0.015, 0.03 and 0.06 microg/kg/min) administered by continuous intravenous (IV) infusion over 24 h as compared with placebo. BACKGROUND: Previous studies have shown beneficial hemodynamic, neurohormonal and renal effects of bolus dose and 6-h infusion administration of nesiritide in HF patients. Longer term safety and efficacy have not been studied. METHODS: This randomized, double-blind, placebo-controlled multicenter trial enrolled subjects with symptomatic HF and systolic dysfunction (left ventricular ejection fraction < or =35%). Central hemodynamics were assessed at baseline, during a 24-h IV infusion and for 4 h postinfusion. RESULTS: One hundred three subjects with New York Heart Association class II (6%), III (61%) or IV (33%) HF were enrolled. Nesiritide produced significant reductions in pulmonary wedge pressure (27% to 39% decrease by 6 h), mean right atrial pressure and systemic vascular resistance, along with significant increases in cardiac index and stroke volume index, with no significant effect on heart rate. Beneficial effects were evident at 1 h and were sustained throughout the 24-h infusion. CONCLUSIONS: The rapid and sustained beneficial hemodynamic effects of nesiritide observed in this study support its use as a first-line IV therapy for patients with symptomatic decompensated HF.

Aerobic exercise attenuates blood pressure reactivity to cold pressor test in normotensive, young adult African-American women.

Exaggerated blood pressure reactivity to behavioral stress has been observed in the African-American population, and such a pressor response is believed to play a role in hypertension. Regular aerobic exercise has been shown to exert an anti-hypertensive effect, and this may alter the blood pressure hyperreactivity observed in African Americans. To test the hypothesis that aerobic exercise attenuates pressor reactivity in African Americans, we studied eight healthy aerobically-trained normotensive African-American females and five similar sedentary females. The stress stimuli consisted of the cold pressor test with the foot immersed in ice water for two minutes. The aerobic exercise training protocol consisted of six weeks of jogging at 60-70% of peak oxygen uptake (VO2peak), three days/week for 35 min/exercise session. Systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, heart rate, cardiac output, total peripheral resistance, and forearm blood flow were measured. Manifestation of a training effect was illustrated by a 24.1 +/- 0.2% increase in VO2peak (26.9 +/- 1.2 mL x kg(-1) min(-1) vs 35.4 +/- 1.6 mL x kg(-1) min(-1)) (P<.05). Within the exercise-trained group there was a 6.3 +/- .15% decrease in systolic pressure (129 +/- 4.6 mm Hg vs. 121 +/- 5.4 mm Hg) (P<.05), and a 5.0 +/- .05% decrement in mean arterial blood pressure (99 +/- 3.3 mm Hg vs 94 +/- 3.6 mm Hg) (P<.05) during the cold pressor test. Pressor reactivity to cold stress did not change in the untrained group. Measures of heart rate, cardiac output, total peripheral resistance, and forearm blood flow were unaltered during conditions of the cold pressor test. We conclude that aerobic exercise attenuates the blood pressure reactivity to behavioral stress in young, adult normotensive African-American females. A lifestyle change such as exercising may play a role in reducing the risk of hypertension in African-American women.

Therapeutic potential of nesiritide (recombinant b-type natriuretic peptide) in the treatment of heart failure.

This review outlines the chemical properties, pharmacology and clinical trials data which support the development of nesiritide (synthetic human B-type natriuretic peptide, or hBNP) as a therapeutic agent for patients with decompensated congestive heart failure. Nesiritide is a 32-amino acid peptide, structurally identical to endogenous hBNP. Clinical trials with single bolus, repeated boluses and sustained infusions of nesiritide have demonstrated prompt, significant and sustained reductions in pulmonary capillary wedge pressure and increases in cardiac output, consistent with a direct vasodilator effect. Nesiritide has a short half-life, approximately 18 min, which is not dependent upon renal function. It not associated with tachyphylaxis through 24 h of therapy. Nesiritide is not an inotrope, and its action is not dependent upon beta adrenergic receptors. The safety profile has been excellent; the major adverse effect is hypotension. The frequency of ventricular arrhythmia is not increased in patients treated with nesiritide. In our opinion, nesiritide has many attributes of an ideal first-line therapeutic agent for decompensated heart failure.

Significance of radiographic cardiomegaly in orthotopic heart transplant recipients.

OBJECTIVE: The purpose of this study is to evaluate the clinical significance of radiographic cardiomegaly in orthotopic heart transplant recipients and to identify causative anatomic and physiologic parameters. MATERIALS AND METHODS: We retrospectively compared the cardiothoracic ratio (CTR) measured using standard posteroanterior chest radiography with left ventricular end-diastolic diameter and left ventricular ejection fraction measured on two-dimensional echocardiography; right ventricular systolic pressure; and systolic, diastolic, and mean blood pressure measured at biopsy in 46 heart transplant recipients. RESULTS: Twenty-eight (61%) of the 46 patients had radiographic cardiomegaly. When we compared heart transplant recipients who had a CTR greater than 0.5 with recipients who had a CTR less than or equal to 0.5, we found no significant difference between their respective left ventricular end-diastolic diameters, left ventricular ejection fractions, right ventricular systolic pressures, systolic blood pressures, or mean blood pressures. A statistically significant difference existed between the mean values of diastolic blood pressure for transplant recipients with and without radiographic cardiomegaly. We found no significant correlation between CTR and left ventricular end-diastolic diameter, left ventricular ejection fraction, systolic blood pressure, diastolic blood pressure, or mean blood pressure. CONCLUSION: The statistically significant difference between the mean values of diastolic blood pressure of transplant recipients with and without radiographic cardiomegaly is clinically insignificant and unlikely to account for the finding of radiographic cardiomegaly. We conclude that radiographic cardiomegaly, which occurs frequently in heart transplant recipients, does not correlate with anatomic or physiologic parameters obtained under the same conditions. Radiographic cardiomegaly in heart transplant recipients does not connote allograft dysfunction or heart failure.

Risk of death or incapacitation after heart transplantation, with particular reference to pilots.

Pilots who have received a heart transplant may subsequently want to resume flying. This study was undertaken to determine whether a group of heart transplant recipients who had a particularly low risk of sudden unexpected death could be identified from clinical data. An event, "rapid-onset death," was defined incorporating a number of possible causes of death that could result in a heart transplant recipient-pilot losing control of an airplane. The survival of 3676 patients undergoing a first heart transplantation was 85% and 73% at 1 and 5 years, respectively, the hazard function having a high early phase of risk. When time zero was moved to the beginning of the second year after transplantation, the freedom from "rapid-onset death" at posttransplantation year 2 and posttransplantation year 5 was 96.8% and 88%, respectively. For patients who had both a "normal" coronary angiogram and no episodes of acute heart rejection during the first year transplantation, the probability of "rapid onset death" during the second posttransplantation year was 1.4%, and given the same circumstances, during the third posttransplantation year the risk of "rapid-onset death" was 1.6%. This information is potentially useful to the Federal Aviation Administration for policy decisions regarding this issue.

Cardiac output responses during exercise in volume-expanded heart transplant recipients.

The mechanisms responsible for immediate adjustments in cardiac output at onset of exercise, in the absence of neural drive, are not well defined in heart transplant (HT) recipients. Seven male HT recipients (mean +/- SD 57 +/- 6 years) and 7 age-matched sedentary normal control subjects (mean age 57 +/- 5 years) performed constant load cycle exercise at 40% of peak power output (Watts). Cardiac output and plasma norepinephrine were determined at rest and every 30 seconds during the first 5 minutes of exercise and at minutes 6, 8, and 10. All subjects were admitted to the General Clinical Research Center for determination of plasma volume. After 3 days of equilibration to a controlled and standardized diet, plasma volume was measured using a modified Evans Blue Dye (T-1824) dilution technique. Heart rate at rest was higher in the HT group (105 +/- 12 vs 74 +/- 6 beats/min), but during submaximum exercise, heart rates in the control group increased more rapidly (p < or = 0.05) and to a greater magnitude (54 +/- 7% vs 17 +/- 4% above rest). Stroke volume at rest was lower in HT recipients (45 +/- 4 vs 68 +/- 9 ml) but was significantly augmented immediately after onset of exercise (30 seconds) and the relative increase was greater than controls at peak exercise (61% vs 38% greater than baseline). Cardiac output at rest was within the normal range in both groups (4.58 +/- 0.27 vs 4.94 +/- 0.40 L/min). Relative increases in cardiac output were similar (p > or = 0.05) for the HT (106 +/- 12%) and control groups (97 +/- 10%). Plasma norepinephrine did not become significantly greater than resting values until approximately 4 minutes after onset of exercise in both groups. Blood volume, normalized for body weight, was 12% greater in the HT group. Thus, HT recipients with expanded blood volume (12%) augment stroke volume immediately after the onset of exercise. Plasma norepinephrine levels contribute negligibly to the rapid adjustment in cardiac output. Rather, we speculate that abrupt on-transit increases in stroke volume are due to augmented venous return, secondary to expanded blood volume.

Resistance exercise prevents glucocorticoid-induced myopathy in heart transplant recipients.

PURPOSE: To determine the effect of resistance exercise training (ET) on glucocorticoid-induced myopathy in heart transplant recipients (HTR), 14 male HTR were randomly assigned to a ET group that trained for 6 months (54 +/- 3 yr old; mean +/- SD) or a control group (51 +/- 8 yr old; mean +/- SD). METHODS: Fat mass, fat-free mass, and total body mass were measured by dual-energy x-ray absorptiometry before and 2 months after transplantation (Tx), and after 3 and 6 months of ET or control period. The exercise regimen consisted of lumbar extension (MedX) performed 1 d.wk-1 and variable resistance exercises (Nautilus) performed 2 d.wk-1. PreTx body composition did not differ between groups. RESULTS: At 2 months after Tx, fat-free mass was significantly decreased below baseline in both control (-3.4 +/- 2.1%) and ET groups (-4.3 +/- 2.4%). Fat mass was significantly increased at 2 months after Tx in both the control (+8.3 +/- 2.8%) and ET groups (+7.3 +/- 4.0%). Six months of ET restored fat-free mass to levels 3.9 +/- 2.1% greater (P < or = 0.05) than before Tx. Fat-free mass of the control group decreased progressively to levels that were 7 +/- 4.4% lower than preTx values (P < or = 0.05). Both groups increased knee extension, chest press, and lumbar extensor strength, but improvements in the ET group were four- to six-fold greater (P < or = 0.05). CONCLUSION: Our results demonstrate that glucocorticoid-induced changes in body composition in HTR occur early after Tx. However, 6 months of specific ET restores fat-free mass to levels greater than before Tx and dramatically increases skeletal muscle strength. Resistance exercise, as part of a strategy to prevent steroid-induced myopathy, appears to be safe and should be initiated early after heart Tx.

Clinical improvement after atrioventricular nodal ablation for atrial fibrillation does not correlate with improved ejection fraction.

A retrospective review of 15 patients with atrial fibrillation and class III to IV congestive heart failure who underwent atrioventricular nodal ablation demonstrated a marked improvement in their functional abilities. This improvement, however, could not be explained by the improvement in ejection fraction alone.

Permanent atrial pacing in cardiac transplant patients.

Thirteen out of 223 consecutive cardiac transplant patients required permanent pacemaker implantation; 11 for sinus node dysfunction and 2 for complete AV block. Patients with sinus node dysfunction were considered for AAIR mode pacemakers if they had intact AV conduction defined as a Wenckebach point of > 120 beats/min. Ten of 11 patients with sinus node dysfunction had a single atrial lead placed. Atrial lead placement was most easily accomplished with a straight, active fixation lead and the use of manually curved stylets to find an optimal position in the donor atrium, although active fixation leads with a preformed atrial J were used as well. Two leads dislodged requiring revision. In contrast, only 1 of 250 atrial leads implanted in nontransplanted hearts dislodged (P < 0.0001). Transvenous endomyocardial biopsies have not caused atrial lead dislodgment. Most transplant recipients requiring permanent pacing have intact AV nodal function and require only atrial pacing. Atrial lead dislodgment requiring lead revision occurs more frequently in heart transplant recipients than in native hearts. Use of a straight active fixation lead with a manually formed curve in the stylet is useful in order to find the optimal position for pacing.

Heart transplant rejection with hemodynamic compromise: a multiinstitutional study of the role of endomyocardial cellular infiltrate. Cardiac Transplant Research Database.

BACKGROUND: The natural history of patients experiencing hemodynamic compromise with rejection has been incompletely characterized. This multiinstitutional study examined the outcome of such episodes, particularly with regard to the extent of cellular infiltrate on the index endomyocardial biopsy. METHODS: From January 1, 1990, through June 30, 1994, 3367 patients in the Cardiac Transplant Research Database experienced 4137 episodes of rejection. Severe hemodynamic compromise occurred in approximately 5% of the rejection episodes, and this proportion remained relatively constant over time. RESULTS: Recipient risk factors for rejection with severe hemodynamic compromise included black race, female recipient sex, and diabetes. The 3-month actuarial survival rate was 60% after rejection with severe hemodynamic compromise versus 95% after rejection with no or mild compromise. Low initial biopsy score conferred a higher early survival, but a lower survival at 2 years after rejection with severe hemodynamic compromise. Among patients who survive an initial rejection episode with severe hemodynamic compromise, survival at 2 years after an episode was 46% among those who had a low initial biopsy score versus 84% with a high biopsy score. CONCLUSIONS: Rejection with hemodynamic compromise, although rare, represents a major complication of heart transplantation with a poor long-term outcome. Survivors of hemodynamically compromising rejection episodes associated with low biopsy scores in the International Society for Heart and Lung Transplantation grading system have a significantly worse long-term outcome than survivors of episodes associated with high scores. These findings suggest that immunologic mechanisms other than lymphocytic infiltration of the cardiac allograft are important and distinct causes of allograft dysfunction.

QT dispersion is a marker for life-threatening ventricular arrhythmias after atrioventricular nodal ablation using radiofrequency energy.

QT dispersion has been cited as a measure of nonuniform myocardial repolarization and a predictor of sudden cardiac death. We describe 38 patients who underwent atrioventricular nodal ablation, 3 of whom had an increase in measured QT dispersion and experienced potentially fatal, pulseless, polymorphic ventricular tachycardia after the procedure.