Placebo treatment in congestive heart failure.

In order to evaluate the effect of placebo treatment in congestive heart failure, we retrospectively studied 24 patients with moderately severe congestive heart failure who participated in heart failure treatment trials performed over the past 10 years in the Ohio State University Heart Failure Research Laboratory. Placebo-treated patients from 4 placebo-controlled trials comprised the placebo treatment group (n = 15), while one natural course-controlled trial provided patients for the non-placebo control group (n = 9). Changes in symptoms, left ventricular function and exercise duration were assessed following an 8-week course of therapy. Chronic placebo therapy resulted in an 81-second improvement in exercise duration which was statistically significant when compared to pretreatment baseline and to the duration achieved by the nonplacebo control group. Clinically, functional class improved significantly by 27% above baseline only for the placebo treatment group. Indices of left ventricular function did not change for either group. The salient feature of this study is that the placebo treatment effect, while believed to exist in congestive heart failure, has never been demonstrated in a manner which controlled for the natural course and variability of the disease process. The operative components of the placebo effect remain unknown, and further investigation will be necessary to elucidate the underlying mechanisms involved. However, the importance of this phenomenon lies not only with the response to and effects of placebo therapy but also in the role that the placebo effect plays in what is generally presumed to be the predominant responses, effects and benefits of active drug therapy.     

Salbutamol in treatment of heart failure.

The haemodynamic effects of oral and intravenous salbutamol were investigated in 22 patients with chronic heart failure. Intravenous salbutamol (13 micrograms/min) increased cardiac index by 53 per cent from 1.5 +/- 0.13 1/min per m2 to 2.3 +/- 0.23 1/min per m2 and decreased systemic vascular resistance by 28 per cent from 29.4 +/- 3.9 units to 21.2 +/- 2.5 units. Heart rate rose by 10 per cent from 101 +/- 3.5 beats per minute to 111 +/- 3.2 beats per minute and pulmonary artery end-diastolic pressure fell by 13 per cent from 26.3 +/- 1.8 mmHg to 22.8 +/- 2.1 mmHg. Similar results were obtained after oral salbutamol (8 mg). Cardiac index rose by 40 per cent and systemic vascular resistance fell by 30 per cent. There was a small rise in heart rate and a variable and not significant change in pulmonary artery end-diastolic pressure. Experiments on isolated rabbit papillary muscle showed that salbutamol, at the concentration which exists in patients, had no detectable positive inotropic effect. It is probable that the increase in cardiac output in patients is primarily the result of reduced afterload caused by vasodilatation. Salbutamol is a useful drug in the treatment of chronic heart failure.     

Aldosterone in heart failure: Pathophysiology and treatment

Aldosterone produces adverse effects on the vasculature (endothelial dysfunction) and on the myocardium (myocardial fibrosis). These effects have adverse clinical consequences that result in increases in deaths caused by sudden death and by progressive heart failure. The Randomized Aldactone Evaluation Study and the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study show this clearly. Aldosterone blockade should become a regular third neuroendocrine-blocking drug in patients with chronic heart failure.     

Diuretic treatment and diuretic resistance in heart failure.

Diuretic therapy decreases capillary wedge pressure and improves New York Heart Association (NYHA) functional class both in acute and chronic heart failure. In advanced symptomatic heart failure, loop diuretics are generally necessary to improve symptoms of congestion. Diuretic resistance in the edematous patient has been defined as a clinical state in which diuretic response is diminished or lost before the therapeutic goal of relief from edema has been reached. The major causes of diuretic resistance are functional renal failure (prerenal azotemia), hyponatremia, altered diuretic pharmacokinetics, and sodium retention caused by counterregulatory mechanisms intended to reestablish the effective arterial blood volume. Therapeutic approaches to combat diuretic resistance include restriction of fluid and sodium intake, use of angiotensin-converting-enzyme (ACE) inhibitors, changes in route (oral, intravenous) and timing (single dose, multiple doses, continuous infusion) of diuretic therapy, and use of diuretic combinations.     

The surgical treatment of heart failure. A new frontier: nontransplant surgical alternatives in heart failure

Heart failure may affect 500,000 new people each year. Heart transplantation has leveled off at approximately 2,500-3,000 cases per year in the United States. Thus, new nontransplant surgical alternatives may be necessary to treat many of the patients who progress to intractable Class III, or especially Class IV heart failure. In addition to left ventricular assist devices, other operations have been used and are now being developed for this purpose. These include left ventricular resection (Batista operation), mitral valve repair, autologous skeletal muscle cardiac assist, splint and compression devices, as well as left ventricular reconstruction by the Dor procedure. All of these procedures have been, and are currently being, evaluated for the surgical treatment of congestive heart failure and they will be reviewed in this article. Although many appear very promising, ongoing trials and retrospective reviews will be increasingly necessary to vigorously define which of the nontransplant surgical alternatives are the best procedures going forward for the large numbers of patients with congestive failure.     

Mild heart failure: diagnosis and treatment

CHF afflicts 15 million persons worldwide despite advances made in its diagnosis and treatment. A thorough physical examination and basic, noninvasive evaluation are essential for establishing the diagnosis of heart failure and for designing an optimal, individualized treatment regimen. Although digitalis and diuretics continue to be used commonly for the treatment of CHF of all severities, the use of vasodilators and ACE inhibitors has increased dramatically, as they are used more widely and earlier in the course of the illness. Because the RAA system contributes significantly to the altered cardiovascular hemodynamics and symptomatology characteristic of heart failure, the ACE inhibitors provide a rational approach to therapy for many patients. Results of controlled clinical trials have shown that selected vasodilators and ACE inhibitors can improve survival in patients with CHF and that patients receiving ACE inhibitors show sustained improvement in clinical class, exercise tolerance, and hemodynamics. Thus the therapeutic spectrum available to the clinician dealing with patients with CHF has broadened substantively over the past decade.     

BNP in hormone-guided treatment of heart failure.

The pharmacotherapy of heart failure has become complex. Angiotensin-converting enzyme inhibitors (or angiotensin II receptor blockers), beta-blockers, spironolactone, diuretics and digoxin can be prescribed concurrently. Endothelin antagonists and combined inhibitors of converting enzyme and neutral endopeptidase are under investigation. Optimal dosing will become increasingly difficult to judge. Plasma brain natriuretic peptide (BNP) indicates the severity of left ventricular dysfunction. The C-terminal bioactive peptide and N-terminal BNP (N-BNP) circulate at concentrations related to cardiac status. We proposed that plasma levels of N-BNP would provide an index to guide drug treatment in established heart failure. Sixty-nine patients were randomized to treatment adjusted according to clinical criteria or plasma N-BNP. Hormone-guided therapy resulted in fewer clinical end points than did clinical management. This encourages further exploration of hormone guidance of anti-heart failure therapy, which could be extended to patients with preserved ejection fraction, in addition to those with established systolic dysfunction.     

Vasopressin antagonism: a future treatment option in heart failure.

Arginine vasopressin plays an important role in volume homeostasis. Patients with heart failure have chronically elevated plasma vasopressin concentrations which may contribute to their clinical syndrome of fluid retention. Recently, a number of agents have been developed to antagonize the effects of vasopressin by targeting its V1a and V2 receptors, which are involved in vascular tone and free water regulation, respectively. Two vasopressin antagonists, in particular, tolvaptan and conivaptan, have shown promise in animal studies and small-scale human trials. The following is a review of current experimental and clinical studies using vasopressin antagonists and their potential role in the treatment of heart failure.