beta-Blocker use in long-term dialysis patients: association with hospitalized heart failure and mortality

BACKGROUND: beta-Blockers have been shown to be beneficial in the treatment and prevention of heart failure (HF) in the general population, but they have not been assessed for their association with nonfatal HF in a nationally representative population of long-term dialysis patients. METHODS: We conducted a retrospective cohort study of 2550 patients enrolled in the US Renal Data System (USRDS) Wave 2 who were Medicare eligible at the start of the study. Analysis was stratified by the presence or absence of a known diagnosis of HF, and patients followed up until December 31, 2000. Cox regression analysis, including propensity scores, was used to model adjusted hazard ratios for beta-blocker use (assessed separately by cardioselective activity and lipid solubility) with time to the first Medicare institutional claim for HF, cardiovascular-related death, or death from any cause. RESULTS: In patients without a previous history of HF, beta-blocker use was significantly associated with a lower adjusted risk of HF (adjusted hazard ratio, 0.69; 95% confidence interval, 0.52-0.91; P=.008), with a similar reduction in risk of cardiac-related and all-cause death. beta-Blocker use had no statistically significant associations with outcomes in patients with previous HF. CONCLUSIONS: In dialysis patients without a previous documented history of HF, beta-blocker use was associated with a lower risk of new HF, cardiovascular death, and death from any cause. No such associations were seen for dialysis patients with a previous history of HF. These results are hypothesis generating only and should be confirmed in randomized trials.     

Gene therapy in heart failure

With increasing knowledge of basic molecular mechanisms governing the development of heart failure (HF), the possibility of specifically targeting key pathological players is evolving. Technology allowing for efficient in vivo transduction of myocardial tissue with long-term expression of a transgene enables translation of basic mechanistic knowledge into potential gene therapy approaches. Gene therapy in HF is in its infancy clinically with the predominant amount of experience being from animal models. Nevertheless, this challenging and promising field is gaining momentum as recent preclinical studies in larger animals have been carried out and, importantly, there are 2 newly initiated phase I clinical trials for HF gene therapy. To put it simply, 2 parameters are needed for achieving success with HF gene therapy: (1) clearly identified detrimental/beneficial molecular targets; and (2) the means to manipulate these targets at a molecular level in a sufficient number of cardiac cells. However, several obstacles do exist on our way to efficient and safe gene transfer to human myocardium. Some of these obstacles are discussed in this review; however, it primarily focuses on the molecular target systems that have been subjected to intense investigation over the last decade in an attempt to make gene therapy for human HF a reality.     

Antiarrhythmic therapy in heart failure

Heart failure is the term used for a cardiovascular syndrome whose definition lacks uniform criteria. It is associated with a very high mortality rate. Approximately 50% of deaths in patients with heart failure are sudden, mostly due to ventricular tachycardia (VT). In severe heart failure, death may also occur due to bradyarrhythmias. Other arrhythmias complicating heart failure include atrial and ventricular extrasystoles, atrial fibrillation, and sustained or non-sustained VT. Depending on the etiology of heart failure, different preconditions, including ischemia or structural alterations (such as fibrosis) may be prominent. Re-entrant mechanisms around scar tissue, afterdepolarizations, and triggered activity due to changes in calcium metabolism significantly contribute to arrhythmogenesis. The treatment of the underlying disease process and optimal management of heart failure is of major importance. Revascularization, beta-blocker therapy, and angiotensin converting enzyme inhibitors are all essential to appropriate therapy. Treatment of arrhythmias is performed either because patients are symptomatic or to reduce the risk of sudden cardiac death. The implantable cardioverter-defibrillator (ICD) is the best available therapy to prevent sudden cardiac death from VT. Devices with back-up pacing also offer protection against bradyarrhythmias. There is evidence that patients with sustained VT or a history of resuscitation have the best outcome with ICD therapy regardless of the degree of heart failure. Many of these patients require additional antiarrhythmic therapy (e.g. amiodarone) because of atrial fibrillation or non-sustained VT that may activate the device.     

Matrix metalloproteinase therapy in heart failure

Opinion statement  Milestones in the progression to heart failure following myocardial infarction (MI) are changes in left ventricular (LV) geometry and function, termed post-MI remodeling. Critical to this adverse remodeling process are changes in the expression, synthesis, and degradation of myocardial extracellular matrix (ECM) proteins. The myocardial ECM is not a passive entity but a complex and dynamic microenvironment that represents an important structural and signaling system within the myocardium. In particular, basic and clinical studies have provided conclusive evidence that abnormal and persistent activation of the ECM degradation pathway, notably through the matrix metalloproteinases (MMPs), contribute to adverse post-MI remodeling. This review examines recent clinical studies that provide further support to the hypothesis that a specific portfolio of MMPs are diagnostic and likely contributory to LV remodeling and the progression to heart failure after MI. Future translational and clinical research focused on the molecular and cellular mechanisms regulating ECM structure and function likely will contribute to an improved understanding of post-MI LV remodeling and yield novel therapeutic targets.     

Growth hormone therapy in heart failure

Summary Clinical and experimental data in animals and patients with endstage heart failure due to dilated cardiomyopathy or ischemic heart disease suggest a beneficial role of growth factors like human recombinant growth hormone or insulin-like growth factor I. Their cardiac effects are an increase in myocardial mass and a decrease in systolic wall stress. Based on the results of animal studies and of preliminary studies in patients with dilated cardiomyopathy, double-blind and placebo-controlled studies have proven the increase in myocardial mass and a significant reduction of left ventricular wall stress, as demonstrated by magnetic resonance imaging. The risk of the additional therapy with human growth factors in this high-risk group of patients with a high mortality is justified, if this new approach becomes a possible alternative to cardiac transplantation or a bridge toward transplantation. If future randomized studies in larger patient groups with an individualized substitution therapy with growth hormone and/or IGF-I can demonstrate a beneficial effect on mortality and morbidity, this new therapeutic approach could become an attractive alternative in these high-risk patients.     

Beta-blocker therapy in heart failure.

beta-blocker therapy in heart failure offers the possibility of arresting or reversing the progressive deterioration in this clinical syndrome. While the mechanism is unclear, improvement in cardiac function has been apparent in virtually every study. Clinical results have shown less consistent improvement. Decrease in hospitalization has been noted, but large-scale clinical trials are underway to assess the effect of beta-blockers on mortality.     

Immune modulation therapy in heart failure

Several lines of evidence suggest that inflammation plays a pathogenic role in the development and progression of congestive heart failure, influencing heart contractility and hypertrophy, promoting apoptosis, and contributing to the myocardial remodeling process. As the prevalence of heart failure continues to increase, novel therapeutic strategies are employed to decrease the burden of this disease. Although multiple studies have suggested a potential for immunomodulatory therapy in heart failure patients, the precise role of this targeted approach still remains to be determined. Further research is needed to identify the key factors in the immunopathogenesis of heart failure, identify the patients who are most likely to respond, and develop management strategies that result in consistent benefit leading to decreased morbidity and mortality in the heart failure patient population.     

Interventional therapy in heart failure management

The incidence and prevalence of congestive heart failure are rapidly increasing because of the progressive decrease in age-adjusted mortality rates for coronary artery disease and hypertensive heart disease, together with the progressive aging of the US population. Despite great advances in maximal medical therapy, most patients with symptomatic congestive heart failure can expect functional impairment, interludes of worsening symptomatology, and a shortened life span. Thus, it is appropriate to ask whether the interventional revolution that is under way for the management of ischemic cardiovascular disease can be applied with benefit to the management of congestive heart failure. The use of interventional therapies for the treatment of elderly patients with congestive heart failure caused by coronary artery disease, valvular heart disease, or renal vascular disease is addressed.     

Diuretic therapy in congestive heart failure

The principal goals of treatment of the patient in heart failure are the relief of their symptoms and improvement in their prognosis. Of all antiheart failure drugs currently available, the diuretics are therapeutically superior in their efficacy in relieving clinical symptoms and signs. Whether administered intravenously or orally, all diuretics result in a substantial reduction in the raised pulmonary vascular pressures in combination with a small reduction in cardiac output. Diuretics stimulate release of renin with subsequent activation of the renin-angiotensin-aldosterone system, particularly if used in large doses, although their quantitative impact on the neuroendocrine profile at different stages of heart failure remains to be defined. In patients with mild heart failure, diuretics reduce plasma catecholamine concentrations, but their sympatholytic effects in more severe cases are unknown, as are their effects on the metabolically active tissues in these patients. Diuretic resistance can be circumvented by segmental nephron blockade with a combination of low-dose diuretics that simultaneously block sodium reabsorption in the proximal tubule, the loop of Henle, the distal tubule, and the collecting duct. Diuretics improve symptoms of breathlessness and signs of peripheral edema in patients with congestive heart failure in direct relationship to the induced diuresis. These benefits are frequently associated with a substantial improvement in patients' appreciation of quality of life and economic capacity. There are few adverse reactions to chronic diuretic therapy, but the serum electrolytes should be monitored for hypokalemia and hypomagnesemia. The impact of diuretics on prognosis of patients with congestive heart failure is unknown; however, diuretics have been a major ingredient of the therapies used in all the survival trials with vasodilators, angiotensin-converting enzyme inhibitors, and beta-blocking drugs. In addition to their clinical benefits, diuretics are the most cost-effective treatment of any single drug group currently available for the treatment of patients with congestive heart failure.     

Diuretic therapy in congestive heart failure

Diuretics are a mainstay of therapy in patients with congestive heart failure. A small number of patients can achieve adequate diuresis with a thiazide diuretic alone, but most require a loop diuretic. Some patients with severe disease require combinations of diuretics. Most patients with congestive heart failure manifest resistance to diuretics by having a diminished natriuresis compared with healthy counterparts. This diminished response even to potent diuretics means that dietary sodium may exceed sodium excretion, resulting in patient decompensation. The pharmacokinetics and pharmacodynamics of loop diuretics have been characterized in patients with congestive heart failure, thereby allowing rational therapeutic strategies in terms of what type of doses should be administered, how often, and when to use diuretic combinations. The purpose of this review is to show how understanding pharmacokinetics and pharmacodynamics results in logical diuretic use. (c)2000 by CHF, Inc.