Activation and release of degradative proteinases within the myocardium are the trigger for ventricular remodeling in chronic heart failure.

Our conceptual framework of chronic heart failure is based upon the neurohormonal model. In this construct, neurohormonal systems that provide short-term homeostasis remain activated after a myocardial injury, producing progressive ventricular dysfunction and worsening heart failure. However, this model fails to explain several aspects of the pathophysiology of heart failure, including the mechanisms that trigger neurohoromone release and those that lead to ventricular dysfunction in the absence of a large myocardial infarction. These gaps in our understanding can be explained by an expanded model of heart failure, which focuses on myocardial matrix events as the triggers for disease progression. This model embraces the neurohormonal model, and integrates the roles of the immune system and the myocardial fibroblast, within the matrix, to more fully describe the initiation and progression of the disease.

Hypertensive end-organ damage and premature mortality are p38 mitogen-activated protein kinase-dependent in a rat model of cardiac hypertrophy and dysfunction.

BACKGROUND: Numerous pathological mediators of cardiac hypertrophy (eg, neurohormones, cytokines, and stretch) have been shown to activate p38 MAPK. The purpose of the present study was to examine p38 MAPK activation and the effects of its long-term inhibition in a model of hypertensive cardiac hypertrophy/dysfunction and end-organ damage. METHODS AND RESULTS: In spontaneously hypertensive stroke-prone (SP) rats receiving a high-salt/high-fat diet (SFD), myocardial p38 MAPK was activated persistently during the development of cardiac hypertrophy and inactivated during decompensation. Long-term oral treatment of SFD-SP rats with a selective p38 MAPK inhibitor (SB239063) significantly enhanced survival over an 18-week period compared with the untreated group (100% versus 50%). Periodic echocardiographic analysis revealed a significant reduction in LV hypertrophy and dysfunction in the SB239063-treatment groups. Little or no difference in blood pressure was noted in the treatment or vehicle groups. Basal and stimulated (lipopolysaccharide) plasma tumor necrosis factor-alpha concentrations were reduced in the SB239063-treatment groups. In vitro vasoreactivity studies demonstrated a significant preservation of endothelium-dependent relaxation in animals treated with the p38 MAPK inhibitor without effects on contraction or NO-mediated vasorelaxation. Proteinuria and the incidence of stroke (53% versus 7%) were also reduced significantly in the SB239063-treated groups. CONCLUSIONS: These results demonstrate a crucial role for p38 MAPK in hypertensive cardiac hypertrophy and end-organ damage. Interrupting its function with a specific p38 MAPK inhibitor halts clinical deterioration.

The myocardial matrix and the development and progression of ventricular remodeling.

Our conceptual framework of chronic heart failure is based upon the neurohormonal model. In this construct, neurohormonal systems that provide short-term homeostasis remain activated after a myocardial injury, producing progressive ventricular dysfunction and worsening heart failure. However, this model fails to explain several important clinical phenomena, that can be explained by an expanded model of heart failure that focuses on myocardial matrix events as the triggers for disease progression. This model embraces the neurohormonal model and integrates the roles of the immune system and the myocardial fibroblast within the matrix to more fully describe the initiation and progression of the disease.

Use of carvedilol in chronic heart failure: challenges in therapeutic management.

In controlled trials, long-term treatment of patients with chronic heart failure with beta-blockers improves symptoms, slows progression of disease, and reduces morbidity and mortality rates. However, in some patients the introduction of therapy can be associated with a period of clinical instability, including risks of fluid retention, hypotension, and bradycardia. Appropriate patient selection and optimization of background therapy can minimize the risk during the introduction of therapy. With vigilance for early signs of clinical deterioration and appropriate adjustment of background medications, the care of most patients exhibiting clinical instability can be successfully managed so the patient is able to continue with the long-term therapy, a prerequisite to realizing beneficial effects. With the initiation of carvedilol, any evidence of fluid retention warrants a prompt increase in the diuretic dosage, and in more pronounced cases the carvedilol dose may need to be reduced or interrupted. In contrast, symptoms of hypotension (most commonly dizziness) generally resolve without intervention, although persistent problems may necessitate adjusting the timing of dose administration or perhaps temporarily reducing the dose of vasodilators or diuretics (the latter with care to avoid fluid retention). Bradycardia should be managed as standard practice would indicate. During long-term treatment, adjustments in beta-blocker dosage may be required in the event of an exacerbation of heart failure. Dosages should be adjusted as would be the case with other heart-failure medications, based on the severity of the clinical decompensation, but with care to minimize abrupt changes unless mandated by the patient's condition and to avoid precipitating ischemia or further deterioration. The occurrence of effects such as these does not necessarily indicate that a patient cannot respond favorably to long-term beta-blockade, but all require understanding, vigilance, and the availability of medical personnel, especially during the introduction of this therapy.

Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise.

BACKGROUND: Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials. METHODS AND RESULTS: We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fraction < or = 0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n = 145) or carvedilol (n = 133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (P = .014) or by a global assessment of progress judged either by the patient (P = .002) or by the physician (P < .001). In addition, treatment with carvedilol was associated with a significant increase in ejection fraction (P < .001) and a significant decrease in the combined risk of morbidity and mortality (P = .029). In contrast, carvedilol therapy had little effect on indirect measures of patient benefit, including changes in exercise tolerance or quality-of-life scores. The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure. CONCLUSIONS: These findings indicate that, in addition to its favorable effects on survival, carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin, diuretics, and an ACE inhibitor.

Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group.

BACKGROUND: We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction. METHODS AND RESULTS: Patients (n = 366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF) < or = 0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n = 232) or placebo (n = 134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% (P = .008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated. CONCLUSIONS: Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

Rationale for treatment of patients with chronic heart failure with adrenergic blockade.

OBJECTIVE: Chronic heart failure is the leading cause of hospital admissions in patients older than 65 years. Heart failure due to systolic dysfunction is accompanied by activation of the sympathetic nervous system that contributes to progressive symptoms and an increased risk of death. While several clinical trials have suggested that antagonizing this sympathetic activation with beta-blocking agents may provide clinical benefit, no clear consensus exists regarding use of beta-blockers for congestive heart failure. Therefore, we review the pathophysiology of the sympathetic nervous system as a basis for examining these clinical trials in order to understand the rationale for beta-blockade as a treatment for heart failure. DATA SOURCE: English language journal articles and reviews from a MEDLINE search and abstracts published at major cardiology meetings that related either to pathophysiology of the sympathetic nervous system or to therapy of patients with chronic heart failure with beta-blockers. STUDY SELECTION: Uncontrolled trials describing the initial use of this therapy and the subsequent randomized, placebo-controlled trials of beta-blockers were included. CONCLUSIONS: Sympathetic nervous system activation in patients with chronic heart failure is a major contributor to the severity of disease as well as its progression over time. Antagonism of its effects, via beta-blocker therapy, appears overall to improve both quality of life and survival. However, its place as a cornerstone in the therapy of this disease depends on the results of large-scale, randomized, placebo-controlled trials.

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.