New Concepts in Diastolic Dysfunction and Diastolic Heart Failure: Part II : Causal Mechanisms and Treatment

The role of cardiac glycosides in treating patients with chronic heart failure and normal sinus rhythm remains controversial. We studied the effect of digoxin on mortality and hospitalization in a randomized, double-blind clinical trial. In the main trial, patients with a left ventricular ejection fraction of 0.45 or less were randomly assigned to digoxin (3397 patients) or placebo (3403 patients) in addition to diuretics and angiotensin-converting-enzyme inhibitors (median dose of digoxin, 0.25 mg per day; average follow-up, 37 months). In an ancillary trial of patients with ejection fractions greater than 0.45, 492 patients were randomly assigned to digoxin and 496 to placebo. In the main trial, mortality was unaffected. There were 1181 deaths (34.8 percent) with digoxin and 1194 deaths (35.1 percent) with placebo (risk ratio when digoxin was compared with placebo, 0.99; 95 percent confidence interval, 0.91 to 1.07; P=0.80). In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio, 0.88; 95 percent confidence interval, 0.77 to 1.01; P=0.06). There were 6 percent fewer hospitalizations overall in that group than in the placebo group, and fewer patients were hospitalized for worsening heart failure (26.8 percent vs. 34.7 percent; risk ratio, 0.72; 95 percent confidence interval, 0.66 to 0.79; P<0.001). In the ancillary trial, the findings regarding the primary combined outcome of death or hospitalization due to worsening heart failure were consistent with the results of the main trial. Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure. These findings define more precisely the role of digoxin in the management of chronic heart failure.

Composed of type I and III collagens, the valve leaflets, chordae tendineae and collagen matrix of the myocardium form a structural continuum. Synthesized by cardiac fibroblasts, these fibrillar collagens support and tether myocytes to maintain their alignment, whereas their respective tensile strength and resilience resist the deformation, maintain the shape and thickness, prevent the rupture and contribute to the passive and active stiffness of the myocardium. An acquired or congenital defect in this collagen network can lead to abnormalities in myocardial architecture, mechanics or valve function. In the hypertrophic process that accompanies a pressure overload, for example, increased collagen synthesis, fibroblast proliferation and a structural and biochemical remodeling of the matrix are seen. This includes distinctive patterns of reparative and reactive myocardial fibrosis, each of which alters diastolic and systolic myocardial stiffness and may lead to pathologic hypertrophy. Alternatively, a loss of collagen tethers or decline in matrix tensile strength can be responsible for regional or global transformations in myocardial architecture and function seen in the reperfused ("stunned") myocardium and in dilated (idiopathic) cardiopathy. Inherited disorders in the transcriptional and posttranslational processing of collagen can also alter the biophysical properties of the network. Future studies into collagen gene regulation, gene switching events and the control of collagen synthesis and degradation are needed to develop a more complete understanding of the relation between the collagen network and acquired and inherited forms of heart disease and to utilize therapeutics that will prevent, retard or regress abnormal collagen matrix remodeling.

A fundamental structural event in the progression of heart failure due to dilated cardiomyopathy is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) are an endogenous family of enzymes which contribute to matrix remodeling in several disease states. The goal of this report is to summarize recent findings regarding the myocardial MMP system and the relation to matrix remodeling in the failing heart. In both experimental and clinical forms of dilated cardiomyopathy (DCM), increased expression of certain species of myocardial MMPs have been demonstrated. Specifically, increased myocardial levels of the gelatinase, MMP-9 has been identified in both ischemic and non-ischemic forms of human DCM. In addition, stromelysin or MMP-3 increased by over four-fold in DCM. The increased levels of MMP-3 in DCM may have particular importance since this MMP degrades a wide range of extracellular proteins and can activate other MMPs. In normal human LV myocardium, the membrane type 1 MMP (MT1-MMP) was detected. These MT-MMPs may provide important sites for local MMP activation within the myocardium. In a pacing model of LV failure, MMP expression and activity increased early and were temporally associated with LV myocardial matrix remodeling. Using a broad-spectrum pharmacological MMP inhibitor in this pacing model, the degree of LV dilation was attenuated and associated with an improvement in LV pump function. Thus, increased LV myocardial MMP expression and activity are contributory factors in the LV remodeling process in cardiomyopathic disease states. Regulation of myocardial MMP expression and activity may be an important therapeutic target for controlling myocardial matrix remodeling in the setting of developing heart failure.