Cellular and subcellular basis for remodeling: Summation

Abstract

In order to treat a disease rationally, one must understand the specific disease process. Heart failure is no exception. Despite daunting complexities regarding mechanisms, remodeling of the heart is emerging as the fundamental phenotypic expression of this syndrome. Whether there is left ventricular (LV) hypertrophy with impaired filling, or LV spheroidal dilation with reduced systolic performance, structural changes appear to be the fundamental basis for many of the signs and symptoms of heart failure. From a clinical perspective, LV remodeling involves a gradual change in the shape and change of the chamber, leading to heightened wall stress and impaired systolic function. This section examines the cellular and subcellular basis for remodeling, which is less understood but of critical importance, offering a glimmer of light on the future evolution of therapy for heart failure. Roger Hajjar and colleagues from the Massachusetts General Hospital, report on their experience with manipulation of signal transduction pathways in isolated cardiac myocytes. Using gene transfer techniques, they have overexpressed wild-type (normal) signaling molecules, or created a mutant protein with no biologic activity (knockout or null mutant) or one that in some cases blocks the endogenous activity of the signaling molecule. Abnormalities of contractile proteins, calcium transient proteins, and neurohumoral receptors are potential targets of gene therapy. Signaling molecules that regulate hypertrophy are also attractive targets. Proteins such as insulin-like growth factor (IGF-1) that control apoptosis can be manipulated. Ultimately, such proteins form the basis of treatment for heart failure. Interpretation of such experiments, however, can be difficult. Isolating effects of downstream signaling pathways from more systemic effects is not simple. Systematic studies of signaling proteins are most enlightening, even if they do not lead directly to improved forms of therapy. Inder Anand, from the University of Minnesota, has pioneered the concept of cell structural change, rather than altered cell function, as the basis of heart failure. Using the rat myocardial infarction model, he and his group clearly demonstrated that cardiac myocytes isolated from failing heart are structurally abnormal (increased cell length and cross-sectional area) but retain normal shortening function in vitro. These important observations suggest that structural changes in the cell may precede or are disassociated from cellular dysfunction. They also support the hypothesis that organ remodeling, and not reduced contractile function, may be the initial response to myocardial injury. Howard Rockman and colleagues, from Duke University, used genetically engineered mice to study myocardial hypertrophy and its role in the development of heart failure. They showed that altered Gq-coupled receptor signaling in transgenic mice significantly reduces the hypertrophic response to in vivo pressure overload. They went on to show that a number of signaling pathways in response to G-protein–coupled receptor stimulation play important roles in the hypertrophic response. These experiments are examples of how we might combine physiologic analysis and genetically engineered mice to broaden the understanding of G-coupled receptors and cardiac hypertrophy. The observations are critical in our unraveling the link between load and signal transduction. Sian Harding and colleagues, from London, present evidence that myocyte size and impairment of contractile function can be dissociated in time and degree. Although impairment in myocyte contractile function and increase in myocyte size both contribute to heart failure, the two appear to develop independently in response to the same stimuli. Both normal-sized cells and large myocytes from the same ventricle were found to have similarly impaired relaxation velocities. Structural changes or architectural rearrangement may, by themselves, impair From the Coronary Intensive Care Unit, Cleveland Clinic Foundation, Cleveland, Ohio. Reprint requests: Gary S. Francis, MD, Desk F-25, Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195 Copyright 2002, Elsevier Science (USA). All rights reserved. 1071-9164/02/0806-0043$35.00/0 doi:10.1054/jcaf.2002.129248 Journal of Cardiac Failure Vol. 8 No. 6 Suppl. 2002