Catecholamines, Calcium and Cardiomyopathy Michael J. Sole, MD, and Choong-Chin Liew, PhD The cardiomyopathic Syrian hamster has a geneti- cally transmitted form of dilated cardiomyopathy and is an important paradigm of myocardial dis- ease, particularly for studies addressing the earli- est stages of myocardial dysfunction. This model exhibits an increase in cardiac sympathetic tone in the presence of an altered expression of sarcolem- mal calcium channels or of (~1receptors, and a de- fective handling of calcium by both cardiomyocytes and vascular smooth muscle cells. Increased ex- pression of the oncogene c-myc is evident in cardio- myocytes before any overt evidence of heart dis- ease. Alterations in a nuclear phosphoprotein, which appears to be important in the regulation of gene expression, have also been identified. The dis- ease becomes phenotypically manifest by the devel- opment of microvascular spasm, reperfusion injury and myocyte loss. Myocyte loss, in turn, burdens the remaining cells with an increasing load, in- creasing sympathetic stimulation, myocyte hyper- trophy and further cell loss-a continuing vicious spiral that culminates in the development of myo- cardial failure. All of the features of hamster car- diomyopathy may be prevented by the administra- tion of verapamil or prazosin to juvenile hamsters before the phenotypic onset of their heart disease. This understanding has led to the study of new im- aging agents that promise the detection of such forms of cardiomyopathy in their earliest stages and a means by which the effects of therapy can be assessed. If such mechanisms are applicable to hu- man cardiomyopathy, early treatment of patients with adrenergic antagonists or calcium antagonists should be beneficial. (Am J Cardiol 1966;62:2OG-246) From the Laboratory for Molecular Cardiology, Departments of Medi- cine and Clinical Biochemistry, Toronto General Hospital, Toronto, Ontario, Canada. These studies were supported in part by grants from the Heart and Stroke Foundation of Ontario, Medical Research Coun- cil, Ontario, Canada, and the US Public Health Service, National Institutes of Health, Bethesda, Maryland. Dr. Sole is a Research Asso- ciate of the Heart and Stroke Foundation of Ontario, Canada. Address for reprints: Michael J. Sole, MD, Suite 13-208 EN, To- ronto General Hospital. 200 Elizabeth Street. Toronto. Ontario. M5G 2C4 Canada. _ C ongestiveheart failure is a major causeof disa- bility and permature death in modern Western societies. The numberof discharges from the hospi- tal with this diagnosis has increased approximately 300% since 1970.’ Coronary artery disease, hypertension, val- vular heart diseaseand viral myocarditis account for most of this disease burden; however, a significant and increasing percentage of patients have dilated cardiomy- opathy of indeterminate origin. Although, modern diag- nostic technology, including myocardial biopsy, can pro- vide a detailed characterization of cardiovascular func- tion, coronary perfusion and myocardial disease, the identification of patients in the earliest stages of dilated cardiomyopathy, and an understanding of its cellular pathobiologic characteristics, remains elusive. The activity of neurohormonal systems, particularly the renin-angiotensin and sympathoadrenal systems, have beenwell studied in heart failure including that due to the dilated cardiomyopathies.These studies have fo- cusedon the later stages of heart disease in which dra- matic activation and inadequate feedback regulation of thesesystems have been observed.2,3 Subsequent under- standing of the importance of this neurohumoral dysreg- ulation in the pathophysiologyof congestive heart failure has brought about a variety of new pharmacologic ap- proaches for the relief of patients with advanced disease. Such therapeutic strategies,however, have proved to be merely palliative, with no real meaningful amelioration of the relentless progression of the underlying heart dis- ease.1,4 Trying to preservecardiac function at the end stages of heart failure must ultimately prove to be a fruitless endeavor; it simply cannot be done over the long term. The solution to this clinical problem lies in defining and preventing,or arresting and reversing,the root causes of myocardial dysfunction. Surgical models of heart failure, although valuable contributors to our understanding of the hemodynamic and neurohumoral responses to myocardial failure, have clear limitations in studies of the early pathobiology of myocardial dysfunction. The cardiomyopathic Syrian hamster is a reproducible and spontaneous (genetically transmitted as an autosomal recessive) animal model of myocardial hypertrophy and failure, particularly well suited for the study of primary events of possible rele- vance to the pathogenesis of cardiac disease.5,6 The courseof hamster cardiomyopathy has beenwell characterized.Animals younger than age 40 to 50 days display little grossor light microscopicevidence of heart disease. At this time, they enter the “necrotic” phaseof the disease, in which multiple focal areas of myocytolytic necrosis develop;all cardiac musclelayers and chambers are involved. Theselesionsare replacedby fibrotic, calci- 206 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62