The pathology of hereditary cardiomyopathy in the hamster has been well documented in recent years (1–10). This primary congestive type of cardiomyopathy develops in characteristic, well-defined and predictable stages, namely: 1. a necrotic phase with multifocal cardiac lesions, which develop in animals between 30 and 120 days of age; 2. a healing phase with scar formation and progressive dilatation of the atrial and ventricular wall, occurring between 120 and 200 days and, finally, 3. a terminal phase with moderate to severe heart failure between 200 and 300 days (2). The changes in the heart are not visible under a light microscope until the animal has reached 30 days. These lesions reflect a more generalized myopathic process and they probably derive from the same genetic molecular defect.

Monoclonal antibodies (MAb) have been used to study the distribution of ventricular heavy-chain (HC) myosins in cardiomyopathic UM-X7.1 Syrian hamsters. The Ab were identified as alpha and beta anti-HC myosins because of their ability to cross-react with ventricular V1 and V3 myosins, respectively. Cryostat frozen sections from the midventricle region of normal and myopathic hearts were processed for demonstration of these isomyosins by indirect immunofluorescence. In myopathic hearts, there was a shift of predominant alpha myosin toward the beta isoform with the time course of the hamster cardiomyopathy. A D-600 treatment while preventing cardiac necrotic lesions had little or no effect on the beta isomyosin conversion. It is inferred that the isomyosin shift during the progression of the hamster cardiomyopathy is unrelated to the necrotizing process and merely reflects the hypokynetism of the cardiomyocytes.

Degeneration of the heart muscle in cardiomyopathic (CM) hamsters follows a staging pattern which thus far has received little explanation. The ventricular myosin changes with time course of the disease (1) and the impaired responsiveness to catecholamines (2) in these animals are two untoward features that led us to investigate the thyroid function. It is commonly accepted that the pathologic changes in myopathic hearts become evident after 30 days of age (3–7). This stands for a depressed oxidative metabolism or changes in activity of ATPases which concur to the necrotizing process (8, 9). Similar metabolic inadequacies have been equally observed in hypothyroid or diabetic hearts (10, 11) and it seemed all important to appraise the vulnerability of heart muscle cells in hamsters as it may relate to thyroid function.

The use of Ca slow channel blockers for the prevention and treatment of ischemic heart diseases has received a wide acceptance in these recent years (1–4). In spite of their potential effectiveness to prevent Ca overload in reversibly injured myocardial cells (5,6), there is as yet little evidence that these slow channel blockers foster any therapeutic interest for the treatment of primary cardiomyopathies. The hamster hereditary cardiomyopathy includes several of the pathologic components which characterize spontaneously-occurring heart cell degeneration (7,8). The myocardial changes that progressively develop in these animals are an expression of a more generalized myopathic process which in all probability derives from an identical genetic molecular defect(s). Some ten years ago, we demonstrated that verapamil, one of the earliest Ca slow channel blockers, prevented the hamster hereditary cardiomyopathy without changing the overall course of the generalized polymyopathy that prevails in these animals (7,9). Until now, the effectiveness of verapamil in hindering the progression of skeletal muscle changes has remained unexplained except for the fact that presumably Ca slow channel blockers have no direct physiologic or pharmacologic effect on skeletal muscle fibers in higher vertebrates (10,11). Indeed therapeutic trials with prenylamine and verapamil were found unsuccessful in human muscular dystrophy (12,13).

The heart muscle is very compliant within a wide range of physiologic impulses. The adaptive energy of the myocardium depends, however, upon adequate oxygen supply and the functional state of the plasmalemma. These limitations have been well demonstrated in a number of experimental models with emphasis on the essential role of Ca2+ transmembrane movements for maintenance of heart functions and its viability. This postulate appeared quite important when we found that Ca2+ slow channel blockers could prevent necrotic changes in hamster hereditary cardiomyopathy. However, the effectiveness of β-adrenoagonists when given in low doses seems more difficult to interpret since these agonists can only promote Ca2+ transmembrane movements. We can only surmise that Ca2+ accumulation in cardiomyopathic hearts does not derive from a primary defect of the plasmalemma but rather from an exhausted hypokinetic state that favours Ca2+ accumulation with progressive deterioration of the structural proteins. It is thus inferred that Ca2+ mediates rather than initiates the degradation process which characterizes this inherited cardiomyopathy.

Isoproterenol (ISO), a potent β‐adrenoreceptor agonist, was found to interfere with the development and progression of hamster hereditary polymyopathy. Cytoprotection involved both skeletal and heart muscles with reduced myofibrillar degeneration, phagocytosis, and an unusual scarring process rarely seen at this stage of the disease. A decrease in the Ca content of heart and hemidiaphragm homogenates corroborated these findings. The significant drop of serum creatine kinase with restoration of alkaline phosphatase activity towards normal values provided additional support to the therapeutic effect of ISO. Except for an increase in magnesium, there were no changes in serum electrolytes. The modifications in plasma membrane permeability together with improvement in microcirculation are some of the features whereby ISO can ameliorate muscle cell energy metabolism. It is inferred that the alleged primary role of calcium in the development of this inherited myopathy should be further scrutinized.

It was previously shown that beta-adrenergic blockers exert a protective action on the development of heart necrotic changes in cardiomyopathic hamsters. To further investigate the possible role of catecholamines in the pathogenesis of the hamster hereditary cardiomyopathy, the ventricular adrenergic nerve terminals were visualized by fluorescence histochemistry, and NE uptake and turnover were determined after i.v. injection of labeled NE. It was found that the fluorescent nerve endings strongly proliferate with the occurrence of heart necrotic changes. With healing of the myocardial lesions, the difference between control and myopathic hearts is less apparent, and NE nerve endings are literally absent in the terminal stage of the disease. There was a marked increase in NE uptake during the necrotic stage and, at the same time, a considerable rise in elimination rate constant with a maximum level at terminal state, suggesting that the NE turnover is related to the progression of the disease. In light of the present findings, it can be surmised that NE plays a permissive role in the genesis of the hamster disease by promoting the heart necrotic changes.

The mitochondrial oxidative phosphorylation, calcium and magnesium contents, and swelling‐contraction activity were investigated in relation to the progression of the hereditary hamster cardiomyopathy. The assessment was made in animals between 22 and 232 days of age, which were divided into 7 groups according to stage of disease. In 24‐day‐old hamsters prior to development of heart necrotic changes, the membrane permeability of isolated mitochondria was altered. In 50‐day‐old animals, at a stage of disease when myocardical cells undergo degeneration, a defect of oxidative phosphorylation resulting from an increase in mitochondrial calcium was demonstrated. With culmination of the heart necrotic changes, at close to 100 days of age, mitochondrial dysfunction and calcium overload were maximal. There was a transient improvement during the healing stage, but the situation deteriorated with the occurrence of circulatory failure. Since the mitochondrial respiratory pattern and calcium overload parallel the cardiac degeneration, it is inferred that the cell energy depletion is a functional consequence of an abnormal calcium influx.

The Syrian hamster polymyopathy is a hereditary disease, transmitted by an autosomal recessive gene, involving the heart and the entire musculature. The chronology of the pathologic events in the myocardium and skeletal muscle has been investigated in UM‐X7.1 myopathic hamsters aged 0–250 days. A phasic pattern in the progression of the disease process was evident. Microscopic necrotic changes in the heart were visible prior to or at 50 days of age with increasing severity until 100 days of age and subsidence thereafter. More than 50% of the animals died before 250 days of age with signs of cardiac failure. The intensity and extent of myocardial calcific changes together with scar formation were determinant factors in curtailing the survival of animals. Changes in serum creatine kinase (CK) activity followed a phasic pattern similar to the progression of the myopathic disease. Because of the disparity of disease manifestations between the different myopathic hamster lines, it is essential to consider the time course of the heart and skeletal muscle microscopic changes when evaluating the severity of the hamster polymyopathy.

Verapamil and prenylamine, which antagonize calcium influx into heart muscle cells, Dibenamine and propanolol, alpha and beta adrenergic bockers, respectively, and prostaglandin E1, which acts on permeability of cell membranes and on adrenergic neurotransmission, were all shown to markedly reduce the severity of heart lesions in UM-X7.1 cardiomyopathic hamsters. The beneficial effects of these compounds seen essentially preventive, in that they do not afford protection for fully developed skeletal muscle lesions. The occurrence of the pathologic changes in the myocardium coincides with an increased adrenergic nerve activity, and it is believed that these drugs function mainly by decreasing calcium conductivity across the sarcolemmal membranes of cardiocytes.