Cardiomyopathy is a multifactorial disease, and the dystrophin-glycoprotein complex has been implicated in the pathogenesis of both hereditary and acquired forms of the disease. Using mouse models of cardiomyopathy made by ablating genes for components of the sarcoglycan complex, we show that long-term treatment with verapamil, a calcium channel blocker with vasodilator properties, can alleviate the severe cardiomyopathic phenotype, restoring normal serum levels for cardiac troponin I and normal cardiac muscle morphology. Interruption of verapamil treatment leads again to vascular dysfunction and acute myocardial necrosis, indicating that predilection for cardiomyopathy is a continuing process. In contrast, verapamil did not prevent cardiac muscle pathology in dystrophin-deficient mdx mice, which neither show a disruption of the sarcoglycan complex in vascular smooth muscle nor vascular dysfunction. Hence, our data strongly suggest that pharmacological intervention with verapamil merits investigation as a potential therapeutic option not only for patients with sarcoglycan mutations, but also for patients with idiopathic cardiomyopathy associated with myocardial ischemia not related to atherosclerotic coronary artery disease.
Ronald D. Cohn, Madeleine Durbeej, Steven A. Moore, Ramón Coral-Vazquez, Sally Prouty, Kevin P. Campbell
Submitter: Ronald D. Cohn and Kevin P. Campbell | kevin-campbell@uiowa.edu
University of Iowa College of Medicine
Published July 6, 2001
To the Editor -- We would like to thank Profs. Factor and Sonnenblick for their constructive thoughts concerning our manuscript, "Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex" (1). We are certainly aware of the authors' significant, though preliminary, findings regarding microvascular spasms as a probably cause of cardiomyopathy in the Syrian hamster as well as in other diseases associated with ischemic-like cardiomyopathy, however, due to limited space, we were not able to reference all of the previous published work.
However, we do not agree, that our study simply replicated previous experiments by simply substituting one rodent animal model for another for several reasons. First, although a deletion in the delta-sarcoglcyan gene has recently been described in the Syrian cardiomyopathic hamster (2), expression of the delta-sarcoglycan gene at the mRNA level can still be detected in several tissues (3). In addition, the muscular dystrophy phenotype observed in the hamster is less severe than generally observed in human patients or mouse models with mutations within the delta-sarcoglycan gene. Hence, in contrast to the mouse model, which we have generated, the hamster cannot be considered as a true "null" for the delta-sarcoglycan gene and therefore does not serve as a valuable model to study the molecular pathogenesis associated with complete absence of delta-sarcoglycan and its impact on perturbations of the sarcoglycan-sarcospan complex. Moreover, our studies in the delta-sarcoglycan null mice, described for the first time (4) that perturbation of the vascular function was indeed a primary phenomenon attributable to the loss of the novel described sarcoglycan-sarcospan complex in vascular smooth muscle.
Second, the current manuscript undoubtedly unveils not only insights into the pathogenetic mechanisms associated with delta-sarcoglycan mutations but also novel insights for cardiomyopathy and muscular dystrophy associated with beta-sarcoglycan mutations. So far only a few mutations within the delta-sarcoglycan gene have been described in patients, whereas numerous mutations within the beta-sarcoglycan gene have been described in patients with muscular dystrophy and cardiomyopathy (1). Moreover, we showed that verapamil treatment in dystrophin-negative mdx mice did not have any beneficial effects of the cardiomyopathic phenotype due to preserved expression of the sarcoglycan-sarcospan complex and normal function of the coronary artery vasculature. These results served as an important additional line of evidence for the specificity of our observation that alterations in vascular function are indeed responsible for the development of cardiomyopathy in mice deficient for beta- and delta-sarcoglycan (4, 5).
Finally, we demonstrated for the first time, that evaluation of cardiac troponin I level in serum of mice serves as an excellent marker for cardiac muscle damage in mice with muscular dystrophy. The value of these findings is not only important for monitoring of possible future therapies but also for the early detection of cardiac muscle damage in patients with muscular dystrophy. Hence, our findings are directly applicable to a disease-defined group of patients with muscular dystrophy and more specifically patients with cardiomyopathy due to mutations within the beta- and delta-sarcoglycan gene.
Ronald D. Cohn and Kevin P. Campbell
1. Cohn, R.D., and Campbell, K.P. 2000. The molecular basis of muscular dystrophy. Muscle Nerve. 23:1456-1471.
2. Nigro, V., et al. 1997. Identification of the Syrian hamster cardiomyopathy gene. Hum. Molec. Genet. 4:601-607.
3. Sakamoto, A., Abe, M., and Masaki, T. 1999. Delineation of genomic deletion in cardiomyopathic hamster. FEBS Lett. 447:124-128.
4. Coral-Vazquez, R., et al. 1999. Disruption of the sarcoglycan-sarcospan complex in vascular smooth muscle: a novel mechanism for cardiomyopathy and muscular dystrophy. Cell. 98:465-474.
5. Durbeej, M., et al. 2000. Disruption of the beta-sarcoglycan gene reveals a complex pathogenetic mechanism for LGMD 2E. Molec. Cell. 5:141-151.
Submitter: Stephen M. Factor and Edmund H. Sonnenblick | factor@aecom.yu.edu
Albert Einstein College of Medicine
Published July 6, 2001
To the Editor — The article by Cohn et al. (1) is an interesting demonstration of the role of microvascular spasm in the development of multifocal myocellular necrosis in a rodent model of cardiomyopathy. The authors further show the efficacy of the L-type calcium channel blocking agent, verapamil, in completely preventing the phenotypic expression of the myocardial damage. They suggest that the drug is functioning on the vascular smooth muscle to prevent microvascular spasm, and they illustrate the positive effects by using silicone rubber (Microfil) perfusion studies of the microcirculation, with direct visualization of the spasm.
The implications of this study, expressed several times in the paper, are that these observations are unique. In fact, this report virtually replicates in detail a study published by our group in 1982, in which we demonstrated, truly for the first time, the presence of microvascular spasm in the Syrian hamster, and the efficacy of verapamil in preventing spasm and myonecrosis in this genetically determined model of cardiomyopathy (2). Although the authors cite our later study (3) in passing (their ref. 18), they only use the citation to suggest that "various early studies have shown beneficial effects of verapamil in the cardiomyopathic hamster ..." Furthermore, the authors fail to cite a vast body of literature from our laboratory in which we have shown the role of microvascular spasm in several different acquired cardiomyopathies, including that due to diabetes mellitus and hypertension, and Chagas' disease; in myocardial necrosis resulting from embolization of microspheres into the coronary circulation; and in brain injury (4-10).
We congratulate the authors for replicating our studies, and for re-establishing the significance of microvascular spasm as a cause of myonecrosis and cardiomyopathy. A more complete recitation of the scientific record would have been useful, along with a recognition that the current study simply substitutes one rodent for another.
Stephen M. Factor, Professor of Pathology & Medicine, and Edmund H. Sonnenblick, Professor of Medicine Emeritus Director, Division of Cardiology, Albert Einstein College of Medicine
1. Cohn, R.D., Durbeej, M., Moore, S.A., Coral-Vazquez, R., Prouty, S., and Campbell, K.P. 2001. Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex. J. Clin. Invest. 107:R1-R7.
2. Factor, SM., Minase, T., Cho, S., Dominitz, R., and Sonnenblick, E.l-t. 1982. Microvascufar spasm in the cardiomyopathic Syrian hamster: A preventable cause of focal myocardial necrosis. Circulation. 66:342-354.
3. Factor, S.M., Cho, S.H., Scheuer, J., Sonnenblick, E.H., and Malhotra, A. 1988. Prevention of cardiomyopathy in the Syrian hamster with chronic verapamil therapy. J. Am. Coll. Cardiol. 12:1599-1604.
4. Factor, SM., and Sonnenblick, E.H. 1982. Hypothesis: Is congestive cardiomyopathy secondary to a hyper-reactive myocardial microcirculation (microvascular spasm)? Am. J. Cardiol. 50:1149-1152.
5. Factor, S. M., and Sonnenblick, E.H. 1983. Microvascular spasm as a cause of cardiomyopathies. Cardiovasc. Rev. Rep. 4:1177-1182.
6. Factor, S.M., Minase, T., Cho, S. Fein, F, Capasso, J.M., and Sonnenblick, E.H. 1984. Coronary microvascular abnormalities in the hypertensive-diabetic rat. A cause of cardiomyopathy? Am. J. Pathol. 116:9-20.
7. Eng, C., Cho, S., Factor, S.M., Sonnenblick, E.H., and Kirk, E.S. 1984. Myocardial micronecrosis produced by microsphere embolization. Role of an alpha adrenergic tonic influence of the coronary microcirculation. Circ. Res. 54:74-82.
8. Factor, S.M., Cho, S., Wittner, M., and Tanowitz, F-f. 1985. Abnormalities of the coronary microcirculation in acute murine Chagas' disease. Am. J. Trop. Med. Hyg. 34:246-253.
9. Conway, R.S., Factor, S.M., Sonnenblick, E.H., and Baez, S. 1987. Microvascular reactivity of the myopathic Syrian hamster cremaster muscle. Cardiovasc. Res. 21:796-803.
10. Shanlin, R.J., Sole, M.J., Rahimifar, M, Tator, C.H., and Factor, S.M. 1988. Increased intracranial pressure elicits hypertension, increased sympathetic activity, electrocardiographic abnormalities and myocardial damage in rats. J. Am. Coil. Cardiol. 12:727-736.