Hypertrophic Cardiomyopathy: One Gene . but Many Phenotypes Barry J. Maron, MDa,*, Tammy S. Haas, RNa, and Jeffrey S. Goodman, MDb
a
The Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota and bCedars-Sinai Heart Institute, UCLA School of Medicine, Los Angeles, California. Manuscript received February 10, 2014; revised manuscript received and accepted February 12, 2014. See page 1772 for disclosure information. *Corresponding author: Tel: (612) 863-3996; fax: (612) 863-3875. E-mail address: [email protected] (B.J. Maron).
Phenotypic expression of hypertrophic cardiomyopathy (HC) can be highly variable, even among closely related family members,1,2 as demonstrated by this informative family pedigree (Figure 1). These observations underscore the diverse spectrum of HC and frequent lack of genotypephenotype correlation between the pattern of left ventricular
(LV) hypertrophy and the disease-causing mutation;3 and that certain morphologic and functional disease expressions may not be generally understood to be part of HC. In this family, the depicted manifestations of HC included a typical nondilated LV with segmental hypertrophy and intact systolic function;1 end stage with LV remodeling and systolic dysfunction4; and, notably, the unusual nonhypertrophied and “restrictive” form (also with impaired ejection fraction).5 The latter 2 patients required heart transplantation for progressive and unrelenting heart failure. These varied phenotypes of HC were all linked to (and caused by) a mutation in the troponin T gene (c487_489delGAG). Disclosures The authors have no conflicts of interest to disclose.
Figure 1. (Top) Family pedigree. Arrow ¼ proband; * ¼ died of nonobstructive HC, but echocardiographic images were not available for review; þ ¼ gene positive; ¼ gene negative; solid symbols ¼ HC phenotype; symbol with slash ¼ died; patient ages appear in parentheses. (Bottom) Two-dimensional echocardiographic demonstration of diverse phenotypic expressions of HC in related patients due to troponin T mutation (c487_489delGAG). continued. Am J Cardiol 2014;113:1772e1773 0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.02.032
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Case Report
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Figure 1 (continues). (A) Patient III.4—a 37-year-old asymptomatic man with nonobstructive HC and hypertrophy of anterior ventricular septum (*) (23 mm); ejection fraction 53%. (B) Patient III.2—a 28-year-old woman with nonobstructive HC and predominant hypertrophy of posterior ventricular septum (*) (21 mm); ejection fraction 75%. (C) Patient II.1—a 57-year-old man with progressive heart failure (and 2 prior cardiac arrests) with heart transplant for endstage HC at age 54, ejection fraction 30%; LV end-diastolic dimension 52 mm; left atrial enlargement (transverse dimension, 58 mm); VS thickening (white line) is mild (16 mm). (D) Patient II.5—a 67-year-old woman with severe heart failure and transplant at age 61, showing a distinctly different and unusual expression of HC with markedly enlarged atria and restrictive physiology; LV wall thickness was normal (9 mm); (arrow) and unchanged over 30 years of observation; ejection fraction is 40%. Myocardial fibrosis was absent by contrast cardiovascular magnetic resonance and examination of the explanted heart although myocyte disarray was reported by histopathology. LA ¼ left atrium; RA ¼ right atrium; RV ¼ right ventricle; VS ¼ ventricular septal.
1. Maron MS, Maron BJ, Harrigan C, Buros J, Gibson CM, Olivotto I, Biller L, Lesser JR, Udelson JE, Manning WJ, Appelbaum E. Hypertrophic ardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol 2009;54:220e228. 2. Ciró E, Nichols PF 3rd, Maron BJ. Heterogeneous morphologic expression of genetically transmitted hypertrophic cardiomyopathy. Twodimensional echocardiographic analysis. Circulation 1983;6:1227e1233. 3. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol 2012;60:705e715.
4. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, Lesser JR, Mackey- Bojack S, Manning WJ, Udelson JE, Maron BJ. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation 2006;114:216e225. 5. Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest 2003;111:209e216.
a
The Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota and bCedars-Sinai Heart Institute, UCLA School of Medicine, Los Angeles, California. Manuscript received February 10, 2014; revised manuscript received and accepted February 12, 2014. See page 1772 for disclosure information. *Corresponding author: Tel: (612) 863-3996; fax: (612) 863-3875. E-mail address: [email protected] (B.J. Maron).
Phenotypic expression of hypertrophic cardiomyopathy (HC) can be highly variable, even among closely related family members,1,2 as demonstrated by this informative family pedigree (Figure 1). These observations underscore the diverse spectrum of HC and frequent lack of genotypephenotype correlation between the pattern of left ventricular
(LV) hypertrophy and the disease-causing mutation;3 and that certain morphologic and functional disease expressions may not be generally understood to be part of HC. In this family, the depicted manifestations of HC included a typical nondilated LV with segmental hypertrophy and intact systolic function;1 end stage with LV remodeling and systolic dysfunction4; and, notably, the unusual nonhypertrophied and “restrictive” form (also with impaired ejection fraction).5 The latter 2 patients required heart transplantation for progressive and unrelenting heart failure. These varied phenotypes of HC were all linked to (and caused by) a mutation in the troponin T gene (c487_489delGAG). Disclosures The authors have no conflicts of interest to disclose.
Figure 1. (Top) Family pedigree. Arrow ¼ proband; * ¼ died of nonobstructive HC, but echocardiographic images were not available for review; þ ¼ gene positive; ¼ gene negative; solid symbols ¼ HC phenotype; symbol with slash ¼ died; patient ages appear in parentheses. (Bottom) Two-dimensional echocardiographic demonstration of diverse phenotypic expressions of HC in related patients due to troponin T mutation (c487_489delGAG). continued. Am J Cardiol 2014;113:1772e1773 0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.02.032
www.ajconline.org
Case Report
1773
Figure 1 (continues). (A) Patient III.4—a 37-year-old asymptomatic man with nonobstructive HC and hypertrophy of anterior ventricular septum (*) (23 mm); ejection fraction 53%. (B) Patient III.2—a 28-year-old woman with nonobstructive HC and predominant hypertrophy of posterior ventricular septum (*) (21 mm); ejection fraction 75%. (C) Patient II.1—a 57-year-old man with progressive heart failure (and 2 prior cardiac arrests) with heart transplant for endstage HC at age 54, ejection fraction 30%; LV end-diastolic dimension 52 mm; left atrial enlargement (transverse dimension, 58 mm); VS thickening (white line) is mild (16 mm). (D) Patient II.5—a 67-year-old woman with severe heart failure and transplant at age 61, showing a distinctly different and unusual expression of HC with markedly enlarged atria and restrictive physiology; LV wall thickness was normal (9 mm); (arrow) and unchanged over 30 years of observation; ejection fraction is 40%. Myocardial fibrosis was absent by contrast cardiovascular magnetic resonance and examination of the explanted heart although myocyte disarray was reported by histopathology. LA ¼ left atrium; RA ¼ right atrium; RV ¼ right ventricle; VS ¼ ventricular septal.
1. Maron MS, Maron BJ, Harrigan C, Buros J, Gibson CM, Olivotto I, Biller L, Lesser JR, Udelson JE, Manning WJ, Appelbaum E. Hypertrophic ardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol 2009;54:220e228. 2. Ciró E, Nichols PF 3rd, Maron BJ. Heterogeneous morphologic expression of genetically transmitted hypertrophic cardiomyopathy. Twodimensional echocardiographic analysis. Circulation 1983;6:1227e1233. 3. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol 2012;60:705e715.
4. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, Lesser JR, Mackey- Bojack S, Manning WJ, Udelson JE, Maron BJ. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation 2006;114:216e225. 5. Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest 2003;111:209e216.
