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Familial conduction system disease associated with hypertrophic cardiomyopathy
International Journal of Cardiology 125 (2008) e44 – e47 www.elsevier.com/locate/ijcard
Letter to the Editor
Familial conduction system disease associated with hypertrophic cardiomyopathy Ajay Bahl * , Uma Nahar Saikia, Kewal K. Talwar Department of Cardiology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India Received 7 November 2006; accepted 31 December 2006 Available online 18 April 2007
Abstract A large family with a new phenotype of conduction system disease including heart blocks and preexcitation associated with hypertrophic cardiomyopathy and transmitted in an autosomal dominant pattern is described. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Heart block; Preexcitation; Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is defined by a hypertrophied, non-dilated left ventricle in the absence of another systemic or cardiac disease capable of producing the magnitude of wall thickening. Conduction system disease is known to occur in a few patients with HCM. However, conduction system disease affecting several family members and forming the predominant phenotype has not been reported. In this report, we describe a large family with a new phenotype of conduction system disease associated with HCM and transmitted in an autosomal dominant pattern. Forty two year old male presented to the cardiology clinic for pacemaker follow up. A DDDR pacemaker had been implanted 6 years back. At initial presentation, he had giddiness and was found to have second degree atrioventricular block with right bundle and left anterior fascicular block. Several members of his family had required pacemaker implantation. He also had family history of sudden death. A detailed family history was taken and he was advised for family screening (Fig. 1). Clinical evaluation, ECG, echocardiography and Holter examination were carried out in family members who
⁎ Corresponding author. Tel.: +91 9815323265; fax: +91 172 2744401. E-mail address: [email protected] (A. Bahl). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.12.050
presented for evaluation. One family member underwent endomyocardial biopsy (III:5) after written informed consent. The tissue was fixed in alcohol and in 10% buffered formalin and was subjected to histopathology and electron microscopy. This North Indian family comprised of 37 members over 3 generations. Of these, 9 were clinically evaluated. Five members had died previously. Of these, 2 had sudden deaths (III:2, IV:1) at 25 and 51 years of age respectively. One individual (III:2) had mild breathlessness on exertion for a few years prior while the other (IV:1) had been totally asymptomatic. Five family members required pacemakers (II:4; II:6; II:7; III:5; III:9). Youngest age at pacemaker implantation was 39 years. The remaining 4 patients required pacemakers between 40 and 55 years of age. There were no consanguineous marriages in the family. The demographic profile and clinical presentation is given in Table 1. 1. Age of presentation Most symptomatic patients presented with heart block in fourth to sixth decades. Affected adolescents remained asymptomatic except for mild breathlessness. The youngest individual evaluated was 12 years old. He had pre-excitation on ECG and complained of breathlessness during sports for
A. Bahl et al. / International Journal of Cardiology 125 (2008) e44–e47
e45
Fig. 1. Pedigree of the family.
the past 1 year. One previously asymptomatic individual died suddenly at the age of 25 years.
also normal with normal wall thickness and chamber dimensions.
2. ECG
5. Histology
The two patients on pacemakers had a completely A paced, V paced rhythm. Remaining patients were in sinus rhythm. Three patients had tall peaked P waves in lead II suggestive of right atrial enlargement. Right atrial enlargement was not seen on echocardiography. Two patients had a short PR interval, one of these had a delta wave while the other had tall narrow QRS complexes. One patient had wide QRS complex with right bundle branch block morphology. Three individuals had normal ECG. All these three also had normal echocardiograms (Fig. 2).
Endomyocardial biopsy done on III:5 showed myofibre disarray with focal hypertrophy of myocytes. There was mild anisonucleosis and myocyte hypertrophy. Patchy interstitial fibrosis and oedema was also seen (Fig. 3A and B). There was no increase in hemosiderin pigment, amyloid deposition or any excess of glycogen. No evidence of any storage disorder was noted. The ultrastructural findings also confirmed the microscopic features. The overall features were consistent with HCM. This family has a novel phenotype transmitted in an autosomal dominant pattern. The main features of this syndrome include left ventricular hypertrophy, heart blocks, intraventricular conduction defects, pre-excitation and sudden death. The phenotype of this family had features of Lenegre– Lev disease and HCM. Lenegre–Lev disease or progressive cardiac conduction defect is one of the most common cardiac conduction disturbances and is a major cause of pacemaker implantation. It is defined on ECG by evidence of bundle branch disease that is right bundle branch block, left anterior or posterior hemiblock, or complete heart block, with broad QRS complexes. Progression has been shown from a normal ECG to right bundle branch block and from the latter to
3. Echocardiography Two individuals had moderate concentric left ventricular hypertrophy. The rest had normal left ventricular wall thickness. All nine had normal left ventricular systolic function. Valves were morphologically normal in all. There were no significant valvular regurgitations. 4. MRI Cardiac MRI was carried out in an individual (IV:13) with abnormal ECG but normal echocardiography. The MRI was
Table 1 Profile of patients clinically evaluated
III:5 III:9 III:10 IV:2 IV:6 IV:7 IV:12 IV:13 IV:14
Age (years) Sex Presentation
ECG
PR interval (ms) QRS duration (ms) LVH
46 44 40 18 22 18 17 15 12
A paced, V paced A paced, V paced Normal Normal Normal RAE, delta wave, tall QRS complexes Normal RAE, RBBB RAE, tall QRS complexes
– – 150 130 130 90 140 160 100
F M F F M M F M M
Heart block Heart block Asymptomatic Mild breathlessness Asymptomatic Mild breathlessness Asymptomatic Mild breathlessness Asymptomatic
– – 90 90 100 130 90 120 90
Concentric maximal—20 mm Absent Absent Absent Absent Concentric maximal—18 mm Absent Absent Absent
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A. Bahl et al. / International Journal of Cardiology 125 (2008) e44–e47
Fig. 2. A: ECG of patient IV:13 showing bizarre intraventricular conduction defect of right bundle branch block morphology. B: ECG of patient IV:7 showing short PR interval, delta wave and tall and bizarre QRS complex.
complete heart block. Similar ECG patterns were seen in our family. In addition, 2 members had pre-excitation. Preexcitation has also been reported in association with familial
heart block [1,2]. The ECG profile of this family is thus similar to that of Lenegre–Lev disease. Lenegre–Lev disease, however is a primary degenerative disease affecting
A. Bahl et al. / International Journal of Cardiology 125 (2008) e44–e47
e47
This family thus had HCM along with cardiac conduction system defects. Though both HCM and familial conduction system disease are transmitted as autosomal dominant disorders, the underlying diseases causing mutations are different. HCM is caused by mutations in genes encoding sarcomeric proteins whereas familial heart blocks are caused by mutations in SCN5A which is an ion channel protein [11]. Since both HCM and conduction system disease coexist in this family, identification of a mutation that can cause both these disorders could provide important information on the pathogenesis of these conditions. Genotyping has not yet been carried out in this family. The possibility of HCM and conduction system disease being transmitted independently through two separate mutations also cannot be excluded. The unique phenotype of HCM and conduction system disease in this family adds to our evolving understanding of the phenotypic variations and overlaps of genetic cardiomyopathies and conduction system disorders. References
Fig. 3. A: Microphotograph showing unremarkable endocardium with myofibre disarray. (H&E × 280). B: Microphotograph showing myofibre disarray with myocyte hypertrophy and mild interstitial fibrosis. (H&E ×420).
only the conduction tissue and is not associated with left ventricular hypertrophy as seen in this family. The age profile, presentation, left ventricular hypertrophy and histology suggests HCM. Although heart blocks and pre-excitation occasionally occur in patients with HCM, such widespread involvement affecting several family members has not been reported [3–7]. Conduction blocks and pre-excitation are commonly seen in association with glycogen storage disorders due to mutations in the PRKAG2 or LAMP2 gene. These patients also have left ventricular hypertrophy and can mimic HCM [8–10]. In these disorders myocyte hypertrophy is due to the presence of glycogen filled vacuoles. Myocyte disarray which is typical of HCM is seen. Cardiomyopathy due to storage disorders was excluded by endomyocardial biopsy.
[1] Wendkos MH, Study RS. Familial congenital complete A–V heart blocks. Am Heart J 1947;34:138–42. [2] Segall HN. Congenital arrhythmias and conduction abnormalities in a father and four children. Canad Med Assoc J 1961;84:1283–96. [3] Doven O, Cicek D, Pekdemir H, et al. Abnormal His–Purkinje system conduction leading to complete atrioventricular block in patients with hypertrophic cardiomyopathy: a report of 3 cases. Jpn Heart J 2004;45:347–52. [4] Cicek D, Camsari A, Doven O. Familial hypertrophic cardiomyopathy complicated by complete atrioventricular block. Acta Cardiol 2004;59:71–4. [5] Yesil M, Bayata S, Susam I, Dinckal H, Postaci N. Rare association of hypertrophic cardiomyopathy and complete atrioventricular block with prompt disappearance of outflow gradient after DDD pacing. Europace 1999;1:280–2. [6] Rosen KL, Cameron RW, Bigham PJ, Neish SR. Hypertrophic cardiomyopathy presenting with 3rd-degree atrioventricular block. Tex Heart Inst J 1997;24:372–5. [7] Maron BJ, Connor TM, Roberts WC. Hypertrophic cardiomyopathy and complete heart block in infancy. Am Heart J 1981;101:857–60. [8] Gollob MH, Green MS, Tang AS, et al. Identification of a gene responsible for familial Wolff–Parkinson–White syndrome. N Engl J Med 2001;344:1823–31. [9] Arad M, Maron BJ, Gorham JM, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2001;344:1861–4. [10] Murphy RT, Mogensen J, McGarry K, et al. Adenosine monophosphate-activated protein kinase disease mimics hypertrophic cardiomyopathy and Wolff–Parkinson–White syndrome. J Am Coll Cardiol 2005;45:922–30. [11] Schott JJ, Alshinawi C, Kyndt F, et al. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet 1999;23:20–1 [Letter].
Letter to the Editor
Familial conduction system disease associated with hypertrophic cardiomyopathy Ajay Bahl * , Uma Nahar Saikia, Kewal K. Talwar Department of Cardiology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India Received 7 November 2006; accepted 31 December 2006 Available online 18 April 2007
Abstract A large family with a new phenotype of conduction system disease including heart blocks and preexcitation associated with hypertrophic cardiomyopathy and transmitted in an autosomal dominant pattern is described. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Heart block; Preexcitation; Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is defined by a hypertrophied, non-dilated left ventricle in the absence of another systemic or cardiac disease capable of producing the magnitude of wall thickening. Conduction system disease is known to occur in a few patients with HCM. However, conduction system disease affecting several family members and forming the predominant phenotype has not been reported. In this report, we describe a large family with a new phenotype of conduction system disease associated with HCM and transmitted in an autosomal dominant pattern. Forty two year old male presented to the cardiology clinic for pacemaker follow up. A DDDR pacemaker had been implanted 6 years back. At initial presentation, he had giddiness and was found to have second degree atrioventricular block with right bundle and left anterior fascicular block. Several members of his family had required pacemaker implantation. He also had family history of sudden death. A detailed family history was taken and he was advised for family screening (Fig. 1). Clinical evaluation, ECG, echocardiography and Holter examination were carried out in family members who
⁎ Corresponding author. Tel.: +91 9815323265; fax: +91 172 2744401. E-mail address: [email protected] (A. Bahl). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.12.050
presented for evaluation. One family member underwent endomyocardial biopsy (III:5) after written informed consent. The tissue was fixed in alcohol and in 10% buffered formalin and was subjected to histopathology and electron microscopy. This North Indian family comprised of 37 members over 3 generations. Of these, 9 were clinically evaluated. Five members had died previously. Of these, 2 had sudden deaths (III:2, IV:1) at 25 and 51 years of age respectively. One individual (III:2) had mild breathlessness on exertion for a few years prior while the other (IV:1) had been totally asymptomatic. Five family members required pacemakers (II:4; II:6; II:7; III:5; III:9). Youngest age at pacemaker implantation was 39 years. The remaining 4 patients required pacemakers between 40 and 55 years of age. There were no consanguineous marriages in the family. The demographic profile and clinical presentation is given in Table 1. 1. Age of presentation Most symptomatic patients presented with heart block in fourth to sixth decades. Affected adolescents remained asymptomatic except for mild breathlessness. The youngest individual evaluated was 12 years old. He had pre-excitation on ECG and complained of breathlessness during sports for
A. Bahl et al. / International Journal of Cardiology 125 (2008) e44–e47
e45
Fig. 1. Pedigree of the family.
the past 1 year. One previously asymptomatic individual died suddenly at the age of 25 years.
also normal with normal wall thickness and chamber dimensions.
2. ECG
5. Histology
The two patients on pacemakers had a completely A paced, V paced rhythm. Remaining patients were in sinus rhythm. Three patients had tall peaked P waves in lead II suggestive of right atrial enlargement. Right atrial enlargement was not seen on echocardiography. Two patients had a short PR interval, one of these had a delta wave while the other had tall narrow QRS complexes. One patient had wide QRS complex with right bundle branch block morphology. Three individuals had normal ECG. All these three also had normal echocardiograms (Fig. 2).
Endomyocardial biopsy done on III:5 showed myofibre disarray with focal hypertrophy of myocytes. There was mild anisonucleosis and myocyte hypertrophy. Patchy interstitial fibrosis and oedema was also seen (Fig. 3A and B). There was no increase in hemosiderin pigment, amyloid deposition or any excess of glycogen. No evidence of any storage disorder was noted. The ultrastructural findings also confirmed the microscopic features. The overall features were consistent with HCM. This family has a novel phenotype transmitted in an autosomal dominant pattern. The main features of this syndrome include left ventricular hypertrophy, heart blocks, intraventricular conduction defects, pre-excitation and sudden death. The phenotype of this family had features of Lenegre– Lev disease and HCM. Lenegre–Lev disease or progressive cardiac conduction defect is one of the most common cardiac conduction disturbances and is a major cause of pacemaker implantation. It is defined on ECG by evidence of bundle branch disease that is right bundle branch block, left anterior or posterior hemiblock, or complete heart block, with broad QRS complexes. Progression has been shown from a normal ECG to right bundle branch block and from the latter to
3. Echocardiography Two individuals had moderate concentric left ventricular hypertrophy. The rest had normal left ventricular wall thickness. All nine had normal left ventricular systolic function. Valves were morphologically normal in all. There were no significant valvular regurgitations. 4. MRI Cardiac MRI was carried out in an individual (IV:13) with abnormal ECG but normal echocardiography. The MRI was
Table 1 Profile of patients clinically evaluated
III:5 III:9 III:10 IV:2 IV:6 IV:7 IV:12 IV:13 IV:14
Age (years) Sex Presentation
ECG
PR interval (ms) QRS duration (ms) LVH
46 44 40 18 22 18 17 15 12
A paced, V paced A paced, V paced Normal Normal Normal RAE, delta wave, tall QRS complexes Normal RAE, RBBB RAE, tall QRS complexes
– – 150 130 130 90 140 160 100
F M F F M M F M M
Heart block Heart block Asymptomatic Mild breathlessness Asymptomatic Mild breathlessness Asymptomatic Mild breathlessness Asymptomatic
– – 90 90 100 130 90 120 90
Concentric maximal—20 mm Absent Absent Absent Absent Concentric maximal—18 mm Absent Absent Absent
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A. Bahl et al. / International Journal of Cardiology 125 (2008) e44–e47
Fig. 2. A: ECG of patient IV:13 showing bizarre intraventricular conduction defect of right bundle branch block morphology. B: ECG of patient IV:7 showing short PR interval, delta wave and tall and bizarre QRS complex.
complete heart block. Similar ECG patterns were seen in our family. In addition, 2 members had pre-excitation. Preexcitation has also been reported in association with familial
heart block [1,2]. The ECG profile of this family is thus similar to that of Lenegre–Lev disease. Lenegre–Lev disease, however is a primary degenerative disease affecting
A. Bahl et al. / International Journal of Cardiology 125 (2008) e44–e47
e47
This family thus had HCM along with cardiac conduction system defects. Though both HCM and familial conduction system disease are transmitted as autosomal dominant disorders, the underlying diseases causing mutations are different. HCM is caused by mutations in genes encoding sarcomeric proteins whereas familial heart blocks are caused by mutations in SCN5A which is an ion channel protein [11]. Since both HCM and conduction system disease coexist in this family, identification of a mutation that can cause both these disorders could provide important information on the pathogenesis of these conditions. Genotyping has not yet been carried out in this family. The possibility of HCM and conduction system disease being transmitted independently through two separate mutations also cannot be excluded. The unique phenotype of HCM and conduction system disease in this family adds to our evolving understanding of the phenotypic variations and overlaps of genetic cardiomyopathies and conduction system disorders. References
Fig. 3. A: Microphotograph showing unremarkable endocardium with myofibre disarray. (H&E × 280). B: Microphotograph showing myofibre disarray with myocyte hypertrophy and mild interstitial fibrosis. (H&E ×420).
only the conduction tissue and is not associated with left ventricular hypertrophy as seen in this family. The age profile, presentation, left ventricular hypertrophy and histology suggests HCM. Although heart blocks and pre-excitation occasionally occur in patients with HCM, such widespread involvement affecting several family members has not been reported [3–7]. Conduction blocks and pre-excitation are commonly seen in association with glycogen storage disorders due to mutations in the PRKAG2 or LAMP2 gene. These patients also have left ventricular hypertrophy and can mimic HCM [8–10]. In these disorders myocyte hypertrophy is due to the presence of glycogen filled vacuoles. Myocyte disarray which is typical of HCM is seen. Cardiomyopathy due to storage disorders was excluded by endomyocardial biopsy.
[1] Wendkos MH, Study RS. Familial congenital complete A–V heart blocks. Am Heart J 1947;34:138–42. [2] Segall HN. Congenital arrhythmias and conduction abnormalities in a father and four children. Canad Med Assoc J 1961;84:1283–96. [3] Doven O, Cicek D, Pekdemir H, et al. Abnormal His–Purkinje system conduction leading to complete atrioventricular block in patients with hypertrophic cardiomyopathy: a report of 3 cases. Jpn Heart J 2004;45:347–52. [4] Cicek D, Camsari A, Doven O. Familial hypertrophic cardiomyopathy complicated by complete atrioventricular block. Acta Cardiol 2004;59:71–4. [5] Yesil M, Bayata S, Susam I, Dinckal H, Postaci N. Rare association of hypertrophic cardiomyopathy and complete atrioventricular block with prompt disappearance of outflow gradient after DDD pacing. Europace 1999;1:280–2. [6] Rosen KL, Cameron RW, Bigham PJ, Neish SR. Hypertrophic cardiomyopathy presenting with 3rd-degree atrioventricular block. Tex Heart Inst J 1997;24:372–5. [7] Maron BJ, Connor TM, Roberts WC. Hypertrophic cardiomyopathy and complete heart block in infancy. Am Heart J 1981;101:857–60. [8] Gollob MH, Green MS, Tang AS, et al. Identification of a gene responsible for familial Wolff–Parkinson–White syndrome. N Engl J Med 2001;344:1823–31. [9] Arad M, Maron BJ, Gorham JM, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2001;344:1861–4. [10] Murphy RT, Mogensen J, McGarry K, et al. Adenosine monophosphate-activated protein kinase disease mimics hypertrophic cardiomyopathy and Wolff–Parkinson–White syndrome. J Am Coll Cardiol 2005;45:922–30. [11] Schott JJ, Alshinawi C, Kyndt F, et al. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet 1999;23:20–1 [Letter].