HYPERTROPHIC CARDIOMYOPATHY IN THE OLDER AGE GROUP: THE EFFECT OF CARDIOMETABOLIC RISK FACTORS AND RS2290149 AND RS10838692 OF THE MADD GENE

Objective. To study the impact of cardiometabolic risk factors and polymorphic variants rs2290149 and rs10838692 of the MADD gene on myocardial remodeling in the elderly patients with hypertrophic cardiomyopathy (HCM). Design and methods. We enrolled 257 patients with left ventricular hypertrophy (LVH) of various origin (mean age 57,7 ± 11,2 years; men — 5 %, women — 48 %): HCM (n = 154) and LVH caused by cardiometabolic risk factors (n = 103). The control group included 288 healthy donors. A standard clinical (laboratory and instrumental) diagnostic methods were applied. Genotyping for SNPs rs2290149 and rs10838692 of the MADD gene was performed using real time polymerase chain reaction (PCR). Results. Pre-obesity and obesity in patients with HCM were associated with increased left ventricular (LV) posterior wall thickness (14,82 ± 3,6 versus 12,77 ± 3,69 mm, respectively, p = 0,01), but not with the LV mass index and the interventricular septum. Obese HCM patients had greater detection rate of the symmetrical LVH (64 versus 10 % in non-obese HCM patients, p = 0,001). We observed a significant increase in frequency of TT genotype of rs2290149 and rs10838692 of the MADD gene in patients with LVH of various origin compared to healthy group: 81,6 vs. 71,5 % (ТТ : ТС+СС, p = 0,007) and 54,1 vs. 43,1 % (ТТ : ТС+СС, р = 0,002), respectively. The allele frequency also differs for rs2290149 (T : C = 89,6 : 10,4 % vs. 82,3 : 17,7 %; odds ratio (OR) = 1,864, 95 % confidence interval (CI) 1,306 to 2,660; p = 0,01) and for rs10838692 (T : C = 72,6: 27,4 % vs. 62,2 : 37,8 %; OR = 1,611, 95 % CI 1,246 to 2,082; p = 0,01). We found a significant increase in frequency of TT genotype of rs10838692 of MADD gene in patients with HCM 55,2 % (ТТ : ТС+СС, р = 0,019) and LVH caused by cardiometabolic risk factors — 52,4 % (ТТ : ТС+СС, p = 0,014) compared to healthy group (43,1 %). We also detected a trend towards the predominance of the TT genotype in rs2290149 of the MADD gene in patients with LVH caused by cardiometabolic risk factors (80,4 %) (ТТ : ТС+СС, р = 0,097), reaching a statistical significance in the HCM group (82,5 %) (ТТ : ТС+СС, р = 0,025) compared to healthy group (71,5 %). The allele frequency also differs for rs2290149 (T : C = 89,9 : 10,1 %, p = 0,01 in HCM; 89,2:10,8 %, р = 0,04 in LVH caused by cardiometabolic risk factors) versus 82,3 : 17,7 % in control group and for rs10838692 (T : C = 72,4 : 27,6 %, p = 0,01; 72,8 : 27,2 %, р = 0,01, respectively) versus 62,2 : 37,8 % in control. Conclusions. Pre-obesity and obesity in patients with HCM led to a greater LV posterior wall thickness and symmetrical myocardial remodelling. The T allele and TT genotype of SNPs rs10838692 and rs2290149 of the MADD gene were associated with the presence of LVH of various origin in the older subjects, but do not affect the degree of myocardial hypertrophy. Patients with HCM showed greater frequency of simultaneous carriage of the TT genotype and сombined carriage of the T allele of the polymorphic variants rs10838692 and rs2290149 of the MADD gene compared to the control group. The presence of obesity/overweight in patients with combined carriage of the TT genotype and simultaneous carriage of the T allele is associated with a greater thickness of the LV posterior wall, an increase in the left atrium size and the LV end-diastolic dimension.

left ventricular hypertrophy of various origin, idiopathic hypertrophic cardiomyopathy, left ventricular hypertrophy, cardiometabolic risk factors, polymorphic variants of MADD gene, comorbidities

1. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35 (39):2733–2779. doi:10.1093/eurheartj/ehu284

2. Ciro E, Nichols PF, Maron BJ. Heterogeneous morphologic expression of genetically transmitted hypertrophic cardiomyopathy. Two-dimensional echocardiographic analysis. Сirculation. 1983;67 (6):1227–33. doi:10.1161/01.CIR.67.6.1227

3. Olivotto I, Girolami F, Nistri S, Rossi A, Rega L, Garbini F et al. The many faces of hypertrophic cardiomyopathy: from developmental biology to clinical practice. J Cardiovasc Transl Res. 2009;2:349–367. doi:10.1007/s12265–009–9137–2

4. Wang P, Zou Y, Fu C, Zhou X, Hui R. MYBPC3 polymorphism is a modifier for expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 2005;329(2):796–9.

5. Marian AJ. Modifier genes for hypertrophic cardiomyopathy. Curr Opin Cardiol. 2002;17(3):242–52. doi:10.1097/01.HCO. 0000013803.40803.6A

6. Brugada R, Kelsey W, Lechin M, Zhao G, Yu QT, Zoghbi W et al. Role of candidate modifier genes on the phenotypic expression of hypertrophy in patients with hypertrophic cardiomyopathy. J Investig Med. 1997;45(9):542–51.

7. Wu CK, Huang YT, Lee JK, Chiang LT, Chiang FT, Huang SW et al. Cardiac myosin binding protein C and MAPkinase activating death domain-containing gene polymorphisms and diastolic heart failure. Plos One. 2012;4(7): e35242. doi:10.1371/journal.pone.0035242

8. Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10(1):45–65.

9. Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 2001;11(9):372–377.

10. Bradley JR. TNF-mediated inflammatory disease. J Pathol. 2008;214(2):149–160.

11. Yokoyama T, Nakano M, Bednerczyk JL, Mclntyre BW, Entman M, Mann DL et al. Tumor necrosis factor-a provokes a hypertrophic growth response in adult cardiac myocytes. Circulation. 1997;95(5):1247–52.

12. Olivotto I, Maron BJ, Tomberli B, Appelbaum E, Salton C, Haas TS et al. Obesity and its association to phenotype and clinical course in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2013;62 (5):449–57. doi:10.1016/j.jacc.2013.03.062

13. Abel ED, Litwin SE, Sweeney G. Cardiac remodeling in obesity. Physiol Rev. 2008;88 (2):389–419. doi:10.1152/physrev. 00017.2007

14. Topol EJ, Traill TA, Fortuin NJ. Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med. 1985;312(5):277–83. doi:10.1056/NEJM198501313120504

15. Karam R, Lever HM, Healy BP. Hypertensive hypertrophic cardiomyopathy or hypertrophic cardiomyopathy with hypertension? A study of 78 Patients. J Am Coll Cardiol. 1989;13(3):580–4. doi:10.1016/0735–1097(89)90596–2

16. Shimizu M, Sugihara N, Shimizu K, Yoshio H, Ino H, Nakajima K et al. Asymmetrical septal hypertrophy in patients with hypertension: a type of hypertensive left ventricular hypertrophy or hypertrophic cardiomyopathy combined with hypertension? Clin Cardiol. 1993;16(1):41–6. doi:10.1002/clc.4960160110

17. Avelar E, Cloward TV, Walker JM, Farney RJ, Strong M, Pendleton RC et al. Left ventricular hypertrophy in severe obesity: interactions among blood pressure, nocturnal hypoxemia, and body mass. Hypertension. 2007;49(1):34–9. doi:10.1161/01.HYP. 0000251711.92482.14

18. Lauer MS, Anderson KM, Kannel WB, Levy D. The impact of obesity on left ventricular mass and geometry. The Framingham Heart Study. J Am Med Assoc. 1991;266(2):231–236. doi:10. 1001/jama.1991.03470020057032

19. Гудкова А. Я. Клинико-морфологические сопоставления и механизмы гипертрофии при обструктивной гипертрофической кардиомиопатии: дис. … д-ра мед. наук: кардиология — 14.00.06, патологическая анатомия — 14.00.15. СанктПетербургский государственный медицинский университет имени академика И. П. Павлова. 2006. 380 c. [Gudkova AYa. Clinical and morphological comparisons and mechanisms of hypertrophy in obstructive hypertrophic cardiomyopathy. Dissertatsiya doktora meditsinskih nauk: kardiologiya — 14.00.06, patologicheskaya anatomiya — 14.00.15. Saint-Petersburg Pavlov Medical University. 2006. 380 p. In Russian].

20. Uwaifo GI, Fallon EM, Calis KA, Drinkard B, McDuffie JR, Yanovski JA. Improvement in hypertrophic cardiomyopathy after significant weight loss: case report. South Med J. 2003;96(6):626– 31. doi:10.1097/01.SMJ.0000053254.23595.14

21. Wong C, Marwick TH. Obesity cardiomyopathy: diagnosis and therapeutic implications. Nat Clin Pract Cardiovasc Med. 2007;4(9):480–90. doi:10.1038/ncpcardio0964

22. Di Bello V, Santini F, Di Cori A, Pucci A, Palagi C, Delle Donne MG et al. Obesity cardiomyopathy: is it a reality? An ultrasonic tissue characterization study. J Am Soc Echocardiogr. 2006;19(8):1063–71. doi:10.1016/j.echo.2006.03.033

23. Kasper EK, Hruban RH, Baughman KL. Cardiomyopathy of obesity: a clinicopathologic evaluation of 43 obese patients with heart failure. Am J Cardiol. 1992;70(9):921–4. doi:10.1016/0002– 9149 (92)90739-L

24. Canepa M, Sorensen LL, Pozios I, Dimaano VL, HongChang L, Pinheiro AC et al. Comparison of clinical presentation, left ventricular morphology and hemodynamics, and exercise tolerance in obese versus non-obese patients with hypertrophic cardiomyopathy. Am J Cardiol. 2013;112(8):1182–1189. doi:10. 1016/j.amjcard.2013.05.070

25. Ommen SR, Lopez-Jimenez F. Obesity and hypertrophic cardiomyopathy: chickens, eggs, and causality: clinical skills remain the key to caring for patients. J Am Coll Cardiol. 2013;62 (5):458–9. doi:10.1016/j.jacc.2013.03.063

26. Smith SC, Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. J Am Coll Cardiol. 2011;58(23):2432–2446. doi:10.1016/j.jacc.2011.10.824

27. Sperling LS, Mechanick JI, Neeland IJ, Herrick CJ, Despres JP, Ndumele CE et al. The cardio metabolic health alliance: working toward a new care model for the metabolic syndrome. J Am Coll Cardiol. 2015;66(9):1050–1067. doi:10.1016/j.jacc.2015. 06.1328

28. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735–52. doi:10.1161/CIRCULATIONAHA.105. 169404

29. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome — a new worldwide definition. Lancet. 2005;366 (9491):1059–1062. doi:10.1016/S0140–6736 (05)67402–8

30. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120 (16):1640–1645. doi:10.1161/CIRCULATIONAHA.109.192644

31. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015;16 (3):233–70. doi:10.1093/ehjci/jev014

32. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, Dokainish H, Edvardsen T et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277–314. doi:10.1093/ehjci/jew082

33. Wong RC, Tan KB. Asymmetric left ventricular hypertrophy associated with morbid obesity mimicking familial hypertrophic cardiomyopathy. Singapore Med J. 2014;55(12): e201–4. doi:10. 11622/smedj.2014186

34. Alpert MA, Fraley MA, Birchem JA, Senkottaiyan N. Management of obesity cardiomyopathy. Expert Rev Cardiovasc Ther. 2005;3(2):225–30. doi:10.1586/14779072. 3.2.225

35. Spinale FG, Coker ML, Heung LJ, Bond BR, Gunasinghe HR, Etoh T et al. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Сirculation. 2000;102(16):1944–9. doi:10.1161/01.CIR.102.16.1944