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Dilated cardiomyopathy: clinical signs of the lamin-related phenotype and predictors of life-threatening tachyarrhythmia

Vaikhanskaya T. G.1, Sivitskaya L. N.2, Shumovets V. V.1, Kurushko T. V.1, Danilenko N. G.2, Frolov A. V.1
1 – State Institution Republican Science and Practice Center “Cardiology”, R. Luxemburg 110, Minsk 220036, Republic of Belarus
2 – State Science Institution, “Institute of Genetics and Cytology of Belarus National Academy of Sciences”, Akademicheskaya 27, Minsk 220072, Belarus

Keywords: DCMP, sudden cardiac death, gene mutations, lamin A/C gene (LMNA), life-threatening ventricular tachyarrhythmias, risk stratification

DOI: 10.18087/rhfj.2016.5.2273

Background. In patients with dilated cardiomyopathy (DCMP), ventricular tachyarrhythmias are life-threatening already at early stages of the disease being not related with symptoms of heart failure or severity of dilatation and LV systolic dysfunction. Thus, the lamin-related DCMP phenotype is associated with high risk of sudden cardiac death (SCD) even in the absence of significant heart chamber dilatation and pronounced left ventricular dysfunction. Aim. To study clinical predictors of the lamin-related DCMP phenotype and to determine noninvasive prognostic markers for life-threatening tachyarrhythmic events. Materials and methods. The study included 165 patients with documented DCMP (age, 49.2±11.5; males, 135/81.8%; NYHA FC, 2.67±0.45; LV EF, 26.7±10.1%). The follow-up period was 39.7±12.4 months. Clinical instrumental examination, genetic screening for the lamin A/C gene (LMNA), measurements of CK and NT-proBNP levels and a neuromuscular study were performed for all patients. Results. In the ROC analysis, only ECG predictors (long PR ≥215 ms: AUC 0.987; 95% CI, 0.973–0.999; р=0.0001; sensitivity 95%, specificity 95%; pathological mTWA test ≥25%: AUC 0.775; 95% CI, 0.701–0.848; р=0.0001; QRS duration ≥122 ms: AUC 0.773; 95% CI, 0.689–0.857; р=0.0001) showed a prognostic significance for evaluation of the LMNA-positive phenotype, which was superior to laboratory tests (serum CK ≥118 U/l: AUC, 0.671; 95% CI, 0.548–0.793; р=0.009; sensitivity, 65%; specificity, 69%; NT-proBNP level: AUC, 0.538; 95% CI, 0.275–0.802; р=0.75) and EchoCG parameters (LV global longitudinal myocardial strain: AUC, 0.645; 95% CI, 0.548–0.793; р=0.092; LV EF: AUC, 0.473; р=0.75). The following parameters were accepted as primary end points in the multifactorial Cox model: sustained ventricular tachycardia (sVT) and/or ventricular fibrillation (VF), documented SCD. The analysis detected two independent predictors of life-threatening tachyarrhythmias (SCD/sVT/VF) – unstable, fast VT (≥5 ventricular complexes with heart rate ≥150 bpm: HR , 2,23; 95% CI, 1.03–4.96; p=0.033) and changes in the LMNA gene (missense mutations and/or rs4641, с.1698С>T: HR , 1.87; 95% CI, 1.09–3.01; р=0.02). Conclusion. The obtained data confirm the strategic significance of LMNA mutations in patients with DCMP for early prediction of unfavorable clinical outcomes. According to the results of Cox regression analysis independent predictors of SCD (and their cumulative effect: uVT + LMNA-positivity = HR , 5.23; 95% CI, 1.45–16.9; р=0.013) can be used for SCD risk stratification and selection of optimum therapeutic tactics for patients with DCMP.
  1. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013 Sep;10 (9):531–47.
  2. Phang RS, Kang D, Tighiouart H, Estes NA, Link MS. High risk of ventricular arrhythmias in patients with nonischemic dilated cardiomyopathy presenting with syncope. Am J Cardiol. 2006 Feb 1;97 (3):416–20.
  3. Spezzacatene A, Sinagra G, Merlo M, Barbati G, Graw SL, Brun F et al. Arrhythmogenic phenotype in dilated cardiomyopathy: natural history and predictors of life-threatening arrhythmias. J Am Heart Assoc. 2015 Oct 16;4 (10):e002149.
  4. Вайханская Т.Г., Сивицкая Л.Н., Даниленко Н.Г., Курушко Т.В., Давыденко О.Г., Фролов А.В., Мрочек А.Г. Аритмогенный фенотип дилатационной кардиомиопатии: предикторы жизнеугрожающих желудочковых тахиаритмий. Кардиология в Беларуси. 2016;3:330–43 [Vajxanskaya T.G., Siviczkaya L.N., Danilenko N.G., Kurushko T.V., Davy`denko O. G., Frolov A.V., Mrochek A.G. Aritmogenny`j fenotip dilataczionnoj kardiomiopatii: prediktory` zhizneugrozhayushhix zheludochkovy`x taxiaritmij. Kardiologiya v Belarusi. 2016;3:330–43].
  5. Merlo M, Pivetta A, Pinamonti B, Stolfo D, Zecchin M, Barbati G et al. Long-term prognostic impact of therapeutic strategies in patients with idiopathic dilated cardiomyopathy: changing mortality over the last 30 years. Eur J Heart Fail. 2014 Mar;16 (3):317–24.
  6. van Berlo JH, de Voogt WG, van der Kooi AJ, van Tintelen JP, Bonne G, Yaou RB et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med (Berl). 2005 Jan;83 (1):79–83.
  7. Pasotti M, Klersy C, Pilotto A, Marziliano N, Rapezzi C, Serio A et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol. 2008 Oct 7;52 (15):1250–60.
  8. Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Peterson A et al. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or idiopathic dilated cardiomyopathy. Am Heart J. 2008 Jul;156 (1):161–9.
  9. van Rijsingen IA, Arbustini E, Elliott PM, Mogensen J, Hermans-van Ast JF, van der Kooi AJ et al. Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study. J Am Coll Cardiol. 2012 Jan 31;59 (5):493–500.
  10. Quarta G, Syrris P, Ashworth M, Jenkins S, Zuborne Alapi K, Morgan J et al. Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2012 May;33 (9):1128–36.
  11. Vaikhanskaya T, Sivitskaya L, Danilenko N, Davydenko O, Kurushka T, Sidorenko I. LMNA-related dilated cardiomyopathy. Oxf Med Case Reports. 2014 Sep 3;2014 (6):102–4.
  12. Brodt C, Siegfried JD, Hofmeyer M, Martel J, Rampersaud E, Li D et al. Temporal relationship of conduction system disease and ventricular dysfunction in LMNA cardiomyopathy. J Card Fail. 2013 Apr;19 (4):233–9.
  13. Sheppard R , Mather PJ, Alexis JD, Starling RC, Boehmer JP, Thohan V et al. Implantable cardiac defibrillators and sudden death in recent onset nonischemic cardiomyopathy: results from IMAC2. J Card Fail. 2012 Sep;18 (9):675–81.
  14. Schliamser JE, Kadish AH, Subacius H, Shalaby A, Schaechter A, Levine J, Goldberger JJ. Significance of follow-up left ventricular ejection fraction measurements in the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial. Heart Rhythm. 2013 Jun;10 (6):838–46.
  15. Anselme F, Moubarak G, Savouré A, Godin B, Borz B, Drouin-Garraud V, Gay A. Implantable cardioverter-defibrillators in lamin A/C mutation carriers with cardiac conduction disorders. Heart Rhythm. 2013 Oct;10 (10):1492–8.
  16. Zecchin M, Merlo M, Pivetta A, Barbati G, Lutman C, Gregori D et al. How can optimization of medical treatment avoid unnecessary implantable cardioverter-defibrillator implantations in patients with idiopathic dilated cardiomyopathy presenting with “SCD-HeFT criteria?”. Am J Cardiol. 2012 Mar 1;109 (5):729–35.
  17. Kuruvilla S, Adenaw N, Katwal AB, Lipinski MJ, Kramer CM, Salerno M. Late gadolinium enhancement on CMR predicts adverse cardiovascular outcomes in non-ischemic cardiomyopathy: a systematic review and meta-analysis. Circ Cardiovasc Imaging. 2014 Mar;7 (2): 250–58.
  18. Kusumoto FM, Calkins H, Boehmer J, Buxton AE, Chung MK, Gold MR et al. HRS/ACC/AHA expert consensus statement on the use of implantable cardioverter-defibrillator therapy in patients who are not included or not well represented in clinical trials. Circulation. 2014 Jul 1;130 (1):94–125.
  19. Hasselberg NE, Edvardsen T, Petri H, Berge KE, Leren TP, Bundgaard H, Haugaa KH. Risk prediction of ventricular arrhythmias and myocardial function in Lamin A/C mutation positive subjects. Europace. 2014 Apr;16 (4):563–71.
  20. Sylvius N, Tesson F. Lamin A/C and cardiac diseases. Curr Opin Cardiol. 2006 May;21 (3):159–65.
  21. Charron P, Arad M, Arbustini E, Basso C, Bilinska Z, Elliott P et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010 Nov;31 (22):2715–26.
  22. Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81 (3):515–26.
  23. Bloomfield DM, Steinman RC, Namerow PB, Parides M, Davidenko J, Kaufman ES et al. Microvolt T-wave alternans distinguishes between patients likely and patients not likely to benefit from implanted cardiac defibrillator therapy: a solution to the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II conundrum. Circulation. 2004 Oct 5;110 (14):1885–9.
  24. Grimm W, Christ M, Maisch B. Long runs of non-sustained ventricular tachycardia on 24-hour ambulatory electrocardiogram predict major arrhythmic events in patients with idiopathic dilated cardiomyopathy. Pacing Clin Electrophysiol. 2005 Jan;28 (Suppl 1):S207–10.
  25. Katritsis DG, Zareba W, Camm AJ. Nonsustained ventricular tachycardia. J Am Coll Cardiol. 2012 Nov 13;60 (20):1993–2004.
  26. Grimm W, Christ M, Bach J, Müller HH, Maisch B. Noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy: results of the Marburg Cardiomyopathy Study. Circulation. 2003 Dec 9;108 (23):2883–91.
  27. Zecchin M, Di Lenarda A, Gregori D, Merlo M, Pivetta A, Vitrella G et al. Are nonsustained ventricular tachycardias predictive of major arrhythmias in patients with dilated cardiomyopathy on optimal medical treatment? Pacing Clin Electrophysiol. 2008 Mar;31 (3):290–9.
  28. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/A merican Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Oct 15;62 (16):e147–239.
  29. Russo AM, Stainback RF, Bailey SR , Epstein AE, Heidenreich PA, Jessup M et al. ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Heart Rhythm Society, American Heart Association, American Society of Echocardiography, Heart Failure Society of America, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol. 2013 Mar 26;61 (12):1318–68.
  30. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 Jul 14;37 (27):2129–200.
  31. Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J. 2015 May 7;36 (18):1123-35a.
Vaikhanskaya T. G., Sivitskaya L. N., Shumovets V. V., Kurushko T. V., Danilenko N. G., Frolov A. V. Dilated cardiomyopathy: clinical signs of the lamin-related phenotype and predictors of life-threatening tachyarrhythmia. Russian Heart Failure Journal. 2016;17 (5):339–349

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