Advertisement
Canadian Journal of Cardiology

QRS Widening Rates and Genetic Polymorphisms of Matrix Metalloproteinases in a Cohort of Patients With Chronic Heart Failure

  • Virgilio Olsen
    Affiliations
    Experimental and Molecular Cardiovascular Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
    Search for articles by this author
  • Luis E. Rohde
    Affiliations
    Experimental and Molecular Cardiovascular Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil

    Heart Failure and Cardiac Transplant Unit, Cardiology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil

    Post-Graduate Program in Cardiology and Cardiovascular Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    Search for articles by this author
  • Luis Beck-da-Silva
    Affiliations
    Heart Failure and Cardiac Transplant Unit, Cardiology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil

    Post-Graduate Program in Cardiology and Cardiovascular Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    Search for articles by this author
  • Kátia G. Santos
    Affiliations
    Experimental and Molecular Cardiovascular Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil

    Post-Graduate Program in Cardiology and Cardiovascular Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

    Laboratory of Human Molecular Genetics, Universidade Luterana do Brasil, Canoas, Rio Grande do Sul, Brazil
    Search for articles by this author
  • Andréia Biolo
    Affiliations
    Experimental and Molecular Cardiovascular Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil

    Heart Failure and Cardiac Transplant Unit, Cardiology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil

    Post-Graduate Program in Cardiology and Cardiovascular Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    Search for articles by this author
  • Nadine Clausell
    Affiliations
    Experimental and Molecular Cardiovascular Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil

    Heart Failure and Cardiac Transplant Unit, Cardiology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil

    Post-Graduate Program in Cardiology and Cardiovascular Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    Search for articles by this author
  • Michael Andrades
    Correspondence
    Corresponding author: Dr Michael Andrades, Experimental and Molecular Cardiovascular Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Sala 12201, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil. Tel./Fax: +55-51-33598844.
    Affiliations
    Experimental and Molecular Cardiovascular Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil

    Post-Graduate Program in Cardiology and Cardiovascular Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    Search for articles by this author
Published:November 21, 2013DOI:https://doi.org/10.1016/j.cjca.2013.11.014

      Abstract

      Background

      QRS duration is considered to be an indicator of adverse outcome in patients with heart failure (HF), and genetic polymorphisms may be involved in this conductivity impairment. We studied the prognostic impact of the QRS widening rate (QRS-WR) on patients with HF and the influence of the matrix metalloproteinases gene polymorphisms on the QRS-WR.

      Methods

      This prospective cohort study included 184 patients with left ventricular (LV) systolic dysfunction (LV ejection fraction [LVEF] < 45%). The QRS-WR was calculated as the difference between 2 electrocardiogram assessments (in ms) divided by the time elapsed between each evaluation (months). The MMP-1 -1607 1G/2G, MMP-2 -790G/T and -1575G/A, MMP-3 -1171 5A/6A, MMP-9 -1562 C/T and R279Q, and MMP-12 -82A/G polymorphisms were genotyped using polymerase chain reaction–restriction fragment length polymorphism.

      Results

      Patients were predominantly white (68%) men (67%) in New York Heart Association functional classes I and II (77%). Patients with HF with a QRS-WR ≥ 0.5 ms/month had more HF-related deaths and more combined clinical events than those with a QRS-WR < 0.5 ms/month (P = 0.03 and P = 0.01, respectively). After adjusting for other covariates, the QRS-WR remained an independent predictor of combined clinical events (hazard ratio, 1.6; 95% confidence interval, 1.1-2.5; P = 0.02). The MMP-1 2G2G genotype was associated with nearly a 2-fold increase in QRS-WR (P = 0.03). Conversely, patients with the MMP-3 5A5A genotype and a nonischemic cause of HF were protected against QRS enlargement (P = 0.03).

      Conclusions

      QRS-WR retains prognostic value in patients with chronic HF receiving guideline-based pharmacologic treatment. MMP gene polymorphisms can influence the rate of QRS enlargement over time.

      Résumé

      Introduction

      La durée du QRS est considérée comme un indicateur de résultats défavorables chez les patients ayant une insuffisance cardiaque (IC) et les polymorphismes génétiques peuvent être impliqués dans cette altération de la conductivité. Nous avons étudié les conséquences pronostiques du taux d’élargissement du QRS (TE-QRS) sur les patients ayant une IC et l’influence des polymorphismes des gènes des métalloprotéinases matricielles (MMP : matrix metalloproteinases) sur le TE-QRS.

      Méthodes

      Cette étude de cohorte prospective incluait 184 patients ayant une dysfonction systolique ventriculaire gauche (VG; fraction d’éjection VG < 45 %). Le TE-QRS a été calculé comme étant la différence entre 2 évaluations d’électrocardiogramme (en millisecondes [ms]) divisée par le temps écoulé entre chaque évaluation (mois). Les polymorphismes MMP-1 -1607 1G/2G, MMP-2 -790G/T et -1575G/A, MMP-3 -1171 5A/6A, MMP-9 -1562 C/T et R279Q, et MMP-12 -82A/G ont été génotypés par le polymorphisme de longueur des fragments de restriction et la réaction en chaîne de la polymérase.

      Résultats

      Les patients étaient en majorité des hommes (67 %) caucasiens (68 %) répondant à la classification fonctionnelle I et II de la New York Heart Association (77 %). Les patients ayant une insuffisance cardiaque qui avaient un TE-QRS ≥ 0,5 ms/mois subissaient plus de décès liés à l’IC et plus d’événements cliniques combinés que ceux qui avaient un TE-QRS < 0,5 ms/mois (P = 0,03 et P = 0,01, respectivement). Après l’ajustement des autres covariables, le TE-QRS demeurait un prédicteur indépendant des événements cliniques combinés (rapport de risque 1,6; intervalles de confiance à 95 % de 1,1–2,5; P = 0,02). Le génotype MMP-1 2G2G a été associé à une augmentation de près de 2 fois du TE-QRS (P = 0,03). Inversement, les patients ayant un génotype MMP-3 5A5A et une étiologie non ischémique étaient protégés contre l’élargissement du QRS (P = 0,03).

      Conclusion

      Le TE-QRS conserve sa valeur pronostique chez les patients ayant une IC chronique recevant le traitement pharmacologique selon les recommandations. Les polymorphismes des gènes MMP peuvent influencer le taux d’élargissement du QRS avec le temps.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Rubart M.
        • Zipes D.P.
        Genesis of Cardiac Arrhythmias: Electrophysiological Considerations.
        in: Braunwald E. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. Saunders, Philadelphia2008: 727-761
        • Beck-da-Silva L.
        • Goldraich L.
        • Bonzanini L.
        • et al.
        Pulse pressure and QRS width evaluation as an inexpensive tool for heart failure assessment.
        Congest Heart Fail. 2009; 15: 222-227
        • Kalra P.R.
        • Sharma R.
        • Shamim W.
        • et al.
        Clinical characteristics and survival of patients with chronic heart failure and prolonged QRS duration.
        Int J Cardiol. 2002; 86: 225-231
        • Grigioni F.
        • Carinci V.
        • Boriani G.
        • et al.
        Accelerated QRS widening as an independent predictor of cardiac death or of the need for heart transplantation in patients with congestive heart failure.
        J Heart Lung Transplant. 2002; 21: 899-902
        • Shamim W.
        • Yousufuddin M.
        • Cicoria M.
        • et al.
        Incremental changes in QRS duration in serial ECGs over time identify high risk elderly patients with heart failure.
        Heart. 2002; 88: 47-52
        • Gajarsa J.J.
        • Kloner R.A.
        Left ventricular remodeling in the post-infarction heart: a review of cellular, molecular mechanisms, and therapeutic modalities.
        Heart Fail Rev. 2011; 16: 13-21
        • Medley T.L.
        • Kingwell B.A.
        • Gatzka C.D.
        • Pillay P.
        • Cole T.J.
        Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression.
        Circ Res. 2003; 92: 1254-1261
        • Langers A.M.
        • Verspaget H.W.
        • Hommes D.W.
        • Sier C.F.
        Single-nucleotide polymorphisms of matrix metalloproteinases and their inhibitors in gastrointestinal cancer.
        World J Gastrointest Oncol. 2011; 3: 79-98
        • Velho F.M.
        • Cohen C.R.
        • Santos K.G.
        • et al.
        Polymorphisms of matrix metalloproteinases in systolic heart failure: role on disease susceptibility, phenotypic characteristics, and prognosis.
        J Card Fail. 2011; 17: 115-121
        • Mizon-Gerard F.
        • de Groote P.
        • Lamblin N.
        • et al.
        Prognostic impact of matrix metalloproteinase gene polymorphisms in patients with heart failure according to the aetiology of left ventricular systolic dysfunction.
        Eur Heart J. 2004; 25: 688-693
        • Tang L.J.
        • Chen X.F.
        • Zhu M.
        • et al.
        Matrix metalloproteinase-1, -3, and -9 gene polymorphisms and the risk of idiopathic dilated cardiomyopathy in a Chinese Han population.
        Clin Biochem. 2007; 40: 1427-1430
        • Hua Y.
        • Song L.
        • Wu N.
        • et al.
        Polymorphisms of MMP-2 gene are associated with systolic heart failure prognosis.
        Clin Chim Acta. 2009; 404: 119-123
        • Lahiri D.K.
        • Nurnberger J.I.
        A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies.
        Nucleic Acids Res. 1991; 19: 5444
        • Dhar R.
        • Alsheikh-Ali A.A.
        • Estes N.A.M.
        • et al.
        Association of prolonged QRS duration with ventricular tachyarrhythmias and sudden cardiac death in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II).
        Heart Rhythm. 2008; 5: 807-813
        • Yerra L.
        • Anavekar N.
        • Skali H.
        • et al.
        Association of QRS duration and outcomes after myocardial infarction: the VALIANT trial.
        Heart Rhythm. 2006; 3: 313-316
        • Katritsis D.G.
        • Siontis K.C.
        • Bigger J.T.
        • et al.
        Effect of left ventricular ejection fraction and QRS duration on the survival benefit of implantable cardioverter-defibrillators: Meta-analysis of primary prevention trials.
        Heart Rhythm. 2013; 10: 200-206
        • Exner D.V.
        • Birnie D.H.
        • Moe G.
        • et al.
        Canadian Cardiovascular Society guidelines on the use of cardiac resynchronization therapy: evidence and patient selection.
        Can J Cardiol. 2013; 29: 182-195
        • Song B.G.
        • Yang H.S.
        • Hwang H.K.
        • et al.
        Correlation of electrocardiographic changes and myocardial fibrosis in patients with hypertrophic cardiomyopathy detected by cardiac magnetic resonance imaging.
        Clin Cardiol. 2013; 36: 31-35
        • Sheridan D.J.
        • Culling W.
        • Penny W.J.
        Electrophysiological disturbances associated with acute myocardial infarction.
        Eur Heart J. 1986; : 11-18
        • Mazzoleni A.
        • Curtin M.E.
        • Wolff R.
        • Reiner L.
        • Somes G.
        On the relationship between heart weights, fibrosis, and QRS duration.
        J Electrocardiol. 1975; 8: 233-236
        • Royer A.
        • van Veen T.A.B.
        • Le Bouter S.
        • et al.
        Mouse model of SCN5A-linked hereditary Lenègre's disease: age-related conduction slowing and myocardial fibrosis.
        Circulation. 2005; 111: 1738-1746
        • Spinale F.G.
        • Coker M.L.
        • Heung L.J.
        • et al.
        A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure.
        Circulation. 2000; 102: 1944-1949
        • Rohde L.E.
        • Ducharme A.
        • Arroyo L.H.
        • et al.
        Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice.
        Circulation. 1999; 99: 3063-3070
        • Cadete V.J.
        • Arcand S.A.
        • Chaharyn B.M.
        • et al.
        Matrix metalloproteinase-2 is activated during ischemia/reperfusion in a model of myocardial infarction.
        Can J Cardiol. 2013; 29: 1495-1503
        • Martin T.N.
        • Penney D.E.
        • Smith J.A.
        • et al.
        Matrix metalloproteinase-1 promoter polymorphisms and changes in left ventricular volume following acute myocardial infarction.
        Am J Cardiol. 2004; 94: 1044-1046
        • Ye S.
        • Gale C.R.
        • Martyn C.N.
        Variation in the matrix metalloproteinase-1 gene and risk of coronary heart disease.
        Eur Heart J. 2003; 24: 1668-1671
        • Wilson E.M.
        • Moainie S.L.
        • Baskin J.M.
        • et al.
        Region- and type-specific induction of matrix metalloproteinases in post-myocardial infarction remodeling.
        Circulation. 2003; 107: 2857-2863
        • Vasku A.
        • Goldbergova M.
        • Holla L.I.
        • et al.
        Two MMP-2 promoter polymorphisms (-790T/G and -735C/T) in chronic heart failure.
        Clin Chem Lab Med. 2003; 41: 1299-1303
        • Price S.J.
        • Greaves D.R.
        • Watkins H.
        Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: role of Sp1 in allele-specific transcriptional regulation.
        J Biol Chem. 2001; 276: 7549-7558
        • Zhang B.
        • Ye S.
        • Herrmann S.M.
        • et al.
        Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis.
        Circulation. 1999; 99: 1788-1794
        • Zhi H.
        • Wang H.
        • Ren L.
        • et al.
        Functional polymorphisms of matrix metallopeptidase-9 and risk of coronary artery disease in a Chinese population.
        Mol Biol Rep. 2010; 37: 13-20