Evaluating the effects of cardiac resynchronization therapy on pathophysiological pathways of heart failure using surrogate biomarkers
Abstract
Background: Several studies have investigated the effects of cardiac resynchronization therapy (CRT) on heart failure (HF), but none have evaluated the pathophysiological pathways involved in a single group of patients. Therefore, this study aims to assess the long-term effects of CRT on six different pathophysiological pathways involved in the process of HF by the use of surrogate biomarkers.
Methods: In a group 44 patients with HF, six groups of biomarkers were measured, both at baseline and 1 year after CRT implantation: inflammation (interleukin [IL]-4, IL-6, tumor necrosis factor [TNF]-a, high sensitive C-reactive protein [hsCRP]); oxidative stress (myeloperoxidase [MPO], oxidized low-density lipoprotein [oxLDL], uric acid); extracellular matrix (ECM) remodeling (matrix metalloproteinase [MMP]-2 and -9, galectin-3, procollagen III N-terminal propeptide [prokol-3NT]); neurohormonal pathways (endothelin-1, chromogranin-A); myocyte injury (troponin T, creatine kinase MB fraction [CK-MB]), myocyte stress (B-type natriuretic peptide [BNP]). CRT responders were defined as patients with ≥ 15% reduction in left ventricular end-systolic volume at 12 months post-CRT.
Results: At 1-year follow-up, 72.7% (n = 32) of the patients were categorized as CRT responders. In these patients, the levels of IL-6, MPO, oxLDL, MMP-2, galectin-3, troponin T, and BNP were significantly reduced as compared to baseline values. While the biomarkers for myocyte stress (effect size = 0.357; p = 0.001), ECM remodeling (effect size = 0.343; p = 0.015) and oxidative stress (effect size = 0.247; p = 0.039) showed a significant change in the CRT responders during follow-up, the biomarkers for other pathophysiological pathways did not show a significant alteration.
Conclusions: In the present study, a significant reduction was only observed in the biomarkers of myocardial stress, ECM remodeling, and oxidative stress among all the CRT responder subjects. (Cardiol J 2018; 25, 1: 42–51)
Keywords: cardiac resynchronization therapyresponderpathophysiologybiomarkers
References
- Braunwald E. Biomarkers in heart failure. N Engl J Med. 2008; 358(20): 2148–2159.
- Kamireddy S, Agarwal SK, Adelstein E, et al. Correlation of electrical and mechanical reverse remodeling after cardiac resynchronization therapy. Ann Noninvasive Electrocardiol. 2009; 14(2): 153–157.
- Karaahmet T, Tigen K, Mutlu B, et al. Prognostic significance of left ventricular systolic dyssynchrony in patients with nonischemic dilated cardiomyopathy. Turk Kardiyol Dern Ars. 2009; 37(5): 301–306.
- Versteeg H, Schiffer AA, Widdershoven JW, et al. Response to cardiac resynchronization therapy: is it time to expand the criteria? Pacing Clin Electrophysiol. 2009; 32(10): 1247–1256.
- El Sabbagh FH, Guzon OJ, Alpert MA, et al. Electrocardiographic clues to identify nonresponders to cardiac resynchronization therapy. Ann Noninvasive Electrocardiol. 2010; 15(4): 369–377.
- Balci KG, Balci MM, Sen F, et al. The role of baseline indirect inflammatory markers in prediction of response to cardiac resynchronisation therapy. Kardiol Pol. 2016; 74(2): 119–126.
- Pitzalis MV, Iacoviello M, Di Serio F, et al. Prognostic value of brain natriuretic peptide in the management of patients receiving cardiac resynchronization therapy. Eur J Heart Fail. 2006; 8(5): 509–514.
- García-Bolao I, Macías A, López B, et al. A biomarker of myocardial fibrosis predicts long-term response to cardiac resynchronization therapy. J Am Coll Cardiol. 2006; 47(11): 2335–2337.
- Gronda E, Genovese S, Padeletti L, et al. Renal function impairment predicts mortality in patients with chronic heart failure treated with resynchronization therapy. Cardiol J. 2015; 22(4): 459–466.
- Morales MA, Maltinti M, Piacenti M, et al. Adrenomedullin plasma levels predict left ventricular reverse remodeling after cardiac resynchronization therapy. Pacing Clin Electrophysiol. 2010; 33(7): 865–872.
- Karaca O, Omaygenc MO, Cakal B, et al. Adjusting the QRS duration by body mass index for prediction of response to cardiac resynchronization therapy: does one QRS size fit all? Ann Noninvasive Electrocardiol. 2016; 21(5): 450–459.
- Pitzalis MV, Iacoviello M, Romito R, et al. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony. J Am Coll Cardiol. 2002; 40(9): 1615–1622.
- Kashani A, Barold SS. Significance of QRS complex duration in patients with heart failure. J Am Coll Cardiol. 2005; 46(12): 2183–2192.
- Cho H, Barth AS, Tomaselli GF. Basic science of cardiac resynchronization therapy: molecular and electrophysiological mechanisms. Circ Arrhythm Electrophysiol. 2012; 5(3): 594–603.
- Emdin M, Vittorini S, Passino C, et al. Old and new biomarkers of heart failure. Eur J Heart Fail. 2009; 11(4): 331–335.
- Sugiura T, Takase H, Toriyama T, et al. Circulating levels of myocardial proteins predict future deterioration of congestive heart failure. J Card Fail. 2005; 11(7): 504–509.
- Shalaby AA, Abraham WT, Fonarow GC, et al. Association of BNP and troponin levels with outcome among cardiac resynchronization therapy recipients. Pacing Clin Electrophysiol. 2015; 38(5): 581–590.
- Pastormerlo LE, Agazio A, Benelli E, et al. Usefulness of high-sensitive troponin elevation after effort stress to unveil vulnerable myocardium in patients with heart failure. Am J Cardiol. 2015; 116(4): 567–572.
- López B, González A, Díez J. Circulating biomarkers of collagen metabolism in cardiac diseases. Circulation. 2010; 121(14): 1645–1654.
- Chalikias GK, Tziakas DN. Biomarkers of the extracellular matrix and of collagen fragments. Clin Chim Acta. 2015; 443: 39–47.
- Stolen CM, Adourian A, Meyer TE, et al. Plasma galectin-3 and heart failure outcomes in MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy). J Card Fail. 2014; 20(11): 793–799.
- Stanciu AE, Vatasescu RG, Stanciu MM, et al. Cardiac resynchronization therapy in patients with chronic heart failure is associated with anti-inflammatory and anti-remodeling effects. Clin Biochem. 2013; 46(3): 230–234.
- Peterson JT, Hallak H, Johnson L, et al. Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation. 2001; 103(18): 2303–2309.
- von Lueder TG, Girerd N, Atar D, et al. Serum uric acid is associated with mortality and heart failure hospitalizations in patients with complicated myocardial infarction: findings from the High-Risk Myocardial Infarction Database Initiative. Eur J Heart Fail. 2015; 17(11): 1144–1151.
- Krupa W, Rozwodowska M, Sielski S, et al. Influence of cardiac resynchronization therapy on oxidative stress markers in patients with chronic heart failure. Cardiol J. 2014; 21(5): 576–582.
- Michowitz Y, Kisil S, Guzner-Gur H, et al. Usefulness of serum myeloperoxidase in prediction of mortality in patients with severe heart failure. Isr Med Assoc J. 2008; 10(12): 884–888.
- Bose A, Truong QA, Singh JP. Biomarkers in electrophysiology: role in arrhythmias and resynchronization therapy. J Interv Card Electrophysiol. 2015; 43(1): 31–44.
- Belperio J, Horwich T, Abraham WT, et al. Inflammatory mediators and clinical outcome in patients with advanced heart failure receiving cardiac resynchronization therapy. Am J Cardiol. 2016; 117(4): 617–625.
- Menardi E, Vado A, Rossetti G, et al. Cardiac resynchronization therapy modifies the neurohormonal profile, hemodynamic and functional capacity in heart failure patients. Arch Med Res. 2008; 39(7): 702–708.
- Boriani G, Regoli F, Saporito D, et al. Neurohormones and inflammatory mediators in patients with heart failure undergoing cardiac resynchronization therapy: time courses and prediction of response. Peptides. 2006; 27(7): 1776–1786.
- Dong YX, Burnett JC, Chen HH, et al. Effect of cardiac resynchronization therapy on broad neurohormone biomarkers in heart failure. J Interv Card Electrophysiol. 2011; 30(3): 241–249.
