Regulation of Cardiomyocyte Apoptosis Associated With CRT

Study Questions:

What are the circulating extracellular microRNAs (miRNAs) that respond to cardiac resynchronization therapy (CRT)?

Methods:

The study investigators assessed pre-implant plasma miRNA profiles in patients with advanced heart failure (HF) and dyssynchrony (HFDYS) with or without subsequent echocardiographic improvement after CRT. The study cohort was comprised of 52 (12 for initial discovery and 40 for initial validation) patients referred for CRT pacemaker implantation for clinical indications (class II-IV heart failure with left ventricular ejection fraction [LVEF] <35% and QRS duration >120 msec with left bundle branch block were studied). Comprehensive miRNA PCR arrays were used to assess baseline levels of 766 plasma miRNA in patients undergoing clinically indicated CRT in an initial discovery set (n = 12) with and without subsequent echocardiographic improvement at 6 months after CRT. CRT response was defined as increase in LVEF ≥10%. Validation of candidate miRNAs was done in 61 additional patients. The study investigators also examined the functional effects of miR-30d in cultured cardiomyocytes (CMs).

Results:

Using the best-overall multivariable linear model (containing serum creatinine, prior revascularization, pre-implant QRS duration, LVEF) in their validation cohort of 61 patients, the study investigators found that baseline plasma miR-30d (ß = 2.69, p = 0.02) was the miRNA associated with CRT response. They also found that levels of plasma miR-30d were 18-fold higher in coronary sinus plasma compared with contemporaneous peripheral plasma samples taken at the time of CRT implantation (n = 6 paired samples, p = 0.011 by paired T-test), suggesting a cardiac origin for plasma miR-30d. Plasma miR-30d levels inversely correlated with high-sensitivity troponin T (Spearman r = -0.51, p = 0.001) in HF patients, suggesting that higher levels of miR-30d may be cardioprotective in HF patients.

The investigators also examined miR-30d levels in a canine model of HFDYS and found that miR-30d was increased in late-contracting myocardium, with maximal expression in areas of high mechanical stress. The investigators also found that miR-30d is expressed in CMs and was released in vesicles in response to mechanical stress (neonatal CMs seeded on a silicone membrane exposed to cyclic stretch at 3 Hz were used as an in vitro model of mechanical stress). When they overexpressed miR-30d in cultured CMs, it led to CM growth (with molecular features most consistent with adaptive hypertrophy) and protected against apoptosis by targeting the mitogen-associated kinase 4, a downstream effector of tumor necrosis factor (TNF).

Conclusions:

The investigators concluded that baseline plasma miR-30d level is associated with response to CRT in HFDYS in this translational pilot study. MiR-30d increase in CMs correlates with areas of increased wall stress in HFDYS, and is protective against deleterious TNF signaling.

Perspective:

This is an important study because it suggests that the RNA biomarker miR-30d is a predictor of CRT response independent of other risk markers. The next step would be to confirm these findings in larger cohorts, and if confirmed, miR-30d could be an important tool in the management of HF patients with ventricular dyssynchrony.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Implantable Devices, EP Basic Science, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound

Keywords: Apoptosis, Biological Markers, Bundle-Branch Block, Cardiac Resynchronization Therapy, Creatinine, Echocardiography, Heart Failure, Hypertrophy, Intracellular Signaling Peptides and Proteins, MicroRNAs, Myocytes, Cardiac, Polymerase Chain Reaction, Stroke Volume, Troponin T, Tumor Necrosis Factor-alpha


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