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Women experience less appropriate implantable cardioverter-defibrillator (ICD) interventions and are underrepresented in randomised ICD trials. Sex-differences in inducible and spontaneous ventricular tachycardia/fibrillation (VT/VF), cardiac arrest and sudden cardiac death (SCD) early post-myocardial infarction (MI) require further study. Methods Consecutive ST-elevation MI patients with left ventricular ejection fraction (LVEF) 40% underwent electrophysiology study (EPS) to target early prevention of SCD. An ICD was implanted for a positive (inducible monomorphic VT) but not a negative (no arrhythmia or inducible VF) EPS. The combined primary endpoint of VT/VF (spontaneous or ICD-treated), cardiac arrest or SCD was assessed using competing risk survival analysis in women versus men with adjustment for confounders. Logistic regression was used to determine independent predictors of inducible VT at EPS. Results A total of 403 patients (16.9% female) underwent EPS. Women were significantly older than men but with similar LVEF (31.5 AE 6.3 versus 31.6 AE 6.4%, p = 0.91). Electrophysiology study was positive for inducible VT in 22.1% and 33.4% (p = 0.066) and an ICD implanted in 25.0% and 33.4% (p = 0.356) of women versus men. Appropriate ICD activations (VT/VF) occurred in 5.9% of women and 36.6% of men (p = 0.012). The adjusted cumulative primary endpoint incidence was significantly lower in women than men (1.6% versus 26.5%, p = 0.03). Female sex was not an independent predictor of inducible VT at EPS (HR 0.63, 95% CI 0.33-1.23, p = 0.178). Conclusions Women with early post-MI cardiomyopathy had lower VT/VF, cardiac arrest and SCD, compared to men. In ICD recipients the rate of appropriate activations was six-fold less in women compared to men.

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BACKGROUND: Myocardial infarction (MI) is among the leading causes of death worldwide. Following MI, necrotic cardiomyocytes are replaced by a stiff collagen-rich scar. Compared to collagen, the extracellular matrix protein elastin has high elasticity and may have more favorable properties within the cardiac scar. We sought to improve post-MI healing by introducing tropoelastin, the soluble subunit of elastin, to alter scar mechanics early after MI. METHODS AND RESULTS: We developed an ultrasound-guided direct intramyocardial injection method to administer tropoelastin directly into the left ventricular anterior wall of rats subjected to induced MI. Experimental groups included shams and infarcted rats injected with either PBS vehicle control or tropoelastin. Compared to vehicle treated controls, echocardiography assessments showed tropoelastin significantly improved left ventricular ejection fraction (64.7±4.4% versus 46.0±3.1% control) and reduced left ventricular dyssynchrony (11.4±3.5 ms versus 31.1±5.8 ms control) 28 days post-MI. Additionally, tropoelastin reduced post-MI scar size (8.9±1.5% versus 20.9±2.7% control) and increased scar elastin (22±5.8% versus 6.2±1.5% control) as determined by histological assessments. Ribonucleic acid sequencing analyses of rat infarcts showed that tropoelastin injection increased genes associated with elastic fiber formation 7 days post-MI and reduced genes associated with immune response 11 days post-MI. To show translational relevance, we performed immunohistochemical analyses on human ischemic heart disease cardiac samples and showed an increase in tropoelastin within fibrotic areas. Using ribonucleic acid sequencing we also demonstrated the tropoelastin gene ELN is upregulated in human ischemic heart disease and during human cardiac fibroblast-myofibroblast differentiation. Furthermore, we showed by immunocytochemistry that human cardiac fibroblast synthesize increased elastin in direct response to tropoelastin treatment. CONCLUSIONS: We demonstrate for the first time that purified human tropoelastin can significantly repair the infarcted heart in a rodent model of MI and that human cardiac fibroblast synthesize elastin. Since human cardiac fibroblasts are primarily responsible for post-MI scar synthesis, our findings suggest exciting future clinical translation options designed to therapeutically manipulate this synthesis.