Cardiac resynchronization therapy (CRT) is an established therapy for patients with heart failure (HF), reduced ejection fraction, and evidence of conduction delay measured on the surface electrocardiogram. In the United States, the first CRT device received US Food and Drug Administration approval 20 years ago and their use became increasingly prevalent as clinical trial results demonstrated a benefit for patients with mild HF as well. Subsequent post hoc substudy analyses and metaanalyses identified patients with either true left bundle branch block (LBBB) or QRS duration $150 ms as likely to achieve greater benefit from CRT and guidelines were updated to reflect the weight of this evidence. Sex-specific differences in CRT response have in many studies been quite dramatic. In 2017, data from a large US registry (61,475 CRT with defibrillator [CRT-D][28% women]), with a median follow-up of 2.9 years, showed that survival in women was markedly better compared with men, with a relative risk reduction of 27%(1). The survival advantage was evident relatively early and the curves continued to diverge over time. The MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) trial was a randomized trial comparing CRT-D with implantable cardioverter-defibrillator (ICD) in New York Heart Association functional class I to II HF, which demonstrated in a prespecified subgroup analysis that women had a significantly greater reduction in the combined endpoint of HF or death, HF, or all-cause mortality compared with men (2). Women also had a greater degree of reverse remodeling over the 2.4-year follow-up (3).

As potential explanations for this better response in women, the MADIT-CRT trial authors identified differences in baseline characteristics with women having a higher prevalence of LBBB (87%) as well as nonischemic etiology. Of note, both men and women had similar QRS durations at enrollment. They also postulated that, because women on average have a shorter QRS duration by 10 ms, for any given QRS duration, women would have a greater degree of conduction delay, and they proposed this as another explanation for a better response to CRT in women. Recently, 2 retrospective studies demonstrated that a QRS duration normalized to the left ventricular (LV) mass or LV end-diastolic volume measured by either echocardiogram or cardiac magnetic resonance was predictive of survival and response and not predictive of sex (4, 5). In addition to the normalized QRS duration, age, atrial fibrillation, creatinine, and HF etiology were all significant predictors of survival, whereas LBBB and LV end-diastolic volume were not (5). Based on these findings, it has been proposed that the advantage in CRT response that women demonstrate may be based on their higher likelihood of true LBBB, higher prevalence of nonischemic cardiomyopathy, and smaller size ventricle, and may not, in fact, be sex specific.