The mechanical and perfusion basis of exercise limitation in apical hypertrophic cardiomyopathy

ABSTRACT Background Apical hypertrophic cardiomyopathy (ApHCM) patients can develop symptoms (chest pain, breathlessness), cardiac structural abnormalities (atrial dilatation, scar, apical aneurysm) and adverse outcomes despite preserved systolic function. Underlying mechanisms are poorly understood. We hypothesized that functional limitation in ApHCM may be associated with altered myocardial mechanics and myocardial perfusion. Methods We recruited 42 ApHCM patients and compared them with healthy controls (n=36). We assessed functional limitation (VO 2 <80% predicted) using cardiopulmonary exercise testing, stress apical myocardial blood flow (MBF) and scar using cardiovascular magnetic resonance, and echocardiography global longitudinal strain (GLS) and twist at rest and during exercise. Results Functional limitation occurred in 35% vs 6% of controls ( P <0.005) and was unrelated to wall thickness or ejection fraction. Myocardial mechanics were abnormal, with impaired GLS (−11.0% vs −18.3%, P<0.001), increased LV twist (22.6±9⸰ vs 16.6±4⸰, P<0.005) and delayed diastolic untwist (17.9% vs 9.2% of diastole, P<0.005). With exercise, GLS, twist and twist rate augmented but diastolic untwist delayed further. Stress apical MBF was reduced in all ApHCM patients and associated with mechanical abnormalities (GLS P<0.001, delayed diastolic untwist P=0.039). Percentage predicted peak VO 2 was worse with lower apical blood flow (P<0.005) and reduced GLS (P=0.017), but the best predictor was prolonged diastolic untwist (β-0.828, P<0.05). Conclusion One third of ApHCM patients have functional limitation - best predicted by delayed diastolic untwist. GLS, twist mechanics and apical MBF were abnormal in all subjects highlighting mechanical and perfusion abnormalities as hallmarks of the disease, but identifying diastolic impairment as the mechanistic link. Graphic Abstract Delayed myocardial untwist predicts functional limitation and is linked to microvascular ischemia in Apical HCM We postulate that increased left ventricular (LV) twist and delayed diastolic untwist results in prolonged systole and shortened diastole, which in turn reduces myocardial blood flow in a positive feedback loop. The net effect of mechanical and perfusion abnormalities is of functional limitation. CLINICAL PERSPECTIVES Apical hypertrophic cardiomyopathy (ApHCM) patients can develop symptoms, functional limitation, and adverse outcomes but the mechanisms underpinning this are unknown. Functional limitation is best assessed using cardiopulmonary exercise testing measuring peak VO 2 , whereby a value <80% predicted (based on age, sex and body size) is abnormal. Peak VO 2 is a known prognostic measure in hypertrophic cardiomyopathy. This multi-modality imaging study aimed to explore whether functional limitation associated with abnormal myocardial mechanics and myocardial perfusion. We found that 35% of ApHCM patients had functional limitation (vs 6% healthy controls), which was independent of wall thickness and ejection fraction. Percentage predicted peak VO 2 was worse with lower apical myocardial blood flow and reduced GLS, but was predicted by delayed diastolic untwist, implicating diastolic impairment as the mechanistic link. Understanding the abnormal mechano-structural and physiological features that contribute to, or predict functional limitation in apical hypertrophic cardiomyopathy strengthens our understanding of the disease and provides focus for future targeted research.