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

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 (VO2 <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 VO2 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. ![Figure][1] 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 VO2, whereby a value <80% predicted (based on age, sex and body size) is abnormal. Peak VO2 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 VO2 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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial This is not a clinical trial ### Funding Statement R.K.H is supported by the British Heart Foundation (grant number FS/17/82/33222). J.W.M. is funded by a National Institute of Health Research Clinical Doctoral Research Fellowship (ICA-CDRF-2016-02-068). IRCCS Istituto Auxologico Italiano is supported by the Italian Ministry of Health.G.C. is supported by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC, #171603) and by NIHR University College London Hospitals Biomedical Research Centre. JCM, CM and TAT are directly and indirectly supported by the University College London Hospitals NIHR Biomedical Research Centre and Biomedical Research Unit at Barts Hospital, respectively. TAT is funded by British Heart Foundation intermediate fellowship (FS/19/35/34374). LRL is supported by an MRC UK Clinical Academic Partnership Award (CARP) MR/T005181/1. GWL has consultancy agreement with GE and acts a speaker for GE, Phillips, Siemens, Janssen and holds research support grants from Medtronic. The remaining authors have nothing to disclose. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: A prospective study approved by the National Health Service Research Ethics Committee (NHS REC) and Health Research Authority (HRA) and conducted in accordance with the Declaration of Helsinki. All subjects provided written, informed consent (REC 18/LO/0188 and 15/LO/0086). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data can be made available upon reasonable request * ApHCM : apical hypertrophic cardiomyopathy AVC : aortic valve closure CMR : cardiac magnetic resonance CPEX : cardiopulmonary exercise testing ECG : electrocardiogram GLS : global longitudinal strain HV : healthy volunteer LGE : late gadolinium enhancement LV : left ventricle/ventricular MWT : maximum wall thickness PP peak VO2 : percentage predicted peak oxygen uptake TTE : transthoracic echocardiography [1]: pending:yes