Mechanisms and prognostic impact of myocardial ischaemia in hypertrophic cardiomyopathy

Abstract

Despite the progress made in risk stratification, sudden cardiac death and heart failure remain dreaded complications for hypertrophic cardiomyopathy (HCM) patients. Myocardial ischaemia is widely acknowledged as a contributor to cardiovascular events, but the assessment of ischaemia is not yet included in HCM clinical guidelines. This review aims to evaluate the HCM-specific pro-ischaemic mechanisms and the potential prognostic value of imaging for myocardial ischaemia in HCM. A literature review was performed using PubMed to identify studies with non-invasive imaging of ischaemia (cardiovascular magnetic resonance, echocardiography, and nuclear imaging) in HCM, prioritising studies published after the last major review in 2009. Other studies, including invasive ischaemia assessment and post-mortem histology, were also considered for mechanistic or prognostic relevance. Pro-ischaemic mechanisms in HCM reviewed included the effects of sarcomeric mutations, microvascular remodelling, hypertrophy, extravascular compressive forces and left ventricular outflow tract obstruction. The relationship between ischaemia and fibrosis was re-appraised by considering segment-wise analyses in multimodal imaging studies. The prognostic significance of myocardial ischaemia in HCM was evaluated using longitudinal studies with composite endpoints, and reports of ischaemia-arrhythmia associations were further considered. The high prevalence of ischaemia in HCM is explained by several micro- and macrostructural pathological features, alongside mutation-associated energetic impairment. Ischaemia on imaging identifies a subgroup of HCM patients at higher risk of adverse cardiovascular outcomes. Ischaemic HCM phenotypes are a high-risk subgroup associated with more advanced left ventricular remodelling, but further studies are required to evaluate the independent prognostic value of non-invasive imaging for ischaemia.

Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy

“…There is therefore a clinical precedent for the antiarrhythmic effects of ranolazine identified in the present study. However, whereas these simulated antiarrhythmic effects were entirely due to reductions in refractoriness gradients due to late Na + block, ranolazine is also an antianginal, so it is unclear whether clinical antiarrhythmic effects may also be attributed to reduced diastolic compression of the microcirculation and prevention of ischaemia ( Coleman et al, 2023 ). Indeed, in ischaemic non-HCM patients, ranolazine reduced the number and duration of ventricular arrhythmias in the RYPPLE trial ( Pelliccia et al, 2015 ), and ranolazine had antiarrhythmic effects in the first week of treatment in the MERLIN-TIMI trial ( Morrow et al, 2007 ; Scirica et al, 2007 ).…”

“…This notion is consistent with the finding that young sudden cardiac death victims have less fibrosis at post-mortem examination ( Varnava et al, 2000 ; Gaspari et al, 2021 ), such that a functional cause of lethal arrhythmias may be present in the early stages of HCM. Functional causes of arrhythmias in HCM include regionally impaired repolarisation (due to enhancement of late Na + and impairment of K + channels) ( Sakata et al, 2003 ; Johnson et al, 2011 ; Coppini et al, 2013 ; Lyon et al, 2018 ) and episodic myocardial ischaemia ( Conway et al, 2022 ; Coleman et al, 2023 ). Unlike irreversible structural causes of arrhythmias, both of these functional causes may be amenable to ranolazine therapy, which targets repolarisation impairment ( Moss et al, 2008 ; Coppini et al, 2013 ) and microvascular ischaemia ( Argirò et al, 2023 ).…”

Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study

“… 1 Acute myocardial ischaemia is acknowledged as a cause of ventricular arrhythmias in clinical guidelines 2 and is considered a key cause of SCD in young patients without major structural remodelling. 3 Despite ischaemia being a predictor of adverse cardiovascular events in some studies, 4 the HCM-specific mechanisms underlying ischaemia-induced arrhythmias are not fully understood, nor how acute ischaemia interacts with other pathological features of HCM such as diffuse fibrosis and chronic ionic remodelling.…”

“…In the general population, acute myocardial ischaemia is well characterized as a substrate and trigger for lethal arrhythmias, with coronary artery disease remaining the major cause of SCD. However, in HCM ventricles, there is a tendency for ischaemia to colocalize with hypertrophy, 4 which generally does not relate to coronary artery territories. Despite being distinct from coronary artery disease, myocardial ischaemia in HCM can still cause acute myocardial infarction, 5 through several pro-ischaemic mechanisms including diffuse small vessel disease, energetic impairment of the sarcomere, increased muscle mass, reductions in capillary density, excessive extravascular compression, and left ventricular (LV) outflow tract obstruction.…”

“…Despite being distinct from coronary artery disease, myocardial ischaemia in HCM can still cause acute myocardial infarction, 5 through several pro-ischaemic mechanisms including diffuse small vessel disease, energetic impairment of the sarcomere, increased muscle mass, reductions in capillary density, excessive extravascular compression, and left ventricular (LV) outflow tract obstruction. 4 …”