Myocardial Perfusion Defects in Hypertrophic Cardiomyopathy Mutation Carriers

Abstract

Background Impaired myocardial blood flow (MBF) in the absence of epicardial coronary disease is a feature of hypertrophic cardiomyopathy (HCM). Although most evident in hypertrophied or scarred segments, reduced MBF can occur in apparently normal segments. We hypothesized that impaired MBF and myocardial perfusion reserve, quantified using perfusion mapping cardiac magnetic resonance, might occur in the absence of overt left ventricular hypertrophy (LVH) and late gadolinium enhancement, in mutation carriers without LVH criteria for HCM (genotype-positive, left ventricular hypertrophy-negative). Methods and Results A single center, case-control study investigated MBF and myocardial perfusion reserve (the ratio of MBF at stress:rest), along with other pre-phenotypic features of HCM. Individuals with genotype-positive, left ventricular hypertrophy-negative (n=50) with likely pathogenic/pathogenic variants and no evidence of LVH, and matched controls (n=28) underwent cardiac magnetic resonance. Cardiac magnetic resonance identified LVH-fulfilling criteria for HCM in 5 patients who were excluded. Individuals with genotype-positive, left ventricular hypertrophy-negative had longer indexed anterior mitral valve leaflet length (12.52±2.1 versus 11.55±1.6 mm/m², P=0.03), lower left ventricular end-systolic volume (21.0±6.9 versus 26.7±6.2 mm/m², P≤0.005) and higher left ventricular ejection fraction (71.9±5.5 versus 65.8±4.4%, P≤0.005). Maximum wall thickness was not significantly different (9.03±1.95 versus 8.37±1.2 mm, P=0.075), and no subject had significant late gadolinium enhancement (minor right ventricle‒insertion point late gadolinium enhancement only). Perfusion mapping demonstrated visual perfusion defects in 9 (20%) carriers versus 0 controls (P=0.011). These were almost all septal or near right ventricle insertion points. Globally, myocardial perfusion reserve was lower in carriers (2.77±0.83 versus 3.24±0.63, P=0.009), with a subendocardial:subepicardial myocardial perfusion reserve gradient (2.55±0.75 versus 3.2±0.65, P=<0.005; 3.01±0.96 versus 3.47±0.75, P=0.026) but equivalent MBF (2.75±0.82 versus 2.65±0.69 mL/g per min, P=0.826). Conclusions Regional and global impaired myocardial perfusion can occur in HCM mutation carriers, in the absence of significant hypertrophy or scarring.

Keywords: genetics; hypertrophic cardiomyopathy; quantitative perfusion mapping; sarcomere mutations carriers without hypertrophy.

Figure 1. Septal perfusion defects in genotype‐positive; left ventricular hypertrophy‐negative.

A, Adenosine stress perfusion maps in the 3 short‐axis slices, where each pixel encodes myocardial blood flow as per the color scale. Perfusion defect in the mid‐basal septum. B, Raw stress perfusion imaging. C, Corresponding short‐axis cine (maximum left ventricular wall thickness was 11.7 mm) (perfusion scans are acquired partly in systole). Arrows demonstrate the perfusion defects. SAX indicates short axis.

Figure 2. Basal septal and mid‐right ventricular insertion point significant perfusion defects in genotype‐positive; left ventricular hypertrophy‐negative with minor inferior right ventricular insertion point late gadolinium enhancement and normal computed tomography coronary angiogram.

A second example, with the perfusion defects in a slightly different location to that of Figure 1. A, Adenosine stress perfusion maps in the 3 short‐axis slices. B, Corresponding raw stress perfusion images and (C) Corresponding short‐axis cine (maximum left ventricular wall thickness was 9.8mm). D, Corresponding short‐axis phase‐sensitive inversion recovery late gadolinium enhancement imaging. E, Computed tomography coronary angiogram image of left anterior descending artery (unobstructed). F, Computed tomography coronary angiogram image of left anterior descending artery (unobstructed). G, Computed tomography coronary angiogram image of right coronary artery (unobstructed). H, Computerized tomography coronary angiogram image of left circumflex coronary artery (unobstructed). Arrows indicate perfusion defects. CTCA indicates computed tomography coronary angiogram; LAD, left anterior descending artery; LCx, left circumflex coronary artery; LGE, late gadolinium enhancement; PSIR, phase‐sensitive inversion recovery; RCA, right coronary artery; and SAX, short axis.

Figure 3. Bar chart comparison between genotype‐positive; left ventricular hypertrophy‐negative and controls of mean global stress myocardial blood flow, subendocardial stress myocardial blood flow, and subepicardial stress myocardial blood flow (A) and mean myocardial perfusion reserve, subendocardial myocardial perfusion reserve, and subepicardial myocardial perfusion reserve (B).

MBF indicates myocardial blood flow, and MPR, myocardial perfusion reserve.