Examining the impact of inducible ischemia on myocardial fibrosis and exercise capacity in hypertrophic cardiomyopathy

Abstract

Myocardial ischemia in hypertrophic cardiomyopathy (HCM) is associated with poor outcomes. Vasodilator stress cardiac magnetic resonance (CMR) can detect and quantitate inducible ischemia in HCM patients. We hypothesized that myocardial ischemia assessed by CMR is associated with myocardial fibrosis and reduced exercise capacity in HCM. In 105 consecutive HCM patients, we performed quantitative assessment of left ventricular volume and mass, wall thickness, segmental wall thickening percent, segmental late Gadolinium enhancement (LGE), and extracellular volume fraction (ECV). Time-signal intensity curves of first pass perfusion sequences were generated for each segment at stress and rest. A myocardial perfusion reserve index (MPRI) (stress/rest slope) was calculated. Patients who underwent an echocardiographic (n = 73) and cardiopulmonary exercise test (n = 37) within 30 days were included. The mean age was 53.2 ± 15.4 years; 60% were male, and 82 patients had asymmetric hypertrophy. Segments with end diastolic thickness ≥ 1.2 cm had a higher burden of LGE (4.1% vs 0.5% per segment), reduced MPRI (2.6 ± 1.5 vs 3.1 ± 1.8) and reduced thickening percent (48.9 ± 41.7% vs. 105.3 ± 59.5%), (P < 0.0001 for all comparisons). Patients with ischemia (any segment with MPRI < 2) were more likely to have dynamic left ventricular outflow tract (LVOT) obstruction (63.3% vs 36.7%, P = 0.01), to be smokers (17% vs 6.9%, P = 0.04), and had a higher ECV (30% vs 28%, P = 0.04). The total LGE burden was similar between the two groups (P = 0.47). Increasing ischemia burden (number of segments with MPRI < 2) was associated with worsened ventilatory efficiency (VE/VCO2) (P < 0.001) but not peak oxygen consumption or anerobic threshold (P > 0.2). In a patient-level multivariable logistic regression model, only LVOT obstruction remained a significant predictor of ischemia burden (P = 0.03). Myocardial ischemia by CMR is associated with myocardial segmental dysfunction and interstitial fibrosis, as assessed by ECV, in HCM patients, even in segments free of LGE. Conversely, quantitative ischemia burden was not associated with replacement fibrosis as assessed by total LGE burden. Patients with ischemia had greater prevalence of dynamic LVOT obstruction; and in a subset of patients with cardiopulmonary exercise testing, ischemia burden was associated with worsened ventilatory efficiency.

A perspective on Notch signalling in progression and arrhythmogenesis in familial hypertrophic and dilated cardiomyopathies

“…Together with diastolic abnormalities, inefficiencies and mismatches in energetics, there is ample evidence for the presence of microvascular defects and micro-infarctions in HCM patients [47–50]. There is also evidence that regional ischaemia is associated with regional fibrosis [51]. These data support the need for further investigation of mechanisms related to Notch especially in the early stages of disease progression.…”

Mechanisms and prognostic impact of myocardial ischaemia in hypertrophic cardiomyopathy

“… Perfusion defects were mostly identified by visual assessment, and in some cases assessed quantitatively with perfusion reserve/flow measurements [ 25 , 31 , 35 , 39 , 41 ]. Studies using visual assessment identified patients with perfusion defects occurring at rest, stress, exclusively stress (reversible), and both at rest and stress (fixed) CMR cardiovascular magnetic resonance, MCE myocardial contrast echocardiography, PET positron emission tomography, SPECT single-photon emission computed tomography, CT computed tomography, CFR coronary flow reserve, MPR myocardial perfusion reserve, CFVR coronary flow velocity reserve, MPRI myocardial perfusion reserve index, N number of HCM patients, n number of non-HCM controls …”

“…Perfusion defects were mostly identified by visual assessment, and in some cases assessed quantitatively with perfusion reserve/flow measurements [ 25 , 31 , 35 , 39 , 41 ]. Studies using visual assessment identified patients with perfusion defects occurring at rest, stress, exclusively stress (reversible), and both at rest and stress (fixed)…”

“…LVOT obstruction is a hallmark feature of HCM and is defined as a peak LVOT pressure gradient ≥ 30 mmHg. LVOT obstruction may be present at rest (in up to 51% of HCM patients [ 41 , 64 – 66 ]) or develop during exercise (in 33–62% [ 65 , 66 ]). Severe obstruction (≥ 50 mmHg) may be seen in up to 20% of patients [ 35 ].…”

Focal ischemic myocardial fibrosis assessed by late gadolinium enhancement cardiovascular magnetic resonance in patients with hypertrophic cardiomyopathy

“…Most patients with HCM have a variable degree of myocardial fibrosis, and myocardial fibrosis is associated with worse outcomes [ 2 – 4 ]. In addition, previous studies have adequately described focal replacement myocardial fibrosis as a result of myocardial ischemia and microvascular dysfunction in patients with HCM [ 5 – 7 ]. Furthermore, myocardial fibrosis can be divided into several subgroups according to whether fibrosis involves the subendocardial layer, and these subgroups include nonischemic myocardial fibrosis and ischemic myocardial fibrosis [ 8 , 9 ].…”