T1 Measurements Identify Extracellular Volume Expansion in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers With and Without Left Ventricular Hypertrophy

Abstract

Background Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a potential substrate for arrhythmias and heart failure. Sarcomere mutations appear to induce profibrotic changes before left ventricular hypertrophy (LVH) develops. To further evaluate these processes, we used cardiac magnetic resonance (CMR) with T1 measurements on a genotyped HCM population to quantify myocardial extracellular volume (ECV). Methods and Results Sarcomere mutation carriers with LVH (G+/LVH+, n = 37) and without LVH (G+/LVH−, n = 29); HCM patients without mutations (sarcomere-negative HCM, n = 11); and healthy controls (n = 11) underwent contrast CMR, measuring T1 times pre- and post-gadolinium infusion. Concurrent echocardiography and serum biomarkers of collagen synthesis, hemodynamic stress, and myocardial injury were also available in a subset. Compared to controls, ECV was increased in patients with overt HCM, as well as G+/LVH− mutation carriers (ECV= 0.36±0.01, 0.33±0.01, 0.27±0.01 in G+/LVH+, G+/LVH−, controls, respectively, P≤0.001 for all comparisons). ECV correlated with NT-proBNP levels (r = 0.58, P<0.001) and global E’ velocity (r = −0.48, P<0.001). Late gadolinium enhancement (LGE) was present in >60% of overt HCM patients but absent from G+/LVH− subjects. Both ECV and LGE were more extensive in sarcomeric HCM than sarcomere-negative HCM. Conclusions Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LVH. These data provide additional support that fibrotic remodeling is triggered early in disease pathogenesis. Quantifying ECV may help characterize the development myocardial fibrosis in HCM and ultimately assist in developing novel disease-modifying therapy, targeting interstitial fibrosis.

Assessment of Myocardial Fibrosis in Hypertrophic Cardiomyopathy by Cardiac Magnetic Resonance: Modalities and Clinical Applications

“…In addition, recent studies have showed the presence of myocardial fibrosis in subjects with pathogenic sarcomere mutations and no LV hypertrophy, [13,14] supporting the hypothesis that fibrotic remodeling is triggered early in HCM pathogenesis.…”

“…Both shorter post-contrast myocardial T1 times [49] and increased ECV [14]. both indexes of diffuse myocardial fibrosis, correlate with non-invasively estimated LV filling pressure, suggesting a mechanistic link between diffuse myocardial fibrosis and abnormal diastolic function in HCM.…”

“…However, it was found an association between ECV and BNP [65], that in its turn has showed to be an independent predictor of morbidity and mortality in HCM patients [66]. Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LV hypertrophy [14] and the quantification of ECV may help characterize the development of myocardial fibrosis in HCM and assist in developing novel disease modifying therapy, targeting interstitial fibrosis.…”

The Role of Cardiac MRI in the Diagnosis and Risk Stratification of Hypertrophic Cardiomyopathy

“…[21][22][23] CMR has added to these insights by demonstrating that a number of additional morphological abnormalities may be present including myocardial crypts (see Figure 1F), elongated mitral valve leaflets, expanded extracellular space (with T1 mapping) and LGE. [24][25][26][27] When genetic testing is negative or ambiguous (as in 60 % of patients), or when not pursued due to financial or personal preference, CMR can identify these abnormalities in the absence of LV hypertrophy, raising suspicion for genotype-positive status among family members. 2,21 This should prompt continued close surveillance with serial CMR for development of LV hypertrophy and conversion to clinical disease.…”

“…In addition, conflicting data exist regarding T1 mapping values in G+P-patients, and if this value can indeed differentiate G+P-patients to normal controls. 24,50 Thereby, continued investigations applying T1 mapping to HCM is necessary to better to define the role of this technique.…”