Microstructural and Microvascular Phenotype of Sarcomere Mutation Carriers and Overt Hypertrophic Cardiomyopathy

Abstract

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups—overt, either genotype-positive (G+LVH+) or genotype-negative (G−LVH+), and subclinical (G+LVH−) HCM—exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G−LVH+), 77 patients with G+LVH−, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P <0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P <0.001). Patients with G−LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle ( P <0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G− patients (100% [51/51] versus 82% [41/50]; P =0.001). Patients with G+LVH− compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P <0.001), and MVD (reduced stress myocardial blood flow [ P =0.015] with perfusion defects in 28% versus 0 healthy volunteers [ P =0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P =0.01; stress myocardial blood flow: odds ratio, 2.8, P =0.015; subclinical: fractional anisotropy odds ratio, 4.0, P =0.001; myocardial perfusion reserve odds ratio, 2.2, P =0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G− patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.

Cardiac Magnetic Resonance Feature-Tracking Identifies Preclinical Abnormalities in Hypertrophic Cardiomyopathy Sarcomere Gene Mutation Carriers

“…9 In any case, CMR parameters (including the more recent and complex diffusion tensor imaging) suggest the presence of altered microstructure in subclinical HCM. 34 In this scenario, we might postulate that CMR-FT reduction reflects the hallmarks of the disease: myocardial disarray, fibrosis and reduced perfusion.…”

“…The study sample was compared with 42 healthy controls similar for both sex (P=0.095) and age at the moment of CMR (P=0.3046; median age at CMR 31 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] years, 50% males, median body surface area, 1.71 m 2 ).…”

Retrofitting the Heart: Explaining the Enigmatic Septal Thickening in Hypertrophic Cardiomyopathy

“…Microvascular dysfunction in HCM frequently manifests early, often before hypertrophy becomes evident, and occurs irrespective of sarcomeric mutations. 33 Its onset is associated with the myocardium's hypercontractile state 23 and correlates with severe changes in the architectural arrangement of muscle fibers throughout the LV cavity (see the section Hypercontractility and Septal Biomechanics in HCM). 33 Hypercontractility not only accelerates ATP consumption and increases mitochondrial oxygen demand but also, counterintuitively, impedes diastolic coronary flow in HCM.…”

Imaging Myofibrillar Disarray and Microvascular Dysfunction in Hypertrophic Cardiomyopathy: Novel Imaging Biomarkers for a New Era in Therapeutics

“…These processes have been elusive both to detect and to quantify to this point. In this issue of Circulation, Joy et al 11 report quantitative CMR myocardial perfusion as a marker of microvascular disease in HCM and an emerging and innovative CMR technique known as cardiac diffusion tensor imaging (cDTI). cDTI measures the diffusion of water within an imaging voxel to quantify the extent of myocardial microstructural pathology.…”

“…15 Many see CMIs as heralds of disease modification, although direct head-to-head comparisons with septal reduction therapies are lacking, and cost-effectiveness remains in question given their high cost at present. Building on the groundwork laid by Joy et al, 11 a logical extension of their work would be to examine changes in cDTI in patients on CMI. These findings might identify patients more or less likely to respond to CMIs or even identify higher-risk G+LVH− patients who might benefit from treatment before development of overt LVH.…”