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.

Keywords: cardiomyopathy, hypertrophic; diffusion tensor imaging; magnetic resonance imaging; microcirculation; perfusion; sarcomeres.

Figure 1.

Cardiac diffusion tensor imaging. A, Representation of the short-axis imaging plane with a magnified imaging voxel containing ≈50 000 myocytes. Diffusion tensor imaging measures magnitudes (eigenvalues λ1, λ2, and λ3) and direction (eigenvectors E1, E2, and E3) of water diffusion. B, Three arrows (green, blue, and red) representing the 3-dimensional directions of diffusion: the 3 principal eigenvectors. E1 (green) is the direction of maximum diffusivity orientated along the myocyte long axis. Myocytes are organized into sheetlets, functional units of myocytes that dynamically reorientate to facilitate wall thickening, reflected by the E2 (blue) angle against the cross-myocyte plane (right angles to E1 projection on the wall tangent plane). C, Sheetlets angled parallel to the wall tangent have a low absolute second eigenvector angle (|E2A|), and sheetlets positioned perpendicular to the wall tangent have a high |E2A|, signifying a more contracted sheetlet configuration. If myocytes were perfectly randomly orientated (isotropic diffusion), fractional anisotropy (FA) would be 0; hence, myocyte disarray causes lower fractional anisotropy (FA) values. Mean diffusivity (MD) is the mean of the eigenvalues, with higher values representing a greater magnitude of diffusion. MD is thought to be sensitive to myocyte packing and intracellular and extracellular volume shifts. HCM indicates hypertrophic cardiomyopathy. Adapted from Ariga et al (Copyright © 2019 Elsevier) and Ferreira et al (Copyright © 2014 Ferreira et al, licensee BioMed Central Ltd), Nielles-Vallespin et al (Copyright © 2017 Elsevier), and Das et al (Copyright © 2021 Radiological Society of America) with permission.

Figure 2.

Abnormalities in perfusion and diffusion tensor parameters (low FA, high MD, and high |E2A|) occurring in the absence of hypertrophy in subclinical HCM (G+LVH−) and more severely in overt disease (G+LVH+ and G−LVH+). |E2A| indicates second eigenvector angle; FA, fractional anisotropy; G+/−, genotype positive/negative; LGE, late gadolinium enhancement; LVH+/−, left ventricular hypertrophy positive/negative; and MD, mean diffusivity.

Figure 3.

Diffusion tensor and quantitative perfusion CMR parameter alterations in phenotype development. A, Diffusion tensor parameter changes are detectable in subclinical (G+LVH−) hypertrophic cardiomyopathy (HCM) and measure more severely in overt disease. Genotype-negative HCM (G−LVH+) is characterized by elevated second eigenvector angle (|E2A|) compared with genotype-positive HCM (G+LVH+). B, Stress myocardial blood flow (MBF), reflecting microvascular disease, is reduced in subclinical HCM and more severely in overt disease. C, Subclinical HCM with perfusion defects had lower fractional anisotropy (FA; suggestive of more disarray) compared with subclinical HCM without perfusion defects. |E2A| indicates second eigenvector angle; HV, healthy volunteer; LVH, left ventricular hypertrophy; MD, mean diffusivity; and MPR, myocardial perfusion reserve. *P<0.05. **P<0.01. ***P<0.001.