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.

Microvascular dysfunction in hypertrophic cardiomyopathy (HCM) is predictive of clinical decline, however underlying mechanisms remain unclear. Cardiac diffusion tensor imaging (cDTI) allows in vivo characterization of myocardial microstructure by quantifying mean diffusivity (MD), fractional anisotropy (FA) of diffusion, and secondary eigenvector angle (E2A). In this cardiac magnetic resonance (CMR) study, we examine associations between perfusion and cDTI parameters to understand the sequence of pathophysiology and the interrelation between vascular function and underlying microstructure. Twenty HCM patients underwent 3.0T CMR which included: spin-echo cDTI, adenosine stress and rest perfusion mapping, cine-imaging, and late gadolinium enhancement (LGE). Ten controls underwent cDTI. Myocardial perfusion reserve (MPR), MD, FA, E2A, and wall thickness were calculated per segment and further divided into subendocardial (inner 50%) and subepicardial (outer 50%) regions. Segments with wall thickness ≤11 mm, MPR ≥2.2, and no visual LGE were classified as ‘normal’. Compared to controls, ‘normal’ HCM segments had increased MD (1.61 ± 0.09 vs. 1.46 ± 0.07 × 10⁻³ mm²/s, P = 0.02), increased E2A (60 ± 9° vs. 38 ± 12°, P < 0.001), and decreased FA (0.29 ± 0.04 vs. 0.35 ± 0.02, P = 0.002). Across all HCM segments, subendocardial regions had higher MD and lower MPR than subepicardial (MD_endo 1.61 ± 0.08 × 10⁻³ mm²/s vs. MD_epi 1.56 ± 0.18 × 10⁻³ mm²/s, P = 0.003, MPR_endo 1.85 ± 0.83, MPR_epi 2.28 ± 0.87, P < 0.0001). In HCM patients, even in segments with normal wall thickness, normal perfusion, and no scar, diffusion is more isotropic than in controls, suggesting the presence of underlying cardiomyocyte disarray. Increased E2A suggests the myocardial sheetlets adopt hypercontracted angulation in systole. Increased MD, most notably in the subendocardium, is suggestive of regional remodelling which may explain the reduced subendocardial blood flow.

Recently developed in-line automated cardiovascular magnetic resonance (CMR) myocardial perfusion mapping has been shown to be reproducible and comparable with positron emission tomography (PET), and can be easily integrated into clinical workflows. Bringing quantitative myocardial perfusion CMR into routine clinical care requires knowledge of sex- and age-specific normal values in order to define thresholds for disease detection. This study aimed to establish sex- and age-specific normal values for stress and rest CMR myocardial blood flow (MBF) in healthy volunteers. A total of 151 healthy volunteers recruited from two centres underwent adenosine stress and rest myocardial perfusion CMR. In-line automatic reconstruction and post processing of perfusion data were implemented within the Gadgetron software framework, creating pixel-wise perfusion maps. Rest and stress MBF were measured, deriving myocardial perfusion reserve (MPR) and were subdivided by sex and age. Mean MBF in all subjects was 0.62 ± 0.13 mL/g/min at rest and 2.24 ± 0.53 mL/g/min during stress. Mean MPR was 3.74 ± 1.00. Compared with males, females had higher rest (0.69 ± 0.13 vs. 0.58 ± 0.12 mL/g/min, P < 0.01) and stress MBF (2.41 ± 0.47 vs. 2.13 ± 0.54 mL/g/min, P = 0.001). Stress MBF and MPR showed significant negative correlations with increasing age (r = −0.43, P < 0.001 and r = −0.34, P < 0.001, respectively). Fully automated in-line CMR myocardial perfusion mapping produces similar normal values to the published CMR and PET literature. There is a significant increase in rest and stress MBF, but not MPR, in females and a reduction of stress MBF and MPR with advancing age, advocating the use of sex- and age-specific reference ranges for diagnostic use. A total of 150 healthy volunteers underwent adenosine stress and rest quantitative perfusion cardiovascular magnetic resonance. Normal values were established in this large cohort with a wide age range. We demonstrated higher stress and rest myocardial blood flow in females compared with males, and a decrease in stress myocardial blood flow and myocardial perfusion reserve with increasing age. Suggested normal ranges referenced to age and sex have been created with this data.

Aims: Develop, calibrate and evaluate with clinical data a human electromechanical modelling and simulation framework for multiscale, mechanistic investigations in healthy and post-myocardial infarction (MI) conditions, from ionic to clinical biomarkers. Methods and results: Human healthy and post-MI electromechanical simulations were conducted with a novel biventricular model, calibrated and evaluated with experimental and clinical data, including torso/biventricular anatomy from clinical magnetic resonance, state-of-the-art human-based membrane kinetics, excitation–contraction and active tension models, and orthotropic electromechanical coupling. Electromechanical remodelling of the infarct/ischaemic region and the border zone were simulated for ischaemic, acute, and chronic states in a fully transmural anterior infarct and a subendocardial anterior infarct. The results were compared with clinical electrocardiogram and left ventricular ejection fraction (LVEF) data at similar states. Healthy model simulations show LVEF 63%, with 11% peak systolic wall thickening, QRS duration and QT interval of 100 ms and 330 ms. LVEF in ischaemic, acute, and chronic post-MI states were 56%, 51%, and 52%, respectively. In linking the three post-MI simulations, it was apparent that elevated resting potential due to hyperkalaemia in the infarcted region led to ST-segment elevation, while a large repolarization gradient corresponded to T-wave inversion. Mechanically, the chronic stiffening of the infarct region had the benefit of improving systolic function by reducing infarct bulging at the expense of reducing diastolic function by inhibiting inflation. Conclusion: Our human-based multiscale modelling and simulation framework enables mechanistic investigations into patho-physiological electrophysiological and mechanical behaviour and can serve as testbed to guide the optimization of pharmacological and electrical therapies.

Cardiac diffusion tensor imaging can be used to detect early and irreversible myocardial microstructural remodeling that may improve the prediction of left ventricular functional recovery at 3 months. Background Cardiac diffusion tensor imaging (cDTI) allows for in vivo characterization of myocardial microstructure. In cDTI, mean diffusivity and fractional anisotropy (FA)—markers of magnitude an...

Background: Hypertrophic cardiomyopathy (HCM) remains the commonest cause of sudden cardiac death among young athletes. Differentiating between physiologically adaptive left ventricular (LV) hypertrophy observed in athletes' hearts and pathological HCM remains challenging. By quantifying the diffusion of water molecules, diffusion tensor imaging (DTI) MRI allows voxelwise characterization of myocardial microstructure.Purpose: To explore microstructural differences between healthy volunteers, athletes, and HCM patients using DTI.Study Type: Prospective cohort.Population: Twenty healthy volunteers, 20 athletes, and 20 HCM patients.Field Strength/Sequence: 3T/DTI spin echo.Assessment: In‐house MatLab software was used to derive mean diffusivity (MD) and fractional anisotropy (FA) as markers of amplitude and anisotropy of the diffusion of water molecules, and secondary eigenvector angles (E2A)—reflecting the orientations of laminar sheetlets.Statistical Tests: Independent samples t‐tests were used to detect statistical significance between any two cohorts. Analysis of variance was utilized for detecting the statistical difference between the three cohorts. Statistical tests were two‐tailed. A result was considered statistically significant at P ≤ 0.05.Results: DTI markers were significantly different between HCM, athletes, and volunteers. HCM patients had significantly higher global MD and E2A, and significantly lower FA than athletes and volunteers. (MD_HCM = 1.52 ± 0.06 × 10⁻³ mm²/s, MD_Athletes = 1.49 ± 0.03 × 10⁻³ mm²/s, MD_volunteers = 1.47 ± 0.02 × 10⁻³ mm²/s, P < 0.05; E2A_HCM = 58.8 ± 4°, E2A_athletes = 47 ± 5°, E2A_volunteers = 38.5 ± 7°, P < 0.05; FA_HCM = 0.30 ± 0.02, FA_Athletes = 0.35 ± 0.02, FA_volunteers = 0.36 ± 0.03, P < 0.05). HCM patients had significantly higher E2A in their thickest segments compared to the remote (E2A_thickest = 66.8 ± 7, E2A_remote = 51.2 ± 9, P < 0.05).Data Conclusion: DTI depicts an increase in amplitude and isotropy of diffusion in the myocardium of HCM compared to athletes and volunteers as reflected by increased MD and decreased FA values. While significantly higher E2A values in HCM and athletes reflect steeper configurations of the myocardial sheetlets than in volunteers, HCM patients demonstrated an eccentric rise in E2A in their thickest segments, while athletes demonstrated a concentric rise. Further studies are required to determine the diagnostic capabilities of DTI.Evidence Level: 1Technical Efficacy Stage: 2