How do hypertrophic cardiomyopathy mutations affect myocardial function in carriers with normal wall thickness? Assessment with cardiovascular magnetic resonance

Abstract

BackgroundClinical data on myocardial function in HCM mutation carriers (carriers) is sparse but suggests that subtle functional abnormalities can be measured with tissue Doppler imaging before the development of overt hypertrophy. We aimed to confirm the presence of functional abnormalities using cardiovascular magnetic resonance (CMR), and to investigate if sensitive functional assessment could be employed to identify carriers.Results28 carriers and 28 controls were studied. Global left atrial (LA) and left ventricular (LV) dimensions, segmental peak systolic circumferential strain (SCS) and peak diastolic circumferential strain rate (DCSR), as well as the presence of late Gadolinium enhancement (LGE) were determined with CMR. Septal and lateral myocardial velocities were measured with echocardiographic tissue Doppler imaging. lv mass and volumes were comparable between groups. Maximal septal to lateral wall thickness ratio (SL ratio) was larger in carriers than in controls (1.3 ± 0.2 versus 1.1 ± 0.1, p < 0.001). Also, LA volumes were larger in carriers compared to controls (p < 0.05). Both peak SCS (p < 0.05) and peak DCSR (p < 0.01) were lower in carriers compared to controls, particularly in the basal lateral wall. Focal LGE was present in 2 carriers and not in controls. The combination of a SL ratio >1.2 and a peak DCSR <105%.s-1 was present in 45% of carriers and in none of the controls, yielding a positive predictive value of 100%. Two carriers and 18 controls had a SL ratio < 1.2 and peak DCSR >105%.s-1, yielding a negative predictive value of 90%. With multivariate analysis, HCM mutation carriership was an independent determinant of reduced peak SCS and peak DCSR.ConclusionsHCM mutation carriership is an independent determinant of reduced peak SCS and peak DCSR when LV wall thickness is within normal limits, and is associated with increased LA volumes and SL ratio. Using SL ratio and peak DCSR has a high accuracy to identify carriers. However, since carriers also display structural abnormalities and focal LGE, we advocate to also evaluate morphology and presence of LGE when screening for carriers.

ADP-stimulated contraction: A predictor of thin-filament activation in cardiac disease

“…The increased myofilament Ca 2+ sensitivity and high sarcomere stiffness in the presence of ADP is in line with our previous study, where we showed that the complex interactions of Ca 2+ and ADP increased myofilament Ca 2+ sensitivity and stiffness in membrane-permeabilized rat cardiomyocytes, limited restoration of diastolic length in intact rat cardiomyocytes, and diminished ventricular compliance in whole rat hearts (17). Altogether, these myofilament changes have the potential to delay the onset of ventricular relaxation and limit proper filling, which are seen in patients (54,55) and animal models (51, 52) of HCM, and human IDCM (4).…”

Abnormal Cardiac Formation in Hypertrophic Cardiomyopathy

“…Elevated EF 21,39,40 and hypercontractility 41 have been previously documented, but diastolic 42 and systolic dysfunction 43 have also been seen, although the latter may have been attributable to myocardial scar, 43 whereas our carriers were entirely free of scar. Elongation of the AMVL was also confirmed.…”

Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation

“…Puntman et al found that in hypertensive patients LV wall stress was increased whereas patients with HCM were characterized by reduced total longitudinal strain [10]. The combination of anatomical and functional parameters have been shown to increase the diagnostic accuracy to detect HCM causing mutation carriers from healthy controls [29]. Also, late gadolinium enhancement (LGE) imaging has been suggested to increase diagnostic accuracy in patients with mild to moderate hypertrophy.…”