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

Abstract

Background: Clinical 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.

Results: 28 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.

Conclusions: HCM 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.

Figure 1

LGE displaying a typical pattern of enhancement in a myosin binding protein C3 mutation carrier with normal LV wall thickness. A. Midventricular LV short axis orientation on which enhancement is visible at the superior and inferior insertion point of the right ventricle into the septum (white arrowheads). These areas often typically display enhancement in manifest HCM patients. Image 1B was planned perpendicular to the inferior area of enhancement as indicated by the dashed line. B. Modified 2 chamber LGE image through the inferoseptum. The area of enhancement is indicated by the white arrowheads and is located in the midwall of the inferoseptum, extending towards the apex. * = anterolateral papillary muscle, LA = left atrium, LV = left ventricle, RV = right ventricle

Figure 2

Segmental comparison of basal left ventricular segments between carriers and controls. Data are presented as mean ± standard error of the mean as indicated by the solid bars (carriers) and open bars (controls). A. EDWT was higher in the septal and inferior segments in carriers compared to controls. Also the asymmetric, predominantly septal distribution of increased wall thickness was observed in the carriers. B. Wall thickening was lower in the septum in carriers compared to controls. C. In controls, peak SCS was higher in the lateral wall compared to the septum, but this difference was less overt in carriers. As a result, peak SCS was significantly larger in the lateral segments of controls compared to carriers. D. Peak diastolic circumferential strain rate is reduced in almost every segment in carriers compared to controls. Again, the heterogeneity in peak DCSR found in controls was less profound in carriers. IS = inferoseptal, AS = anteroseptal, AN = anterior, AL = anterolateral, IL = inferolateral, IN = inferior, EDWT = end diastolic wall thickness, peak DCSR = peak diastolic circumferential strain rate, peak SCS = peak systolic circumferential strain. * = p < 0.05, ^† = p < 0.01, ^‡ = p < 0.001

Figure 3

Relation between functional parameters and different categories of EDWT. Note that both peak SCS (A) and peak DCSR (B) tend to decrease with an increase in wall thickness in carriers (solid dots), but not in controls (open dots). EDWT = end diastolic wall thickness, peak DCSR = peak diastolic circumferential strain rate, peak SCS = peak systolic circumferential strain. * = p < 0.05, ^† = p < 0.01, ^‡ = p < 0.001

Figure 4

Combining the evaluation of SL ratio and peak DCSR in the basal inferolateral segment from the identification of carriers. Optimal cut-off was >1.2 and < 105%·s^-1 to positively identify carriers (solid bars). Note that only 2/25 (8%) of carriers did not meet neither this criteria, and no controls (open bars) met both criteria. Peak DCSR = peak diastolic circumferential strain rate, SL ratio = septal to lateral wall ratio. ^† = p < 0.01, ^‡ = p < 0.001.