Myocardial structural alteration and systolic dysfunction in preclinical hypertrophic cardiomyopathy mutation carriers

Abstract

Background: To evaluate the presence of myocardial structural alterations and subtle myocardial dysfunction during familial screening in asymptomatic mutation carriers without hypertrophic cardiomyopathy (HCM) phenotype.

Methods and findings: Sixteen HCM families with pathogenic mutation were studied and 46 patients with phenotype expression (Mut+/Phen+) and 47 patients without phenotype expression (Mut+/Phen-) were observed. Twenty-five control subjects, matched with the Mut+/Phen- group, were recruited for comparison. Echocardiography was performed to evaluate conventional parameters, myocardial structural alteration by calibrated integrated backscatter (cIBS) and global and segmental longitudinal strain by speckle tracking analysis. All 3 groups had similar left ventricular dimensions and ejection fraction. Basal anteroseptal cIBS was the highest in Mut+/Phen+ patients (-14.0±4.6 dB, p<0.01) and was higher in Mut+/Phen- patients as compared to controls (-17.0±2.3 vs. -22.6±2.9 dB, p<0.01) suggesting significant myocardial structural alterations. Global and basal anteroseptal longitudinal strains (-8.4±4.0%, p<0.01) were the most impaired in Mut+/Phen+ patients as compared to the other 2 groups. Although global longitudinal strain was similar between Mut+/Phen- group and controls, basal anteroseptal strain was lower in Mut+/Phen- patients (-14.1±3.8%, p<0.01) as compared to controls (-19.9±2.9%, p<0.01), suggesting a subclinical segmental systolic dysfunction. A combination of >-19.0 dB basal anteroseptal cIBS or >-18.0% basal anteroseptal longitudinal strain had a sensitivity of 98% and a specificity of 72% in differentiating Mut+/Phen- group from controls.

Conclusion: The use of cIBS and segmental longitudinal strain can differentiate HCM Mut+/Phen- patients from controls with important clinical implications for the family screening and follow-up of these patients.

Figure 1. Schematic representation of the individual diagnosis of hypertrophic cardiomyopathy (HCM) within the study population, using the echocardiographic (Echo) and electrocardiographic (ECG) criteria proposed by McKenna et al¹⁰.

The diagnosis of HCM is made in the presence of 1 major criterion or of 2 minor Echo criteria or of 1 minor Echo +2 minor ECG criteria. A total of 46 mutation carriers with phenotype expression (Mut+/Phen+) and 47 mutation carriers without phenotype expression (Mut+/Phen−) were identified.

Figure 2. Assessment of left ventricular (LV) myocardial structural alteration by calibrated integrated backscatter (IBS) in a mutation carrier without HCM phenotype expression (Mut+/Phen−).

A fixed region of interest is positioned at the level of the basal anteroseptal wall (ASW, yellow circle), of the basal posterior wall (PW, blue circle) and in the pericardium (red circle, for calibration). The basal ASW calibrated IBS of this Mut+/Phen− patient was −14.4 dB and the basal PW calibrated IBS was −19.8 dB, indicating an altered myocardial structure.

Figure 3. Example of impaired segmental strain measured by speckle tracking in the apical long-axis view (left panel), in a mutation carrier without HCM phenotype expression.

The basal anteroseptal wall (ASW) is colored in red, while the basal posterior wall (PW) is colored in yellow. In the right panel, the corresponding longitudinal systolic strain curves: peak strain of basal ASW and PW are −14.8% and −24.8% respectively, suggesting segmental systolic dysfunction of the ASW with a preserved function of the PW. Conversely, global longitudinal strain (white dotted line) shows a normal value (−19.8%) in the apical long-axis view.

Figure 4. Calibrated integrated backscatter (IBS) of the basal anteroseptal and basal posterior walls in each group: controls, mutation carriers without phenotype expression (Mut+/Phen−) and mutation carriers with phenotype expression (Mut+/Phen+).

Structural alterations of the basal anteroseptum are the greatest in the Mut+/Phen+ group, followed by Mut+/Phen− group and by controls. Similarly, structural alterations of the basal posterior wall are the greatest in the Mut+/Phen+ group, but are similar between the Mut+/Phen− group and controls.

Figure 5. Segmental strain measured by speckle tracking of the basal anteroseptal and posterior walls in each group: controls, mutation carriers without phenotype expression (Mut+/Phen−) and mutation carrier with phenotype expression (Mut+/Phen+).

Basal anteroseptal strain is the most impaired in Mut+/Phen+ group, followed by Mut+/Phen− group and controls. Basal posterior wall strain is the most impaired in Mut+/Phen+ group, while is similar between Mut+/Phen− group and controls.

Figure 6. Receiver operator characteristic curve analysis to determine the accuracy of basal anteroseptal calibrated integrated backscatter (IBS), and longitudinal strain and È velocity to differentiate Mut+/Phen− patients from controls.

Basal anteroseptal calibrated IBS >−19.0 dB yielded a sensitivity of 89% and a specificity of 84% to differentiate Mut+/Phen− patients from controls. Basal anteroseptal strain >−18.0% yielded a sensitivity of 85% and specificity of 84%. È velocity <10 cm/s provided a modest sensitivity of 62% and specificity of 60% to differentiate Mut+/Phen− patients from controls. AUC = area under the curve.