Cardiac magnetic resonance markers of pre-clinical hypertrophic and dilated cardiomyopathy in genetic variant carriers

Abstract

Background: Patients with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) exhibit structural and functional cardiac abnormalities. We aimed to identify imaging biomarkers for pre-clinical cardiomyopathy in healthy participants carrying cardiomyopathy-associated variants (G +).

Methods: We included 40,169 UK Biobank participants free of cardiac disease at the time of cardiac magnetic resonance imaging (CMR) and with whole exome sequencing. We validated 22 CMR measurements by associating them with incident atrial fibrillation (AF) or heart failure (HF). We subsequently assessed associations of these CMR measurements with HCM G+, DCM G + , or specific genes, utilising generalised linear models conditional on cardiac risk factors.

Results: Thirteen CMR measurements were associated with incident AF and 15 with HF. These included left ventricular (LV) ejection fraction (EF; hazard ratio [HR] 0.61, 95% confidence interval [95%CI] 0.54; 0.69) for HF and indexed maximum left atrial volume (LAVi max; HR 1.47, 95%CI 1.29; 1.67) for AF. Five measurements associated with HCM G + , amongst which right ventricular (RV) end-systolic volume (RV-ESV; odds ratio [OR] 0.62, 95%CI 0.53; 0.74), RV-EF (OR 1.36, 95%CI 1.19; 1.55), and right atrial (RA) EF (OR 1.22, 95%CI 1.08; 1.39). Associations overlapping with incident disease and HCM G + had opposite effect directions, such as RV-ESV with HF (HR 1.22, 95%CI 1.07; 1.40). Two CMR measurements associated with DCM G + : LV-ESVi (OR 1.35, 95%CI 1.15; 1.58) and LV-EF (OR 0.75, 95%CI 0.64; 0.88). We observed significant associations with individual cardiomyopathy genes, finding that mitral annular plane systolic excursion associated with TTN and TNNT2, and LA pump volume and RA-EF associated with MYH7.

Conclusions: We identified right-heart CMR measurements associated with HCM G + in healthy individuals, indicating early compensation of cardiac function. LV measurements associated with DCM G + , where CMR associations varied across individual DCM genes, suggesting distinct early pathophysiology.

Keywords: Cardiac magnetic resonance; Dilated cardiomyopathy; Genetics; Hypertrophic cardiomyopathy; Whole exome sequencing.

Fig. 1

Study design to identify CMR measurements associated with HCM G + and DCM G +. Abbreviations: AF = atrial fibrillation, CMR = cardiac magnetic resonance imaging, DCM = dilated cardiomyopathy, G + = participants carrying disease-associated variants, HCM = hypertrophic cardiomyopathy, HF = heart failure

Fig. 2

Association of CMR measurements with incident atrial fibrillation or heart failure and carriership of genetic variants associated with hypertrophic cardiomyopathy or dilated cardiomyopathy. Associations are presented as − log₁₀(p value) multiplied by the effect direction. Significant results, as defined by the Bonferroni-corrected p value threshold of 6.25 × 10⁻³, are indicated with a star. Abbreviations: AF = atrial fibrillation, CI = compliance index, CMR = cardiac magnetic resonance imaging, DCM = dilated cardiomyopathy, EDV = end-diastolic volume, EF = ejection fraction, ESV = end-systolic volume, HCM = hypertrophic cardiomyopathy, HF = heart failure, i = body surface area indexed, LA = left atrial, LV = left ventricular, MAPSE 2Ch = mitral annular plane systolic excursion in 2-chamber view, pump = pump volume, RA = right atrial, res = reservoir volume, RV = right ventricular, SV = stroke volume, TAPSE 4Ch = tricuspid annular plane systolic excursion in 4-chamber view, Vi max = maximum indexed volume, Vi min = minimum indexed volume

Fig. 3

Hazard ratios for the association of CMR measurements with incident atrial fibrillation or heart failure. Effect magnitudes are presented per standard deviation increase in CMR measurements. Abbreviations: AF = atrial fibrillation, CI = compliance index, CMR = cardiac magnetic resonance imaging, EDV = end-diastolic volume, EF = ejection fraction, ESV = end-systolic volume, HF = heart failure, HR = hazard ratio, i = body surface area indexed, LA = left atrial, LV = left ventricular, MAPSE 2Ch = mitral annular plane systolic excursion in 2-chamber view, RA = right atrial, RV = right ventricular, SV = stroke volume, TAPSE 4Ch = tricuspid annular plane systolic excursion in 4-chamber view, Vi max = maximum indexed volume, 95% CI = 95% confidence interval

Fig. 4

Odds ratios for the association of CMR measurements with hypertrophic cardiomyopathy or dilated cardiomyopathy G +. Model 1 is univariable, model 2 is adjusted for age and sex, and model 3 is adjusted for age, sex, and the comorbidities hypertension, diabetes, hypercholesterolaemia, and smoking. Abbreviations: CMR = cardiac magnetic resonance imaging, DCM = dilated cardiomyopathy, EF = ejection fraction, ESV = end-systolic volume, G + = participants carrying disease-associated variants, HCM = hypertrophic cardiomyopathy, i = body surface area indexed, LV = left ventricular, RA = right atrial, RV = right ventricular, OR = odds ratio, TAPSE 4Ch = tricuspid annular plane systolic excursion in 4-chamber view, 95% CI = confidence interval

Fig. 5

Frequency of genetic variants in cardiomyopathy-associated genes associating with CMR measurements. Genetic variants were selected within 1 megabase pair of cardiomyopathy-associated genes and searched in genome-wide association study summary statistics. Associations with dilated cardiomyopathy are depicted left of the vertical line, those with hypertrophic cardiomyopathy to the right. Abbreviations: EF = ejection fraction, ESV = end-systolic volume, LV = left ventricular, RV = right ventricular