Early genetic screening and cardiac intervention in patients with cardiomyopathies in a multidisciplinary clinic

Abstract

Aims: Patients with cardiomyopathies are a heterogeneous group of patients who experience high morbidity and mortality. Early cardiac assessment and intervention with access to genetic counselling in a multidisciplinary Cardiomyopathy Clinic may improve outcomes and prevent progression to advanced heart failure.

Methods and results: Our prospective cohort study was conducted at a multidisciplinary Cardiomyopathy Clinic with 421 patients enrolled (42.5% female, median age 58 years), including 224 patients with dilated cardiomyopathy (DCM, 42.9% female, median age 57 years), 72 with hypertrophic cardiomyopathy (HCM, 43.1% female, median age 60 years), 79 with infiltrative cardiomyopathy (65.8% female, median age 70 years) and 46 who were stage A/at risk for genetic cardiomyopathy (54.3% female, median age 36 years). Patients were seen in follow-up at a median of 18 months. A pathogenic/likely pathogenic variant was identified in 28.5% of the total cohort, including 33.3% of the DCM cohort (28% TTN mutations) and 34.1% of the HCM cohort (60% MYBPC3 and 20% MYH7) who underwent genetic testing. The use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor neprilysin inhibitor (48.3-69.5% of total cohort, P < 0.001), β-blockers (58.4-72.4%, P < 0.001), mineralocorticoid receptor antagonists (33.9-41.4%, P = 0.0014) and sodium/glucose cotransporter-2 inhibitors (5.3-27.9%, P < 0.001) all increased at follow-up. Precision-based therapies were also implemented, including tafamidis for transthyretin amyloidosis (n = 21), enzyme replacement therapy for Fabry disease (n = 14) and mavacamten (n = 4) for HCM. Optimization of medications and devices resulted in improvements in left ventricular ejection fraction (LVEF) from 27% to 43% at follow-up for DCM patients with reduced LVEF at baseline (P < 0.001) and reduction in left ventricular mass index (LVMI) from 156 g/m² to 128 g/m² at follow-up for HCM patients with abnormal LVMI at baseline (P = 0.009). Optimization of therapies was associated with stable plasma biomarkers in stage B patients while lowering levels of BNP (619-517.5 pg/mL, P = 0.048), NT-proBNP (777.5-356 ng/L, P < 0.001) and hsTropT (31-22 ng/L, P = 0.005) at follow-up relative to baseline values for stage C patients. Despite stage B patients having overt cardiomyopathy at baseline, stage A and B patients had a similarly high probability of survival (χ2 = 0.204, P = 0.652). The overall cardiovascular mortality rate was low at 1.7% for the cohort (0.5% for stage B and 3.3% for stage C) over a median of 34-month follow-up.

Conclusion: Our study demonstrates that a multidisciplinary cardiomyopathy clinic can improve the clinical profiles of patients with diverse genetic cardiomyopathies.

Keywords: Cardiac imaging; Cardiomyopathy; Genetic testing; Genetics; Medical therapy; Multidisciplinary care.

Figure 1

Overview of genetic testing modalities and genotype–phenotype correlations of patients enrolled at the Cardiomyopathy Clinic (CMC). ACTC1, actin alpha 1; ALMS, ALMS1 centrosome and basal body associated protein; BAG3, Bcl‐2‐associated athanogene 3; CM, cardiomyopathy; DCM, dilated cardiomyopathy; DES, desmin; DMD, dystrophin; DMPK, DM1 protein kinase; DSC2, desmocollin 2; DSP, desmoplakin; FHOD3, formin homology 2 domain containing 3; FLNC, filamin C; FKRP, fukutin‐related protein; GATA4, GATA binding protein 4; GLA, galactosidase alpha; HCM, hypertrophic cardiomyopathy; HFE, homeostatic iron regulator; LMNA, lamin A/C; MYBPC3, myosin binding protein C; MYH7, myosin heavy chain; MYL2, myosin light chain 2; PLN, phospholamban; PRKAG2, protein kinase AMP‐activated non‐catalytic subunit gamma 2; SCN5A, sodium voltage‐gated channel alpha subunit 5; SMAD3, mothers against decapentaplegic homologue 3; TBX20, T‐box transcription factor 20; TMEM43, transmembrane protein 43; TNNI3, troponin I3; TNNT2, troponin T2; TPM1, tropomyosin 1; TTN, titin; TTR, transthyretin; VUS, variants of unknown significance; WES, whole exome sequencing.

Figure 2

Up‐titration of medical therapies, increased cascade family screening and increase in device implantation following the initial clinic visit in patients seen at the Cardiomyopathy Clinic (CMC). Use of cardiac mediations before and after initial CMC visit (A). Up‐titration of targeted therapies for patients with Fabry disease and ATTR amyloidosis (B). Cascade cardiac and genetic family screening before and after initial CMC visit (C). Pacemaker, cardiac resynchronization therapy and implantable cardioverter‐defibrillator utilization before and after the initial CMC visit (D). ACEi, angiotensin‐converting enzyme inhibitors; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor neprilysin inhibitor; BB, β‐blockers; CRT‐D/CRT‐P, cardiac resynchronization therapy‐defibrillator/pacemaker; ICD, implantable cardioverter‐defibrillator; MRA, mineralocorticoid receptor antagonist; PM, pacemaker; SGLT2i, sodium/glucose cotransporter‐2 inhibitors. Gradient fill indicates before, while solid fill indicates after. n = 346 patients had a follow‐up visit. Two‐sided P < 0.05 was considered significant.

Figure 3

Distribution and improvement of cardiac imaging parameters amongst dilated cardiomyopathy (DCM) patients. Improvement in left ventricular ejection fraction (LVEF) for DCM patients in response to multidisciplinary care (A). Improvement in TAPSE for DCM patients with abnormal TAPSE at baseline (B). Improvement in LVEF for DCM patients with heart failure reduced ejection fraction (HFrEF) stratified by ACC/AHA stage (C). Improvement in left ventricular internal diameter end diastole (LVIDd) for DCM patients stratified by ACC/AHA stage (D). LVEF, left ventricular ejection fraction; LVIDd, left ventricular internal diameter end diastole; mrEF, mid‐range ejection fraction; pEF, preserved ejection fraction; rEF, reduced ejection fraction. LVEF was obtained from cardiac magnetic resonance imaging (CMR) and/or transthoracic echocardiography (TTE). Gradient fill indicates before, while solid fill indicates after. n = 314 patients had baseline and follow‐up imaging. Two‐sided P < 0.05 was considered significant.

Figure 4

Distribution and improvements of cardiac imaging parameters amongst hypertrophic cardiomyopathy (HCM) patients. Improvement in left ventricular mass index (LVMI) for HCM patients with abnormal LVMI at baseline in response to multidisciplinary care (A). Improvement in E/e′ ratio for HCM patients with abnormal E/e′ ratio at baseline (B). Improvement in left ventricular mass index (LVMI) for HCM patients stratified by ACC/AHA stage (C). Reduction in both MAP and SBP at baseline relative to follow‐up amongst HCM patients (D). LVMI, left ventricular mass index; MAP, mean arterial pressure. LVMI and E/e′ ratio were obtained from transthoracic echocardiography (TTE). Gradient fill indicates before, while solid fill indicates after. n = 314 patients had baseline and follow‐up imaging. Two‐sided P < 0.05 was considered significant.

Figure 5

Trends in plasma biomarkers from baseline to follow‐up and associated clinical outcomes stratified by AHA stage. Reduction in plasma biomarkers at baseline relative to follow‐up stratified by AHA stage (A). Kaplan–Meier analysis for HF ED visits since the time of clinic enrolment compared by AHA stage (Bi). Kaplan–Meier analysis for CV hospitalization since the time of clinic enrolment compared by AHA Stage (Bii). Kaplan–Meier analysis for CV‐death since the time of clinic enrolment compared by AHA Stage (Biii). BNP indicates B‐type natriuretic peptide; NT‐BNP, N‐terminal prohormone of brain natriuretic peptide; hsTropT, high‐sensitive troponin T; HF, heart failure; ED, emergency department; CV, cardiovascular. Gradient fill indicates before, while solid fill indicates after. n = 201 patients had baseline and follow‐up biomarker data. n = 421 patients had longitudinal outcome data. Two‐sided P < 0.05 was considered significant.