Alex Hørby Christensen

BACKGROUND: Cardiomyopathy guidelines recommend routine screening of at-risk relatives with dilated cardiomyopathy (DCM). Titin-truncating variants are the most prevalent cause. However, the diagnostic yield of screening is low. Risk-based stratification could optimize screening intervals and resource allocation. This study aims to develop a safe, evidence-based gene-specific longitudinal screening algorithm for DCM development. METHODS: We included likely pathogenic/pathogenic titin-truncating variant relatives from 7 centers who underwent cardiac screening. Relatives were stratified based on their baseline clinical phenotype: genotype-positive/phenotype-negative (no left ventricular dysfunction and dilatation) or partial DCM (ie, fulfilling only 1 criterion). DCM development predictors were identified based on follow-up data. Risk profiles were established and used to develop a multistate model to create a longitudinal screening algorithm to safely and effectively monitor titin-truncating variant relatives. RESULTS: Among 413 relatives, follow-up data were available in 301 relatives (median follow-up 5.7 years), of whom 24.6% developed left ventricular dysfunction or dilatation and 17.3% developed DCM. In total, 16 relatives (5.3%) experienced a major adverse cardiac event after DCM diagnosis. Based on the identified risk factors, age ≥30 years, male sex, and partial DCM, 3 distinct profiles were established: (1) relatives with partial DCM, (2) females ≥30 years and males, and (3) female relatives <30 years. A screening algorithm was developed, recommending intervals of 1, 3, and 5 years, optimizing the balance between safety and effectiveness. CONCLUSIONS: An evidence-based genotype-specific longitudinal screening algorithm that integrates age, sex, and echocardiographic measurements may improve patient care and improve efficiency of clinical resource allocation.

BACKGROUND: We aimed to characterize the genetic architecture of resistant hypertension (rHTN), which affects up to 18% of hypertensive individuals and increases cardiovascular disease risk. METHODS: We conducted a genome-wide association study on rHTN, defined as use of 3 or more concomitant antihypertensive drugs for at least 6 months without reaching blood pressure target (in the 3-drug case), comparing it to controlled hypertension (cHTN), in which persons on 1 or 2 antihypertensives for at least 6 months reach target BP after 30 days of therapy initiation. The study included 23 508 rHTN cases and 24 393 cHTN controls, identified through drug prescription and blood pressure data from Iceland (deCODE), the UK (UK Biobank), and the US (eMERGE). Further analyses included comparisons with all hypertensive individuals (diagnosed with International Classification of Diseases, Tenth Revision code I10) and normotensives (no hypertension diagnosis). RESULTS: We found 24 rHTN variants, 17 of which used published BP variants as prior. Fifteen risk-increasing rHTN alleles are associated with lower serum potassium and increased hyperaldosteronism risk. Individuals with rHTN and cHTN had lower potassium levels before drug therapy than normotensives. All antihypertensive drug classes increased potassium levels in cHTN, while only aldosterone antagonists increased levels in rHTN. Mendelian randomization analysis was consistent with rHTN being a manifestation of hyperaldosteronism. The variant conferring the largest effect on both rHTN and hyperaldosteronism is a stop-gain variant in ENPEP in the aldosterone pathway. CONCLUSIONS: We discovered sequence variants that have different effects on rHTN and cHTN. Our study indicates that genetically determined hyperaldosteronism may be largely accountable for rHTN.

Aims: Catheter ablation (CA) for atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy (HCM) poses unique challenges due to structural and electrical remodelling. This study examines AF recurrence and complication rates following CA in HCM patients compared to a matched AF non-HCM cohort. Methods and results: A retrospective cohort study of Danish nationwide registries from 2010 to 2022 was conducted. Rates of AF recurrence, heart failure, ischaemic stroke, and death were analysed using propensity score matching and Cox regression models. Among 28 231 patients undergoing first-time CA for AF, 299 had a confirmed diagnosis of HCM. Patients with HCM demonstrated significantly higher rates of AF recurrence compared to a matched non-HCM cohort, with 40% experiencing recurrence vs. 30% in the non-HCM group after 1 year and 67% vs. 58% after 5 years [hazard ratio (HR) 1.41, P < 0.001]. Despite the elevated recurrence rates, no significant differences were observed in the incidence of ischaemic stroke (HR 0.99, P & 0.9) or all-cause mortality (HR 1.18, P & 0.3). However, the risk of heart failure was significantly increased (HR 2.45, P & <0.001). Conclusion: HCM patients experience higher AF recurrence rates post-CA as well as a higher risk of heart failure. These findings highlight the need for tailored strategies to improve outcomes in this high-risk group.

Background: Hypertrophic cardiomyopathy is a complex disease with variable clinical presentation and familial impact. Age at diagnosis may influence phenotypic expression, but it is unclear if age also affects clinical outcomes, genetic findings, and yield of family screening. Methods: This was a retrospective cohort study of families screened for hypertrophic cardiomyopathy in eastern Denmark (2006–2023). Probands were analyzed by age at diagnosis both continuously and in quartiles: 18 to 45, 46 to 56, 57 to 65, and >65 years. Results: A total of 612 probands (62% men; median age, 56 years; median follow‐up, 9 years) and 919 relatives (45% men; median age, 42 years) were studied. A higher proband age at diagnosis was associated with more left ventricular outflow tract obstruction (odds ratio [OR], 1.19/10 years), hypertension (OR, 1.57/10 years) and atrial fibrillation (OR, 1.24/10 years), but less left ventricular hypertrophy (wall thickness ≥30 mm; OR, 0.52/10 years), and ventricular arrhythmias (OR 0.81/10 years). Older age at diagnosis was associated with higher all‐cause death, but similar cardiovascular death. Sarcomere variants were less common in the oldest versus youngest quartile of probands (13% versus 42%, P <0.001). The yield of family screening at baseline was higher in probands diagnosed at a younger age (OR, 1.34/10‐year decrease). Long‐term hypertrophic cardiomyopathy incidence in relatives was not associated with proband age at diagnosis, and overall yield of family screening was comparable across all proband ages at diagnosis. Conclusions: The proband’s age at hypertrophic cardiomyopathy diagnosis was associated with clinical and genetic findings, but the cardiovascular death and the yield of family screening were similar across all ages at diagnosis, supporting the presently recommended follow‐up and family screening irrespective of the proband’s age at diagnosis.

Background and Aims: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results: A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions: Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Aims: Up to 70% of sudden cardiac death (SCD) cases in younger individuals are potentially caused by an inherited heart disease. However, long-term diagnostic yield and risk of cardiac events in SCD relatives remain unclear. This study aimed to determine the 10-year diagnostic yield of inherited heart diseases and frequency of cardiac events in SCD relatives. Methods and results: This retrospective study included SCD probands and their relatives referred to the Unit for Inherited Heart Diseases at Rigshospitalet, Denmark, from 2005 to 2018. Relatives underwent guideline-recommended screening and follow-up. Diagnoses and cardiac events, such as new-onset reduced left ventricular ejection fraction ≤45%, sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator therapy, cardiac death, and (aborted) SCD, were registered. A total of 686 relatives (47% males, median baseline age 35 years) to 299 probands (75% males, median death age 41 years) were followed for a median of 10.6 years. At 10-year follow-up, 12% of relatives (n = 82) were diagnosed with an inherited heart disease, with 93% (n = 76) diagnosed within 5 years. Cardiac events occurred in 18 (3%) and 24 (4%) relatives after 5- and 10-year follow-up, respectively. Five (0.7%) relatives of probands with no established diagnosis, who had no diagnosis nor cardiac event within 5 years of follow-up, were diagnosed between >5 and 10 years of follow-up. Conclusion: Long-term follow-up identified an inherited heart disease in 12% of SCD relatives, primarily diagnosed within 5 years. Cardiac events were rare (4%). These findings suggest that follow-up may be considered limited to 5 years for specific adult SCD relatives.

Background Hypertrophic cardiomyopathy (HCM) is a complex disease with variable clinical presentation and familial impact. Age at diagnosis may influence phenotypic expression, but it is unclear if age also affects clinical outcomes, genetic findings, and yield of family screening. Methods Retrospective cohort study of families screened for HCM in Eastern Denmark (2006-2023). Probands were analyzed by age at diagnosis both continuously and in quartiles: 18-45, 46-56, 57-65, and >65 years. Results 612 probands (62% male, median 56 years, median follow-up 9 years) and 919 relatives (45% male, median 42 years) were studied. A higher proband age at diagnosis was associated with more left ventricular (LV) outflow tract obstruction (OR 1.19/10-years), hypertension (OR 1.57/10-years) and atrial fibrillation (OR 1.24/10-years), but less LV hypertrophy (wall thickness ≥30 mm, OR 0.52/10-years), and ventricular arrhythmias (OR 0.81/10-years). Older age at diagnosis was associated with higher all-cause mortality, but similar cardiovascular mortality. Sarcomere variants were less common in the oldest versus youngest quartile of probands (13 vs. 42%, pConclusions The probands age at HCM diagnosis influenced clinical and genetic findings but the cardiovascular mortality and the yield of family screening were similar across all ages at diagnosis, supporting the presently recommended follow-up and family screening irrespective of the probands age at diagnosis. What is new? The study demonstrates that the age at diagnosis in HCM probands is significantly associated with distinct clinical and genetic profiles. It provides novel insights into family screening yield, revealing that despite differences in baseline genetic yield and clinical presentation across age groups, the overall prevalence and incidence of HCM in relatives remain similar regardless of the proband’s age at diagnosis. What are the clinical implications? These findings support the recommendation for consistent family screening in HCM, regardless of the age at which the proband is diagnosed, as the risk for developing HCM appears comparable across all age groups. The identification of age-related differences in clinical phenotype and genetic findings could inform tailored risk stratification and management strategies, potentially enhancing personalized care for HCM patients.

Background and Aims: Familial ST-depression syndrome (FSTD) is a recently identified inherited cardiac disease associated with arrhythmias and systolic dysfunction. The underlying genetic aetiology has remained elusive. This study aimed at finding the causative variant. Methods: A total of 67 FSTD patients (20 families) were studied. Linkage analysis and whole-genome sequencing (WGS) were initially performed. An identified non-coding variant was functionally characterized in AC16 human cardiomyocytes, muscle tissue, and human myocardium. In silico analyses, luciferase and dCas9-activator/repressor assays, protein–DNA experiments, chromosome conformation capture (4C), and RNA sequencing were also performed. Results: The electrocardiographic (ECG) phenotype was inherited in an autosomal dominant manner in all families. Linkage analysis revealed a single peak on chromosome 20, and WGS identified a single, rare, non-coding variant located 18 kb downstream of KCNB1 on chromosome 20 in all affected individuals. Perfect co-segregation with the ECG phenotype was observed together with full penetrance in all families. The variant creates a MEF2-binding site and presence of the variant allele or MEF2 co-expression enhanced transcriptional activity. dCas9-activator/repressor assays showed that KCNB1 was the only gene consistently regulated by the locus and 4C experiments in AC16 cells and human muscle tissue confirmed the locus–KCNB1 promoter interaction. Expression analysis in human endocardial tissue did not document any change in gene expression likely explained by expressional heterogeneity. Conclusions: A gain-of-function enhancer variant creates a hyperactive regulatory locus that interacts with the KCNB1 promoter and causes FSTD. This is the first time that KCNB1 has been implicated in human cardiac electrophysiology and arrhythmogenesis.

Background: The diagnostic role of signal‐averaged ECG (SAECG) in arrhythmogenic right ventricular cardiomyopathy (ARVC) has lately been questioned. We assessed the value of SAECG‐derived late ventricular potentials (LP) in ARVC diagnosis and its association with disease manifestations. Methods and Results: Patients with definite ARVC diagnosis or genotype‐positive family members who underwent SAECG were included in register‐based observational study (n=357, mean age 41 years, 47% female, 43% probands). LP and terminal activation duration (TAD) were defined by Task Force Criteria 2010. We assessed the association of TAD and LP with structural RV abnormalities and ventricular tachycardia (VT), defined as sustained VT, appropriate implantable cardioverter‐defibrillator shock, aborted cardiac arrest, or sudden cardiac death, at diagnosis. LP were documented in 210 patients (59%) and abnormal TAD in 66 patients (18%). Each of the SAECG parameters was significantly associated with definite ARVC diagnosis in receiver‐operator characteristics curve analysis with area under the curve between 0.67 and 0.74. Exclusion of SAECG from diagnostic workup led to reclassification of 37 patients (16%) from definite to borderline ARVC (13 probands, 9 of whom had prevalent VT). Ninety patients (25%) had history of VT. LP, but not TAD, were associated with VT (adjusted odds ratio [OR _adj ], 2.42 [95%CI, 1.07–5.48]). LP had lower specificity (72% versus 97%) but higher sensitivity (71% versus 25%) for association with RV structural abnormalities than TAD. Conclusions: In the Nordic ARVC cohort SAECG‐derived LP are associated with VT and structural RV abnormalities and were critical for ascertainment of ARVC diagnosis in 16% of patients with narrow QRS complexes, including 8% of all probands.