Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers.

Formin homology 2 domain-containing 3 (FHOD3) gene has emerged as one of the main non-sarcomeric genes associated with hypertrophic cardiomyopathy (HCM), but no cases of biallelic variants associated with disease have been described to date. From 2014 until 2021, FHOD3 was evaluated in our center by next-generation sequencing in 22 806 consecutive unrelated probands. The p.Arg637Gln variant in FHOD3 was enriched in our HCM cohort (284 of 9668 probands; 2.94%) compared with internal controls (64 of 11 480; 0.59%) and gnomAD controls (373 of 64 409; 0.58%), with ORs of 5.40 (95% CI: 4.11 to 7.09) and 5.19 (95% CI: 4.44 to 6.07). The variant affects a highly conserved residue localised in a supercoiled alpha helix considered a clustering site for HCM variants, and in heterozygosis can act as a predisposing factor (intermediate-effect variant) for HCM, with an estimated penetrance of around 1%. Additionally, seven homozygous carriers of p.Arg637Gln in FHOD3 were identified. All but one (unaffected) showed an early presentation and a severe HCM phenotype. All this information suggest that p.Arg637Gln variant in FHOD3 is a low-penetrant variant, with an intermediate effect, that contributes to the development of HCM in simple heterozygosis, being associated with a more severe phenotype in homozygous carriers.

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

Endomyocardial biopsy-confirmed myocarditis and inflammatory cardiomyopathy: clinical profile and prognosis.

INTRODUCTION AND OBJECTIVES: Endomyocardial biopsy (EMB) is the only technique able to establish an etiological diagnosis of myocarditis or inflammatory cardiomyopathy (ICM). The aim of this study was to analyze the clinical profile, outcomes, and prognostic factors of patients with suspected myocarditis/ICM undergoing EMB. METHODS: We retrospectively analyzed the clinical characteristics, histological findings, and follow-up data of all patients with suspected myocarditis or ICM who underwent EMB between 1997 and 2019 in a Spanish tertiary hospital. The diagnostic yield was compared using the Dallas criteria vs immunohistochemical criteria (IHC). RESULTS: A total of 99 patients underwent EMB (67% male; mean age, 42±15 years; mean left ventricular ejection fraction [LVEF], 34%±14%). Myocarditis or ICM was confirmed in 28% with application of the Dallas criteria and in 54% with the IHC criteria (P <.01). Lymphocytic myocarditis was diagnosed in 47 patients, eosinophilic myocarditis in 6, sarcoidosis in 3, and giant cell myocarditis in 1 patient. After a median follow-up of 18 months, 23 patients (23%) required heart transplant (HTx), a left ventricular assist device (LVAD), and/or died. Among the patients with IHC-confirmed myocarditis, 21% required HTx/LVAD or died vs 7% of those without inflammation (P=.056). The factors associated with a worse prognosis were baseline LVEF ≤ 30%, left ventricular end-diastolic diameter ≥ 60mm, and NYHA III-IV, especially in the presence of inflammation. CONCLUSIONS: EMB allows an etiological diagnosis in more than half of patients with suspected myocarditis/ICM when IHC techniques are used. IHC-confirmed inflammation adds prognostic value and helps to identify patients with a higher probability of developing complications.

Prognosis of Transthyretin Cardiac Amyloidosis Without Heart Failure Symptoms.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers. Objectives: The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms. Methods: Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers. Results: A total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82; P = 0.019) and remained significant after adjusting for sex, age, ATTR-CM type, and estimated glomerular filtration rate (HR: 0.18; 95% CI: 0.06-0.55; P = 0.002). Conclusions: After a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis.

Combination of late gadolinium enhancement and genotype improves prediction of prognosis in non-ischaemic dilated cardiomyopathy.

AIMS: Genotype and left ventricular scar on cardiac magnetic resonance (CMR) are increasingly recognized as risk markers for adverse outcomes in non-ischaemic dilated cardiomyopathy (DCM). We investigated the combined influence of genotype and late gadolinium enhancement (LGE) in assessing prognosis in a large cohort of patients with DCM. METHODS AND RESULTS: Outcomes of 600 patients with DCM (53.3 ± 14.1 years, 66% male) who underwent clinical CMR and genetic testing were retrospectively analysed. The primary endpoints were end-stage heart failure (ESHF) and malignant ventricular arrhythmias (MVA). During a median follow-up of 2.7 years (interquartile range 1.3-4.9), 24 (4.00%) and 48 (8.00%) patients had ESHF and MVA, respectively. In total, 242 (40.3%) patients had pathogenic/likely pathogenic variants (positive genotype) and 151 (25.2%) had LGE. In survival analysis, positive LGE was associated with MVA and ESHF (both, p < 0.001) while positive genotype was associated with ESHF (p = 0.034) but not with MVA (p = 0.102). Classification of patients according to genotype (G+/G-) and LGE presence (L+/L-) revealed progressively increasing events across L-/G-, L-/G+, L+/G- and L+/G+ groups and resulted in optimized MVA and ESHF prediction (p < 0.001 and p = 0.001, respectively). Hazard ratios for MVA and ESHF in patients with either L+ or G+ compared with those with L-/G- were 4.71 (95% confidence interval: 2.11-10.50, p < 0.001) and 7.92 (95% confidence interval: 1.86-33.78, p < 0.001), respectively. CONCLUSION: Classification of patients with DCM according to genotype and LGE improves MVA and ESHF prediction. Scar assessment with CMR and genotyping should be considered to select patients for primary prevention implantable cardioverter-defibrillator placement.

Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy.

BACKGROUND: Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular systolic dysfunction (LVSD), its result is negative in a significant number of patients, limiting its widespread adoption. OBJECTIVES: This study sought to develop and externally validate a score that predicts the probability for a positive genetic test result (G+) in DCM/LVSD. METHODS: Clinical, electrocardiogram, and echocardiographic variables were collected in 1,015 genotyped patients from Spain with DCM/LVSD. Multivariable logistic regression analysis was used to identify variables independently predicting G+, which were summed to create the Madrid Genotype Score. The external validation sample comprised 1,097 genotyped patients from the Maastricht and Trieste registries. RESULTS: A G+ result was found in 377 (37%) and 289 (26%) patients from the derivation and validation cohorts, respectively. Independent predictors of a G+ result in the derivation cohort were: family history of DCM (OR: 2.29; 95% CI: 1.73-3.04; P < 0.001), low electrocardiogram voltage in peripheral leads (OR: 3.61; 95% CI: 2.38-5.49; P < 0.001), skeletal myopathy (OR: 3.42; 95% CI: 1.60-7.31; P = 0.001), absence of hypertension (OR: 2.28; 95% CI: 1.67-3.13; P < 0.001), and absence of left bundle branch block (OR: 3.58; 95% CI: 2.57-5.01; P < 0.001). A score containing these factors predicted a G+ result, ranging from 3% when all predictors were absent to 79% when ≥4 predictors were present. Internal validation provided a C-statistic of 0.74 (95% CI: 0.71-0.77) and a calibration slope of 0.94 (95% CI: 0.80-1.10). The C-statistic in the external validation cohort was 0.74 (95% CI: 0.71-0.78). CONCLUSIONS: The Madrid Genotype Score is an accurate tool to predict a G+ result in DCM/LVSD.

Association of Genetic Variants With Outcomes in Patients With Nonischemic Dilated Cardiomyopathy.

BACKGROUND: The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled. OBJECTIVES: The study sought to assess the prognostic impact of disease-causing genetic variants in DCM. METHODS: Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR). RESULTS: After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene. CONCLUSIONS: In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene.