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Dilated cardiomyopathy (DCM) can be caused by truncating variants in the filamin C gene (FLNC). A new pathogenic FLNC variant, c.6864_6867dup, p.(Val2290Argfs∗23), was recently identified in Dutch patients with DCM. The report aimed to evaluate the phenotype of FLNC variant carriers and to determine whether this variant is a founder variant. Clinical and genetic data were retrospectively collected from variant carriers. Cardiovascular magnetic resonance studies were reassessed. Haplotypes were reconstructed to determine a founder effect. The geographical distribution and age of the variant were determined. Thirty-three individuals (of whom 23 [70%] were female) from 9 families were identified. Sudden cardiac death was the first presentation in a carrier at the age of 28 years. The median age at diagnosis was 41 years (range 19–67 years). The phenotype was heterogeneous. DCM with left ventricular dilation and reduced ejection fraction (<45%) was present in 11 (33%) individuals, 3 (9%) of whom underwent heart transplantation. Cardiovascular magnetic resonance showed late gadolinium enhancement in 13 (65%) of the assessed individuals, primarily in a ringlike distribution. Nonsustained ventricular arrhythmias were detected in 6 (18%), and 5 (15%) individuals received an implantable cardioverter-defibrillator. A shared haplotype spanning 2.1 Mb was found in all haplotyped individuals. The variant originated between 275 and 650 years ago. The pathogenic FLNC variant c.6864_6867dup, p.(Val2290Argfs∗23) is a founder variant originating from the south of the Netherlands. Carriers are susceptible to developing heart failure and ventricular arrhythmias. The cardiac phenotype is characterized by ringlike late gadolinium enhancement, even in individuals without significantly reduced left ventricular function. [Display omitted] [ABSTRACT FROM AUTHOR]

Truncating variants in filamin C (FLNC) can cause arrhythmogenic cardiomyopathy (ACM) through haploinsufficiency. Noncanonical splice-altering variants may contribute to this phenotype. The purpose of this study was to investigate the clinical and functional consequences of a recurrent FLNC intronic variant of uncertain significance (VUS), c.970-4A>G. Clinical data in 9 variant heterozygotes from 4 kindreds were obtained from 5 tertiary health care centers. We used in silico predictors and functional studies with peripheral blood and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Isolated RNA was studied by reverse transcription polymerase chain reaction. iPSC-CMs were further characterized at baseline and after nonsense-mediated decay (NMD) inhibition, using quantitative polymerase chain reaction (qPCR), RNA-sequencing, and cellular electrophysiology. American College of Medical Genetics and Genomics (ACMG) criteria were used to adjudicate variant pathogenicity. Variant heterozygotes displayed a spectrum of disease phenotypes, spanning from mild ventricular dysfunction with palpitations to severe ventricular arrhythmias requiring device shocks or progressive cardiomyopathy requiring heart transplantation. Consistent with in silico predictors, the c.970-4A>G FLNC variant activated a cryptic splice acceptor site, introducing a 3-bp insertion containing a premature termination codon. NMD inhibition upregulated aberrantly spliced transcripts by qPCR and RNA-sequencing. Patch clamp studies revealed irregular spontaneous action potentials, increased action potential duration, and increased sodium late current in proband-derived iPSC-CMs. These findings fulfilled multiple ACMG criteria for pathogenicity. Clinical, in silico , and functional evidence support the prediction that the intronic c.970-4A>G VUS disrupts splicing and drives ACM, enabling reclassification from VUS to pathogenic. [ABSTRACT FROM AUTHOR]

• A substantial number of patients with bicuspid aortic valve (BAV) have elevated levels of NT-proBNP, hsTnT, and hs-CRP. • Higher NT-proBNP is associated with aortic valve stenosis and regurgitation in BAV patients. • Higher hsTnT is associated with aortic valve regurgitation in BAV patients. • BAV patients have lower transforming growth factor-beta 1 levels than healthy controls. • This is the first study evaluating associations between biomarkers and disease stage in BAV patients. Patients with a bicuspid aortic valve (BAV) are at risk of developing valve deterioration and aortic dilatation. We aimed to investigate whether blood biomarkers are associated with disease stage in patients with BAV. Serum levels of high sensitivity C-reactive protein (hsCRP), high sensitivity troponin T (hsTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and total transforming growth factor-beta 1 (TGF-ß1) were measured in adult BAV patients with valve dysfunction or aortic pathology. Age-matched general population controls were included for TGFß-1 measurements. Correlation analyses and multivariable linear regression were used to determine the association between (2log-transformed) biomarker levels and aortic valve regurgitation, aortic valve stenosis, aortic dilatation, or left ventricular function. hsCRP and hsTnT were measured in the total group of 183 patients (median age 34 years, 25th–75th percentile 23−46), NT-proBNP in 162 patients, and TGF-ß1 beta in 108 patients. Elevated levels of NT-proBNP were found in 20% of the BAV patients, elevated hsTnT in 6%, and elevated hsCRP in 7%. Higher hsTnT levels were independently associated with aortic regurgitation [odds ratio per doubling (OR 2log) 1.34, 95% CI 1.01;1.76] and higher NT-proBNP levels with aortic valve maximal velocity (ß 2log 0.17, 95%CI 0.07;0.28) and aortic regurgitation (OR 2log 1.41, 95%CI 1.11;1.79). Both BAV patients with (9.9 ± 2.7 ng/mL) and without aortic dilatation (10.4 ± 2.9 ng/mL) showed lower TGF-ß1 levels compared to general population controls (n = 85, 11.8 ± 3.2 ng/mL). Higher NT-proBNP and hsTNT levels were associated with aortic valve disease in BAV patients. TGF-ß1 levels were lower in BAV patients than in the general population, and not related to aortic dilatation. Longitudinal data are needed to further investigate the prognostic value of biomarkers in these patients. [ABSTRACT FROM AUTHOR]

Background: Aneurysms-osteoarthritis syndrome (AOS), caused by SMAD3 mutations, is a recently described autosomal dominant condition characterized by aneurysms throughout the arterial tree in combination with osteoarthritis. The objective of the present study was to evaluate progression rate of aortic dilation and surgical outcome in AOS patients. Methods: All AOS patients are regularly monitored according to our clinical AOS protocol. Patients with at least two follow-up visits or who underwent aortic root surgery during follow-up were included in this cohort study. Clinical and surgical data were obtained from chart abstraction. Results: We included 22 patients (aged 38 ± 15 years; 41% male) with the molecular diagnosis of AOS. Follow-up duration was 3.3 years (interquartile range, 1.6 to 5.1). In the 17 patients who were managed conservatively, aortic root diameter increased from 37.5 ± 5.1 mm at baseline to 40.3 ± 6.2 mm at follow-up (p = 0.008). Progression rate of aortic dilation was highest at the level of the sinus of Valsalva (2.5 ± 5.8 mm per year) and significantly correlated with the initial diameter (r = 0.603, p = 0.017). Ten patients successfully underwent valve-sparing aortic root replacement, 5 after previous watchful waiting. Mean preoperative aortic diameter was 46.6 ± 4.0 mm. The operations were not complicated by fragility of tissue. After a postoperative period of 2.8 years (interquartile range, 0.7 to 5.4), no mortality or reoperations had occurred, and all patients remained asymptomatic. Conclusions: Aneurysm growth in AOS patients can be fast and unpredictable, warranting extensive and frequent cardiovascular monitoring. Valve-sparing aortic root replacement is a safe and effective procedure for the management of aortic root aneurysms in AOS patients. [ABSTRACT FROM AUTHOR]

Background: There is overlap in genetic causes and cardiac features in noncompaction cardiomyopathy (NCCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM).Objectives: The goal of this study was to predict phenotype and outcome in relatives according to the clinical features and genotype of NCCM index cases.Methods: Retrospective DNA and cardiac screening of relatives of 113 families from 143 index patients were used to classify NCCM cases according to the cardiac phenotype. These cases were classified as isolated NCCM, NCCM with left ventricular (LV) dilation (DCM), and NCCM with LV hypertrophy (HCM).Results: In 58 (51%) families, screening identified 73 relatives with NCCM and 34 with DCM or HCM without NCCM. The yield of family screening was higher in families with a mutation (p < 0.001). Fifty-four families had a mutation. Nonpenetrance was observed in 37% of the relatives with a mutation. Index cases were more often symptomatic than affected relatives (p < 0.001). NCCM with DCM (53%) was associated with LV systolic dysfunction (p < 0.001), increased risk for major adverse cardiac events, mutations in the tail of MYH7 (p < 0.001), and DCM without NCCM in relatives (p < 0.001). Isolated NCCM (43%) was associated with a milder course, mutations in the head of MYH7, asymptomatic NCCM (42%) (p = 0.018), and isolated NCCM in relatives (p = 0.004). NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in relatives (p < 0.001).Conclusions: The phenotype of relatives may be predicted according to the NCCM phenotype and the mutation of index patients. NCCM phenotypes were related to outcome. In this way, clinical and genetic features of index patients may help prediction of outcome in relatives. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was describe the cardiovascular phenotype of the aneurysms-osteoarthritis syndrome (AOS) and to provide clinical recommendations. Background: AOS, caused by pathogenic SMAD3 variants, is a recently described autosomal dominant syndrome characterized by aneurysms and arterial tortuosity in combination with osteoarthritis. Methods: AOS patients in participating centers underwent extensive cardiovascular evaluation, including imaging, arterial stiffness measurements, and biochemical studies. Results: We included 44 AOS patients from 7 families with pathogenic SMAD3 variants (mean age: 42 ± 17 years). In 71%, an aortic root aneurysm was found. In 33%, aneurysms in other arteries in the thorax and abdomen were diagnosed, and in 48%, arterial tortuosity was diagnosed. In 16 patients, cerebrovascular imaging was performed, and cerebrovascular abnormalities were detected in 56% of them. Fifteen deaths occurred at a mean age of 54 ± 15 years. The main cause of death was aortic dissection (9 of 15; 60%), which occurred at mildly increased aortic diameters (range: 40 to 63 mm). Furthermore, cardiac abnormalities were diagnosed, such as congenital heart defects (6%), mitral valve abnormalities (51%), left ventricular hypertrophy (19%), and atrial fibrillation (22%). N-terminal brain natriuretic peptide (NT-proBNP) was significantly higher in AOS patients compared with matched controls (p < 0.001). Aortic pulse wave velocity was high-normal (9.2 ± 2.2 m/s), indicating increased aortic stiffness, which strongly correlated with NT-proBNP (r = 0.731, p = 0.005). Conclusions: AOS predisposes patients to aggressive and widespread cardiovascular disease and is associated with high mortality. Dissections can occur at relatively mildly increased aortic diameters; therefore, early elective repair of the ascending aorta should be considered. Moreover, cerebrovascular abnormalities were encountered in most patients. [ABSTRACT FROM AUTHOR]