Pulmonary arterial hypertension (PAH) is a rare disease caused by pulmonary vascular remodeling. Current vasodilator treatments have substantially improved patients' survival. This improved survival ...has led to the appearance of complications related to conditions previously underdiagnosed or even ignored, such as pulmonary artery aneurysm (PAA). The presence of a dilated pulmonary artery has been shown to be related to an increased risk of sudden cardiac death among PAH patients. This increased risk could be associated to the development of left main coronary artery compression or pulmonary artery dissection. Nevertheless, very little is currently known about the molecular mechanisms related to PAA. Thoracic aortic aneurysm (TAA) is a well-known condition with an increased risk of sudden death caused by acute aortic dissection. TAA may be secondary to chronic exposure to classic cardiovascular risk factors. In addition, a number of genetic variants have been shown to be related to a marked risk of TAA and dissection as part of multisystemic syndromes or isolated familial TAA. The molecular pathways implied in the development of TAA have been widely studied and described. Many of these molecular pathways are involved in the pathogenesis of PAH and could be involved in PAA. This review aims to describe all these common pathways to open new research lines that could help lead to a better understanding of the pathophysiology of PAH and PAA and their clinical implications.
TTN gene truncating variants (TTNtv) are a frequent cause of dilated cardiomyopathy (DCM). However, there are discrepant data on the associated prognosis. Our objectives were to describe the ...prevalence of TTNtv in our cohort and to compare the clinical course with that described in the literature.
We included patients with DCM and genetic testing performed using next-generation sequencing. Through a systematic literature research, we collected information about carriers and affected relatives with TTNtv. We compared the cumulative percentage of affected carriers and the survival free of cardiovascular death.
One hundred and ten DCM patients were evaluated. A total of 13 TTNtv distributed in 14 probands were identified (12.7%). We found a 21.4% prevalence in familial cases. No significant differences in the relation between age and clinical disease expression were identified. Survival free of cardiovascular death curves constructed from data in the literature seems not to overestimate the risk in our population.
The identification of TTNtv in patients with DCM is frequent and provides relevant information about the disease prognosis. The risk of cardiovascular death should not be underestimated. Age related penetrance need to be considered in the familial evaluation.
•Identification of TTN gene truncating variants in DCM patients is frequent.•Limited information about prognosis in genetic carriers.•Risk of cardiovascular death and arrhythmias is high in these patients.•Incomplete and age related penetrance; follow up should be recommended.
Calmodulin 1, 2 and 3 (CALM) mutations have been found to cause cardiac arrest in children at a very early age. The underlying aetiology described is long QT syndrome (LQTS), catecholaminergic ...polymorphic ventricular tachycardia (CPVT) and idiopathic ventricular fibrillation (IVF). Little phenotypical data about CALM2 mutations is available.
The aim of this paper is to describe the clinical manifestations of the Asn98Ser mutation in CALM2 in two unrelated children in southern Spain with apparently unexplained cardiac arrest/death.
Two unrelated children aged 4 and 7, who were born to healthy parents, were studied. Both presented with sudden cardiac arrest. The first was resuscitated after a VF episode, and the second died suddenly. In both cases the baseline QTc interval was within normal limits. Peripheral blood DNA was available to perform targeted gene sequencing.
The surviving 4-year-old girl had a positive epinephrine test for LQTS, and polymorphic ventricular ectopic beats were seen on a previous 24-hour Holter recording from the deceased 7-year-old boy, suggestive of a possible underlying CPVT phenotype. A p.Asn98Ser mutation in CALM2 was detected in both cases. This affected a highly conserved across species residue, and the location in the protein was adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain, predicting a high pathogenic effect.
Human calmodulin 2 mutation p.Asn98Ser is associated with sudden cardiac death in childhood with a variable clinical penetrance. Our results provide new phenotypical information about clinical behaviour of this mutation.
Abstract
Aims
Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according ...to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns.
Methods and results
Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE.
Conclusion
LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing.
Graphical Abstract
Graphical Abstract
A cohort of 577 individuals with DCM phenotyped with genetic testing and CMR was analysed. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. LGE patterns in genetic DCM have a specific distribution. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. Abbreviations: CMR, cardiovascular magnetic resonance; DCM, dilated cardiomyopathy; HR, hazard ratio; IQR, interquartile range; LGE, late gadolinium enhancement; L.Midwall, lineal midwall; LVEF, left ventricular ejection fraction; MVA, major ventricular arrhythmias; RV, right ventricle.
Up to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. Mutations in CSRP3 have been associated with HCM, but evidence supporting ...pathogenicity is inconclusive. In this study, we describe an HCM cohort with a missense variant in CSRP3 (p.Cys150Tyr) with supporting evidence for pathogenicity and a description of the associated phenotype.
CSRP3 was sequenced in 6456 index cases with a diagnosis of HCM and in 5012 probands with other cardiomyopathies. In addition, 3372 index cases with hereditary cardiovascular disorders other than cardiomyopathies (mainly channelopathies and aortopathies) were used as controls.
The p.(Cys150Tyr) variant was identified in 11 unrelated individuals of the 6456 HCM probands, and it was not identified in patients with other cardiomyopathies (p < 0.0001) or in our control population (p < 0.0001). Ten of the index cases were heterozygous and one was homozygous. Homozygous had a more severe phenotype. Family screening identified 17 other carriers. Wild-type individuals showed no signs of disease. The mean age at diagnosis of affected individuals was 55 ± 13 years, and the mean left ventricular wall thickness was 18 ± 3 mm. The variant showed highly age-dependent penetrance. After a mean follow-up of 11 (±8) years, no adverse events were reported in any of the HCM patients.
The p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hypertrophic cardiomyopathy in heterozygous carriers.
Truncating TTN variants (TTNtv) are the main cause of dilated cardiomyopathy (DCM). The dynamic nature of this entity has previously been described. Based on own empirical observations and previous ...evidences, this study assessed repolarisation patterns and the possible association with morphological and functional status of TTNtv-DCM patients.
Electrocardiograms (ECGs) of index patients with TTNtv-DCM and their relatives were included and matched in time with an echocardiogram. All individuals were classified into five phenotype groups: 1) Reduced left ventricular ejection fraction (LVEF <50%); 2) Recovered LVEF: at least 10% increase and LVEF >30% after optimal medical treatment; 3) Borderline phenotype (mildly enlarged ventricle and/or hyper-trabeculation); 4) Genotype positive, phenotype negative; and 5) Non-carriers. All electrocardiograms were evaluated by two blinded observers in qualitative and quantitative terms T index (mm)=Σ T-wave amplitude (V5, V6, II, aVF) and these data were compared with demographic and clinical information. The Δ T-index was calculated in those individuals with more than one electrocardiogram.
Seventy-eight (78) electrocardiograms were included (46% female, mean age 50 years). T-index and prevalence of an abnormal T-wave had significantly different results among the groups (p<0.0001). Age and haemodynamic factors were shown to be ECG-modifiers, especially in phenotype-negative patients. T-index enabled individuals with reduced LVEF (<2.5) to be identified and to differentiate patients with favourable and unfavourable responses to treatment (Δ T index >3.5 and ≤2, respectively).
Repolarisation changes enabled characterisation of the spectrum of TTNtv-DCM. The T-index identified potential carriers and patients with the worst profiles of the spectrum of the disease.
Pulmonary Arterial Hypertension (PAH) is a severe complication of Connective Tissue Disease (CTD), with remarkable morbidity and mortality. However, the molecular and genetic basis of CTD-PAH remains ...incompletely understood. This study aimed to screen for genetic defects in a cohort of patients with CTD-PAH, using a PAH-specific panel of 35 genes. During recruitment, 79 patients were studied, including 59 Systemic Sclerosis patients (SSc) and 69 females. Disease-associated variants were observed in nine patients: 4 pathogenic/likely pathogenic variants in 4 different genes (TBX4, ABCC8, KCNA5 and GDF2/BMP9) and 5 Variants of Unknown Significance (VUS) in 4 genes (ABCC8, NOTCH3, TOPBP1 and CTCFL). One patient with mixed CTD had a frameshift pathogenic variant in TBX4. Two patients with SSc-PAH carried variants in ABCC8. A patient diagnosed with Systemic Lupus Erythematous (SLE) presented a pathogenic nonsense variant in GDF2/BMP9. Another patient with SSc-PAH presented a pathogenic variant in KCNA5. Four patients with SSc-PAH carried a VUS in NOTCH1, CTCFL, CTCFL and TOPBP1, respectively. These findings suggest that genetic factors may contribute to Pulmonary Vascular Disease (PVD) in CTD patients.
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