Cardiogenetics

Purpose: To evaluate the clinical features, laboratory and instrumental tests results and the effectiveness of complex treatment in a patient with multiple etiologies of dilated cardiomyopathy (DCM) with a high risk of sudden cardiac death. Methods: Female patient was 34 years old. Follow up period was seven years. Since the age of 23 (after a respiratory infection), chest pains and shortness of breath appeared. Coronary arteries were intact. After syncope in 2013, Holter-ECG was performed: 2048 premature ventricular beats (PVBs)/day and episode of sustained ventricular tachycardia (VT, 1 min) were registered. MRI was performed, and a cardioverter defibrillator (ICD) was implanted. Results: ECG showed low QRS voltage and negative T waves in leads V2-V6, III, aVF. In signal-averaged ECG, late potentials were detected. Echocardiography (EchoCG) demonstrated left and right ventricular dilatation, diffuse reduction of left ventricular (LV) contractility and multiple pseudochordae in LV. MRI showed LV noncompaction (LVNC), thickening of the epicardial fat and hypo-/dyskinesia of the anterior wall of the right ventricular (RV), dilatation of both ventricles with decrease of their ejection fraction and subepicardial gadolinium enhancement in the early and late phase in the LV, intraventricular septum and the free walls of the RV. The presence of LVNC was confirmed by cardiac computed tomography (CT). Late contrast enhancement in the middle and subendocardial layer of the LV was observed as well. The level of anticardiac antibodies was high (1:160–1:320). The reasons for statement of a possible diagnosis of myocarditis in this case were the connection of the onset of symptoms with viral infection, high titers of anticardiac antibodies, and early and late subepicardial contrast enhancement by MRI and CT. The endomyocardial biopsy was obtained, and subendocardial lipomatosis, separation of myocardium by fibrous septa, lymphocytic infiltrates (more than 14 cells/mm²) and vasculitis were found. Viral genome in myocardium was not detected. A new splicing mutation in the desmoplakin (DSP) gene was found (NM_004415.4: c.1141-2A>G/N (rs794728111)). Combination of arrhythmogenic right ventricular cardiomyopathy (ARVC), LVNC and myocarditis was diagnosed. Immunosuppressive therapy (prednisone and azathioprine) was prescribed, LV ejection fraction stabilized at the level of 40%. The appropriate shocks of the ICD due to sustainedVT (HR 210/min) with transformation into ventricular fibrillation were recorded twice. For this reason, sotalol was temporarily replaced with amiodarone. After the suppression of myocarditis activity, sustained VT and ICD interventions were not observed. Conclusions: In a young patient with arrhythmogenic syncope and DCM syndrome, a combination of ARVC (two major and three minor criteria, definite diagnosis) and LVNC with the biopsy proved virus-negative chronic myocarditis was diagnosed. DCM as a syndrome can have multiple causes, and the combination of myocarditis and primary cardiomyopathy is not rare. LVNC can be observed in patients with typical desmosomal protein mutations. The use of immunosuppressive therapy led to the stabilization of heart failure and decreased the risk of arrhythmic events. Full article

Heart involvement in Cardiac Amyloidosis (CA) results in a worsening of the prognosis in almost all patients with both light-chain (AL) and transthyretin amyloidosis (ATTR). The mainstream CA is a restrictive cardiomyopathy with hypertrophic phenotype at cardiac imaging that clinically leads to heart failure with preserved ejection fraction (HFpEF). An early diagnosis is essential to reduce cardiac damage and to improve the prognosis. Many therapies are available, but most of them have late benefits to cardiac function; for this reason, novel therapies are going to come soon. Full article

We describe a 55 year old male diagnosed with cardiomyopathy due to Fabry disease. Biochemical testing of blood spot and plasma showed low-normal alpha-galactosidase A (α-Gal A) levels. Genetic testing revealed somatic mosaicism for GLA c.901C>T, p.(Arg301Ter). Usually, males with Fabry disease due to loss of function variants in GLA show symptoms of the multisystemic features of the condition early in life, and have very low levels of the α-Gal A enzyme. This demonstrates that the diagnosis of Fabry disease in males with cardiomyopathy should still be considered even in the context of a normal plasma enzyme assay. Full article

Objectives: Fetuin-A is a circulating calcification inhibitor that prevents coronary artery calcification (CAC) by increasing calcium phosphate solubility and inhibiting VSMC differentiation and apoptosis. In this study, we investigated the correlation between rs4918 and CAC in patients with coronary artery disease (CAD). Methods: Forty-two healthy individuals and eighty-one CAD patients were recruited in the present study. The CAC score (CACS) was measured by CT angiography and the genotype analysis of rs4918 single-nucleotide polymorphism SNP was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Results: The CACS was significantly higher in CAD patients compared to healthy individuals (p < 0.001); however, there was no significant difference between the mean CACS in the presence and absence of rs4918 (p = 0.792). The mean calcium score of the left main coronary artery (LMCA) was significantly lower in carriers of the rs4918 allele (p = 0.036). The frequency of rs4918 SNP was almost similar in the control group and CAD patients (p = 0.846). Conclusions: in patients with CAD, we found no significant association between rs4918 SNP and CACS, indicating that carriers of this allele are not at increased risk of developing cardiovascular diseases compared with those without. Full article

Anomalous Left Coronary Artery from the Pulmonary Artery (ALCAPA) is a rare coronary artery anomaly which accounts for 0.25–0.5% of all congenital cardiac diseases, where most die within the first year of life. We present a case report of a 50-year-old lady who presented to hospital with persistent palpitations. Her admission electrocardiogram found her to be in Atrial Fibrillation (AF). She was rate-controlled and subsequently discharged. Despite that, she represented with further episodes of AF and was referred for an outpatient transthoracic echocardiogram. This revealed a dilated right coronary artery, retrograde flow in the left coronary artery and collateral flow in the myocardium. To investigate, the patient had undergone further imaging which confirmed the diagnosis. As such, she was later shortlisted for surgical intervention. Conclusively, our case exemplifies the role of multimodal imaging to identify the features of ALCAPA and may be useful for the purposes of surgical intervention. Full article

We report the first case of a 294 kb loss, notable for including the entirety of GPD1L, on chromosome 3p22.3—p24 in a 3-year-old girl with multiple congenital anomalies including absent left foot, single umbilical artery, bilateral vesico-ureteral reflux, rectovaginal fistula, and imperforate anus. Although GPD1L mutations have been associated with cardiac arrhythmias, including Brugada syndrome and sudden unexpected infant death syndrome, full deletions in the GPD1L gene have not been reported neither the patient nor her mother, who was later identified to carry the variant, have any signs or symptoms of Brugada syndrome. This may indicate these individuals have findings that have not yet been identified, full gene deletions of GDP1L are not necessarily disease causing, or there is incomplete penetrance of this gene or cardiac manifestations can occur at a later age. Full article

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme, agalactosidase A. The inadequate enzymatic activity leads to systemic storage of glycosphingolipids, mostly globotriaosylceramide, in the lysosomes. As of now, enzyme replacement therapy is the only approved treatment for AFD. However, it does not induce a complete and lasting response in several clinical contexts. Genemediated enzyme replacement is an emerging approach that could overcome these limits. The single gene nature of AFD enhances the possibility to transfect and modify a small number of cells, making them capable to affect the correction of a larger number of cells. This review summarizes the history and the state of the art of gene therapy in AFD, showing potential benefits and limits. Full article

Heterozygous RYR2 missense variants cause catecholaminergic polymorphic ventricular tachycardia. Rarely, loss of function variants can result in ventricular arrhythmias. We used splice prediction tools and an ex vivo splicing assay to investigate whether RYR2 missense variants result in altered splicing. Ten RYR2 variants were consistently predicted to disrupt splicing, however none altered splicing in the splicing assay. In summary, missense RYR2 variants are unlikely to cause disease by altered splicing. Full article

Intense athletic training and competition can rarely result in sudden cardiac death (SCD). Despite the introduction of pre-participation cardiovascular screening, especially among young competitive athletes, sport-related SCD remains a debated issue among medical personnel, sports communities and laypersons alike, and generates significant media attention. The most frequent cause of SCD is a hidden inherited cardiomyopathy, the athletes may not even be aware of. Predictive medicine, by searching the presence of pathogenic alterations in cardiac genes, may be an integrative tool, besides the conventional ones used in cardiology (mainly electro and echocardiogram), to reach a definitive diagnosis in athletes showing signs/symptoms, even borderline, of inherited cardiomyopathy/ channelopathy, and in athletes presenting family history of SCD and/or of hereditary cardiac disease. In this review, we revised the molecular basis of the major cardiac diseases associated to sudden cardiac death and the clinical molecular biology approach that can be used to perform risk assessment at DNA level of sudden cardiac death, contributing to the early implementation of adequate therapy. Alterations can occur in ion channel genes, in genes encoding desmosomal and junctional proteins, sarcomeric and Z-disc proteins, proteins for the cytoskeleton and the nuclear envelope. The advent of next generation sequencing (NGS) technology has provided the means to search for mutations in all these genes, at the same time. Therefore, this molecular approach should be the preferred methodology for the aforementioned purpose. Full article

Management of symptoms in patients with inoperable aortic stenosis is often hard in clinical practice. We report a case of a patient with Hutchinson-Gilford progeria syndrome and end-stage aortic stenosis, considered not suitable for surgical or percutaneous approach, to whom the administration of ranolazine resulted in a considerable improvement of angina, refractory to other treatments. Full article

The majority of familial noncompaction cardiomyopathy (NCCM) is explained by pathogenic variants in the same sarcomeric genes that are associated with hypertrophic (HCM) and dilated (DCM) cardiomyopathy. Pathogenic variants in the filamin C gene (FLNC) have been linked to HCM and DCM. We expand the spectrum of FLNC related cardiomyopathies by presenting two families with likely pathogenic FLNC variants showing familial segregation of NCCM and concurrent coarctation of the aorta and/or mitral valve abnormalities. Full article

Kearns-Sayre syndrome (KSS) is a rare mitochondrial disease in which cardiac involvement has been associated with poor prognosis. Although the most common clinical manifestation is progressive conduction system impairment, patients can suffer from ventricular arrhythmias. Yet, they show a high prevalence of sudden cardiac death, whose etiopathological mechanism is not completely understood. Cardiac magnetic resonance is a rising tool to detect subclinical heart involvement in many heart diseases and was recently able to detect nonischemic scar, which is an arrhythmogenic substrate, in patients affected by KSS. Full article

Carcinoid syndrome is a paraneoplastic condition, which usually affects the lungs or gastrointestinal tract but uncommonly cardiac valves can be involved, causing carcinoid heart disease. We describe a case of a 60-year-old man presented with a twelve-month history of worsening shortness of breath and decreased exercise tolerance. Investigations confirmed grade 1 metastatic neuroendocrine carcinoma (carcinoid tumour) of likely gastrointestinal tract origin. Two months after diagnosis he underwent successful tricuspid valve replacement and pulmonary root replacement. Cytoreductive surgery of the right lobe of the liver and the ileal primary is planned. Cardiac surgery is the only definitive treatment for carcinoid heart disease and should be considered in all those with symptoms and evidence of severe valvular disease. Full article