A Novel Homozygous PKP2 Variant in Severe Neonatal Non-compaction and Concomitant Ventricular Septal Defect: A Case Report

Left ventricular non-compaction (LVNC) is a rare and genetically heterogeneous cardiomyopathy. The disorder vastly affects infants and young children. Severe neonatal LVNC is relatively rare. The prevalence of genetic defects underlying pediatric and adult-onset LVNC is about 17–40%. Mutations of MYH7 and MYBPC3 sarcomeric genes are found in the vast majority of the positive pediatric cases. PKP2 encodes plakophilin-2, a non-sarcomeric desmosomal protein, which has multiple roles in cardiac myocytes including cell–cell adhesion, tightening gap junction, and transcriptional factor. Most of the reported PKP2 mutations are heterozygous missense and truncating variants, and they are associated with an adult-onset autosomal dominant disorder, namely arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Homozygous PKP2 mutations have been rarely described. Herein, we present a rare case of an infant with neonatal onset of congestive heart failure owing to severe LVNC and multiple muscular VSD. Medical treatments failed to control the heart failure and the patient died at 11 months of age. Whole-exome sequencing identified a novel homozygous PKP2 variant, c.1511-1G>C, in the patient. An mRNA analysis revealed aberrant transcript lacking exon 7, which was predicted to cause a frameshift and truncated peptide (p.Gly460GlufsTer2). The heterozygous parents had normal cardiac structures and functions as demonstrated by electrocardiogram and echocardiography. Pathogenic variants of sarcomeric genes analyzed were not found in the patient. We conducted a literature review and identified eight families with biallelic PKP2 mutations. We observed that three families (our included) with null variants were linked to lethal phenotypes, while homozygous missense mutations resulted in less severe manifestations: adolescent-onset ARVD/C and childhood-onset DCM. Our data support a previous notion that severe neonatal LVNC might represent a unique entity and had distinct genetic spectrum. In conclusion, the present study has extended the phenotypes and genotypes of PKP2-related disorders and lethal LVNC.

Long-term Results of Drug and Interventional Treatment in Patients with Morphologically Verified Idiopathic Arrhythmias

Aim. To study the late results of medical and interventional treatment in patients with morphologically verified nature of idiopathic arrhythmias.Methods. The prospective study included 20 patients (mean age 43.1±11.3 years, 10 female) with atrial fibrillation (AF), supraventricular and ventricular extrasystole, supraventricular and ventricular tachycardia, conduction disturbance without structural heart changes. In addition to the standard examination, the level of anti-heart antibodies was initially determined; endomyocardial biopsy (EMB) of the right ventricle with PCR study for the viral genome; DNA diagnostics (n=4), coronary angioraphy (n=6), skin biopsy (n=1) were performed. The median follow-up was 134 [128; 138] months.Results. By EMB in the initial examination were diagnosed: active (n=8)/borderline (n=3) infectious immune myocarditis; parvovirus-positive endomyocarditis (n=1); undifferentiated vasculitis (n=2); myocardial vasculitis (n=1); Fabry disease (n=1); arrhythmogenic right ventricular dysplasia (n=1); unspecified cardiomyopathy (n=2). Anti-heart antibodies were the most important in myocarditis diagnosis and monitoring. All patients with myocarditis/vasculitis (n=15) received its basic therapy: acyclovir (n=10); immunoglobulin G 10-12.5 g (n=2); hydroxychloroquine 200 mg/day (n=15); glucocorticoids (n=14); azathioprine 150 mg/day (n=2). The late results were evaluated in all patients with myocarditis. Initially, in 62.5% of patients a resistance of AF to all antiarrhythmic drugs was noted. After treatment the average frequency of AF paroxysms decreased (from 8 [5; 8] to 3 [1,25; 7,75] points). By the end of the follow-up, six patients underwent radiofrequency ablation (RFA) for AF, the full effect was achieved once. All patients without RFA have AF partially or completely resistant to drugs. Two patients (without RFA) died from ischemic stroke/ pulmonary embolism.Conclusion. Using EMB the causes of idiopathic arrhythmias (mainly AF) were diagnosed: immune inflammatory diseases in 75% and genetic in 25% of patients. As a result of complex treatment, the general burden of arrhythmias has decreased. But the presence of myocarditis and primary cardiomyopathy, without reducing the cardiac contractility and dilatation, does not allow achieving a stable antiarrhythmic effect. Lethality for 11 years was 10%. The causes of death were thromboembolic complications.

Rationale for endomyocardial biopsy in the diagnosis of heart disease in children and adults

Endomyocardial biopsy (EMB) is the method of choice for diagnosing a wide range of myocardial diseases.Aim. To assess the rationale for diagnostic EMB in children and adults.Material and methods. Morphological and statistical analysis of 2803 diagnostic EMBs in adults (n=811) and children (n=83), including those in heart transplantation (n=1909), was carried out.Results. In 231 (28%) cases, adults were diagnosed with myocarditis, of which in 6 patients — granulomatous, in 5 — eosinophilic and in 6 — lymphocytic-macrophage myocarditis after coronavirus infection. In children, myocarditis was found in 22 cases (27%). Arrhythmogenic right ventricular dysplasia took the second place in detection rate in children and adults. Immunohistochemical study revealed viral envelope protein 1 (VP1) antigen of enteroviruses in one third of myocarditis cases, and in half — other cardiotropic viruses. Dotted dystrophin expression was observed in myocarditis. A correlation was established between the perforin expression and myocarditis presence (Pearson χ2=27,8; Fisher's exact test=27,3; p=0,01).Conclusion. Analysis of diagnostic EMB results confirmed its rationale in adults and children not only for heart transplantation, but also for identifying cardiac pathology, including for myocarditis diagnosis. It has been shown that immunohistochemical study with antiviral antibodies can be considered as an alternative method for detecting viral infection. An immunohistochemical analysis for perforin and dystrophin can be recommended as additional morphological markers of myocarditis.

Thyroidectomy in patients with amiodarone-induced thyrotoxicosis

The OBJECTIVE of the study was to analyze the experience of performing thyroidectomy (TE) in patients with amiodarone-induced thyrotoxicosis (AmIT) at our centre.METHODS AND MATERIALS. The study included 12 patients with AmIT who underwent TE. Medical records were analyzed to assess the features of the AmIT and indications for TE. We also studied the operation protocols and postoperative follow-up data. Intraoperative, early and long-term postoperative complications were recorded. The long-term TE results were evaluated by the dynamics of the left ventricular ejection fraction (LVEF) based on the echocardiography data.RESULTS. The main indications for TE included the resistance of thyrotoxicosis to medication and worsening of the cardiac pathology. No cases of thyrotoxicosis progression or thyrotoxic crisis were registered during the operation. The vocal cord paresis developed in one case, completely restored in a year. Blood loss was minimal in all cases. Other intraoperative complications were absent. Not a single death was registered in the early postoperative period. At this period, a short paroxysm of atrial fibrillation resolved on its own was registered in patient with arrhythmogenic right ventricular dysplasia. A patient with biventricular chronic heart failure of a high functional class died 39 days after the operation due to a massive pulmonary thromboembolism. The long-term results of TE were evaluated in eight patients. In four out of five patients with initially reduced LVEF, it increased. In three patients with initially normal LVEF, it did not change.CONCLUSION. Thyroidectomy is an effective and safe treatment in patients with AmIT, including those with the persistent thyrotoxicosis and severe cardiac pathology. The success is possible when the preparation of patients for the intervention is carried out by a team of specialists experienced in treating of such patients.

Ventricular disturbance of rhythm as a symptom of cardiovascular disease

The questions of the differential diagnosis of diseases accompanied by ventricular premature beats (ischemic heart disease, myocarditis, arrhythmogenic right ventricular dysplasia) are thrusted into the spotlight.

Evolution of diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy and their application in clinical practice

This article describes evolution of criteria for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The novel diagnostic criteria for ARVD/C published in 2020 are analyzed in detail, among which biventricular and leftdominant arrhythmogenic cardiomyopathy are identified for the first time. The need to develop novel criteria was fed on the accumulation of new data on ARVD/C, in particular, significant advances in magnetic resonance imaging technologies. The novel criteria retained high sensitivity and specificity in relation to traditional right ventricular disease form and became more sensitive in relation to the biventricular and left-dominant arrhythmogenic cardiomyopathy.Nevertheless, the addition of left-dominant disease forms reduces the criteria specificity in general, since left ventricle involvement with a similar clinical performance can have different etiology that goes beyond the ARVD/C, even when mutations are detected in typical genes, which is demonstrated by case reports described in the article. Like the previous two versions, the novel criteria will be fully assessed only with a large sample of patients after their introduction into the routine cardiology clinical practice.

Long Term Follow-Up in a Patient with Arrhythmogenic Right Ventricular Dysplasia

This case report describes eight years of follow-up in a young adult with arrhythmogenic right ventricular dysplasia (ARVD). He presented with exertional palpitations, symmetric T wave inversions and possible epsilon waves in the right precordial leads on electrocardiogram (EKG), raising suspicion for ARVD. Transthoracic echocardiography revealed a dilated and excessively trabeculated right ventricle (RV), and cardiac magnetic resonance imaging showed fatty infiltration of the RV myocardium. These findings established the diagnosis of ARVD, and given his palpitations, a defibrillator was implanted. Over the next years, he had several episodes of ventricular tachycardia requiring therapy from his device, despite escalating medical therapy. He therefore underwent radiofrequency catheter ablation for the VT, which successfully controlled the VT.

Cullin Deneddylation Suppresses the Necroptotic Pathway in Cardiomyocytes

Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research reveal that not all necrosis is accidental, but rather there are multiple forms of necrosis that are regulated. Necroptosis, the earliest identified regulated necrosis, is perhaps the most studied thus far, and potential links between necroptosis and Cullin-RING ligases (CRLs), the largest family of ubiquitin E3 ligases, have been postulated. Cullin neddylation activates the catalytic dynamic of CRLs; the reverse process, Cullin deneddylation, is performed by the COP9 signalosome holocomplex (CSN) that is formed by eight unique protein subunits, COPS1/CNS1 through COPS8/CNS8. As revealed by cardiomyocyte-restricted knockout of Cops8 (Cops8-cko) in mice, perturbation of Cullin deneddylation in cardiomyocytes impairs not only the functioning of the ubiquitin–proteasome system (UPS) but also the autophagic–lysosomal pathway (ALP). Similar cardiac abnormalities are also observed in Cops6-cko mice; and importantly, loss of the desmosome targeting of COPS6 is recently implicated as a pathogenic factor in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Cops8-cko causes massive cardiomyocyte death in the form of necrosis rather than apoptosis and rapidly leads to a progressive dilated cardiomyopathy phenotype as well as drastically shortened lifespan in mice. Even a moderate downregulation of Cullin deneddylation as seen in mice with Cops8 hypomorphism exacerbates cardiac proteotoxicity induced by overexpression of misfolded proteins. More recently, it was further demonstrated that cardiomyocyte necrosis caused by Cops8-cko belongs to necroptosis and is mediated by the RIPK1–RIPK3 pathway. This article reviews these recent advances and discusses the potential links between Cullin deneddylation and the necroptotic pathways in hopes of identifying potentially new therapeutic targets for the prevention of cardiomyocyte death.

Left ventricular fibro-fatty replacement in arrhythmogenic right ventricular dysplasia/cardiomyopathy: prevalence, patterns, and association with arrhythmias

Background Left ventricular (LV) fibrofatty infiltration in arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C) has been reported, however, detailed cardiovascular magnetic resonance (CMR) characteristics and association with outcomes are uncertain. We aim to describe LV findings on CMR in ARVD/C patients and their relationship with arrhythmic outcomes. Methods CMR of 73 subjects with ARVD/C according to the 2010 Task Force Criteria (TFC) were analyzed for LV involvement, defined as ≥ 1 of the following features: LV wall motion abnormality, LV late gadolinium enhancement (LGE), LV fat infiltration, or LV ejection fraction (LVEF) < 50%. Ventricular volumes and function, regional wall motion abnormalities, and the presence of ventricular fat or fibrosis were recorded. Findings on CMR were correlated with arrhythmic outcomes. Results Of the 73 subjects, 50.7% had CMR evidence for LV involvement. Proband status and advanced RV dysfunction were independently associated with LV abnormalities. The most common pattern of LV involvement was focal fatty infiltration in the sub-epicardium of the apicolateral LV with a “bite-like” pattern. LGE in the LV was found in the same distribution and most often had a linear appearance. LV involvement was more common with non-PKP2 genetic mutation variants, regardless of proband status. Only RV structural disease on CMR (HR 3.47, 95% CI 1.13–10.70) and prior arrhythmia (HR 2.85, 95% CI 1.33–6.10) were independently associated with arrhythmic events. Conclusion Among patients with 2010 TFC for ARVD/C, CMR evidence for LV abnormalities are seen in half of patients and typically manifest as fibrofatty infiltration in the subepicardium of the apicolateral wall and are not associated with arrhythmic outcomes.