[Dilated cardiomyopathy caused by p.E446K mutation in SCN5A gene].

Dilated cardiomyopathy (DCM) is myocardial disorder characterized by progressive heart chambers enlargement and impairment of myocardial contractility. This disorder is the most common cause of advanced heart failure requiring the heart transplantation. The prevalence of the disease is 36.5 per 100 000 in population. About 20-30% of cases are familial. Disease is genetically heterogenous, there more than 100 genes when mutated can give rise a DCM. In 2004, the role of SCN5A gene mutations was shown in origin of DCM with cardiac conduction defects and arrhythmias. In this work we present a clinical case of dilated cardiomyopathy with cardiac arrhythmias and p.E446K mutation in SCN5A gene. We have observed DCM with mild left ventricular hypertrophy, progressive AV block, atrial fibrillation and congenital heart defect (atrium septal defect) in two generations. The congenital heart defect did not co-segregate with SCN5A mutation and DCM.

[Clinical polymorphisms and approaches of arrhythmias treatment in a family with δKPQ1505-1507 deletion in SCN5A gene].

BACKGROUND: The aim of the study was to analyze spectrum of manifestation and treatment response in large family with rhythm disturbances caused by p.delKPQ1505-1507 mutation in SCN5A gene. PATIENTS AND METHODS: We had under our observation 18 members of large Iranian family with various combination of inherited arrhythmic syndromes. Careful cardiological examination, genetic councelling and venous blood sampling for molecular genetic study were performed for family members. Mutation screening in SCN5A gene was performed using bidirectional Sanger sequencing. RESULTS: Here by we show the observation of Iranian family with known mutation p.delKPQ 1505-1507 in SCN5A gene, who display not only LQ-TS phenotype but also some of the carriers of this mutation have had LQ-TS and Brugada syndrome (combine phenotype), interestingly. CONCLUSION: The overlapping phenotype associated with high risk of sudden cardiac death may require complex approaches to antiarrhythmic therapy, surgical treatment and prevention of sudden cardiac death in the family.

[Clinic and genetic polymorphism of Brugada syndrome in Russian patients, caused by mutation in SCN5A gene].

Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder, characterized by ST-segment elevation in right precordial leads V1-V2>2 mm, pseudo right bundle branch block (RBBB), T-wave inversion and an increased risk of cardiac sudden death (SCD) due to molymorphic VT. It is estimated to be responsible for 12% of SCD cases and about 20% of deaths in patients with structurally normal hearts in autopsy. Mutations in the SCN5A gene account 15-30% of all cases. Clinical, instrumental and genetic analyses were performed for 25 Russian probands with BrS (19 males and 6 female). Phenotype-genotype correlation was studied in SCN5A-positive and SCN5A-negative patients. Rare genetic variants in SCN5A gene were found in 7 of 21 Russian probands (28%). Two variants affect protein splicing (c.IVS16DS-5A>G and c.IVS24AS+1G>A), three missense mutations (p,Y87C, p.R893H and p.S1787N), one in-frame deletion p.del848l, and one non-sense-mutation p.E553X. All mutations were unique for each family. There were no clinical or instrumental parameters were found to be effective in prediction of SCN5A mutations. The protocols of genetic counceling for SCN5A-positive and SCN5A-negative families were established.

[Possibilities myocardial biopsy in the diagnosis of myocarditis verification in patients with idiopathic arrhythmias].

UNLABELLED: Aim of the study was to elucidate nosological nature of "idiopathic" arrhythmias by means of right ventricular endomyocardial biopsy (EMB) and to assess effect of etiotropic and pathogenetic treatment. MATERIAL AND METHODS: We included into this study 19 patients (mean age 42.6 +/-11.3 years, 9 women) with atrial fibrillation (AF, n = 16), supraventricular (n = 10) and ventricular (n = 4) extrasystoles (SVE and VE), supraventricular (n = 2) and ventricular (n = 1) tachycardia (SVT and VT), left bundle branch block (LBBB, n = 2), atrioventricular block (n = 2) without structural changes of the heart. In addition to standard examination we performed the following tests: determination of IgG to herpes and Coxsackie B virus, polymerase chain reaction (PCR) for DNA detection of human herpesviruses 1, 2, and 6, Epstein-Barr virus, Varicellae-zoster virus (human herpesvirus 3) and cytomegalovirus in blood; determination of anticardiac antibodies; EMB with subsequent PCR-diagnostics including that of parvovirus B19 and pathomorphological study. DNA diagnostics (n = 4), coronary angiography (n = 6), skin biopsy (n = 1) and some other studies were also performed when indicated. RESULTS AND CONCLUSIONS: Histological picture was abnormal in all cases. Nosological diagnosis was established in all patients: infectious-immune myocarditis (n = 11), parvovirus positive endomyocarditis (n = 1); systemic vasculitis (n = 2); myocardial vasculitis (n = 1), Fabri disease (n = 1), arrhythmogenic right ventricular dysplasia (ARVD, n = 1), undetermined genetic cardiomyopathy (n = 2). Level of various anticardiac antibodies including antinuclear factor with bovine heart antigen was most valuable for diagnosis of myocarditis (sensitivity 78.6%, prognostic value of positive result 91.7%). The following therapy was used in patients with myocarditis/vasculitis: intravenous or oral acyclovir (n = 10), gabreglobine (n = 2), meloxicam (n = 12), hydroxychloroquine (n = 15 for 15 [7.0; 24.] months), glucocorticosteroids (n = 14 for 18 [4.0; 25.5] months), azathioprine (n = 2). Mean duration of follow up was 4 years (48 [31; 62] months). At baseline 62.5% of patients with AF were resistant to all antiarrhythmic drugs. Treatment of myocarditis resulted in significant reduction of mean frequency of attacks of AF from 8 to 3 points, more than in 40% of patients AF emerged less than once a month and 1 patient had no attacks at all. Disappearance of tachycardia dependent LBBB was also noted. Cardioverter defibrillator and cardiac pacemaker were implanted to patients with ARVD and Fabri disease, respectively. EMB helped to establish immunoinflammatory and genetic diseases as causes of idiopathic arrhythmias (in 78.9 and 21.1% of patients, respectively). Antiviral immunosuppressive therapy of myocarditis allowed to increase efficacy of antiarrhythmic therapy in resistant patients and when necessary to optimize their preparedness to interventional treatment.

[Noncompaction myocardium as a primary phenomenon or consequence of myocardial dysfunction: clinical masks of the syndrome].

Noncompaction myocardium (NCM) is a genetic heterogeneous primary cardiomyopathy which affects both children and adults and can be either isolated or combined with other congenital heart disorders. It has common pathogenesis of symptoms but is distinguished by pronounced clinical polymorphism. We have observed 25 adult patients (15 men, 10 women aged from 20 to 62 years, mean age 42.9+/-13.3 years) with NCM syndrome. Heart failure have been found in 96% of patients (functional class [FC] I in 7, II - in 6, III in 7, and IV - in 4 patients). Ninety two percent of patients have ventricular extrasystoles, 32% - atrial fibrillation, 28% - FC I-III angina. Mean end diastolic left ventricular dimension is 6.5+/-0.8cm, ejection fraction 29.7+/-13.0%, mean pulmonary artery pressure - 42.6+/-13.5 mm Hg. Intracardiac thrombosis have been found in 24% of patients. In 7 patients morphological study of myocardium has been performed. NCM syndrome was diagnosed at initial investigation just in 1 case. We distinguished the following clinical masks (variants of diagnosis) of NCM: 1) clinically not manifest, is revealed at accidental examination (4%); 2) exists under mask of "idiopathic" rhythm disturbances (8%); 3) has a mask of ischemic heart disease; 4) is revealed in patients with acute or subacute myocarditis (12%); 5) has a mask of dilated cardiomyopathy (52%); 6) NCM in patients with other primary cardiomyopathies (hypertrophic, restrictive, genetic myopathy, arrhythmogenic right ventricular dysplasia). Combination of NCM with congenital heart defects has been found in 20% of patients. In 56% of cases myocarditis was diagnosed (it was viral in no less than 44%). Only in 32% of patients it is possible to consider presence of isolated NCM syndrome. This paper contains discussion of problems of diagnostics (including morphological) and treatment in the presented group of patients, significance of myocarditis for development of decompensation, role of NCM in patients with other primary cardiomyopathies, possibility of compensatory (secondary) character of NCM in severe systolic dysfunction.

[Arrhythmogenic right ventricular dysplasia: polymorphism of clinical manifestations].

We observed 15 patients with arrhythmogenic right ventricular dysplasia (ARVD): 9 with definite and 5 with probable ARVD (modified European Criteria, 2010). Eight patients had typical ARVD (frequent right ventricular extrasystoles, nonsustained right ventricular tachycardia without heart failure with or without myocarditis). Five patients had ARVD with progressive heart failure (right- or biventricular with or without myocarditis). Two patients had full scale arrhythmic form (sustained right ventricular tachycardia without or with right ventricular dilation, with or without myocarditis). In 3 cases diagnosis was confirmed morphologically or with DNA-diagnostics. This material allowed us to highlight the following specific points related to diagnostics of ARVD. Detection of fat at MRT is not obligatory for diagnosis, fat can be detected by MSCT; ventricular arrhythmias can move backwards in the picture of the disease; leading clinical manifestation can be unexplained right ventricular insufficiency; ARVD can be combined with other genetic cardiomyopathies as well as with infectious immune myocarditis (up to 50% of patients); elevated titer of anticardiac antibodies is not characteristic for isolated ARVD; myocardial biopsy allows to verify both ARVD and concomitant myocarditis. The paper also contains discussion of the role of myocarditis in various forms of ARVD and possibilities of its diagnosis and treatments.

[Dilated cardiomyopathy as clinical syndrome: experience with nosological diagnostics with biopsy and treatment approaches].

AIM: To study possibility of nosological diagnosis in patients with dilated cardiomyopathy (DCMP) with use of myocardial biopsy. MATERIAL AND METHODS: The trial enrolled 62 patients (23 females) with DCMP syndrome (end diastolic left ventricular size > 5.5 cm, ejection fraction < 55%). Mean age of the patients was 46.0 +/- 12.8 years. The examination included diagnosis of viral infections (Herpes virus, parvovirus B19), measurement of anticardial antibodies titer, 99Tc-MIBI single photon emission computed tomography of the myocardium, multislice computed tomography, MRT of the heart, coronarography, morphological study of the myocardium (n=20) with application of polymerase chain reaction (PCR) for H.simplex viruses of types 1, 2 and 6, herpes zoster, Epstein-Barr, cytomegalovirus, parvovirus B-19, adenoviruses. The control group (20 operated patients with valvular heart disease and coronary heart disease) was examined for viral genome in the blood and myocardium. RESULTS: Complex examination of DCMP patients showed the following distribution by nosological entuities: myocarditis (n=41, 66.1%) including virus-positive (n=14), primary DCMP (n=16, 25.9%) including with non-compact myocarditis (NCM) in 3, with debute at delivery of the child--in 3. Arrhythmogenic right ventricular dysplasia combined with viral myocarditis (n=2), genetic myopathy (n=1) and Takayasu disease (n=1) combined with NCM, isolated NCM (n=1) were diagnosed in the rest cases. Morphological investigation of the myocardium was made in 20 patients: diagnosis of myocarditis and primary DCMP were made in 70% (including in 2 patients with CHD) and 20%. Detection of viral genome was 20 and 15% in the study and control group, respectively, in the myocardium--in 57.9 (test for parvovirus B19 was not made in 26%) and 65.0% (complete diagnosis). All the virus-positive patients with DCMP were diagnosed to have signs of active/borderline myocarditis. Diagnostic criteria and poor prognosis factors were defined. CONCLUSION: The nosological diagnosis of DCMP was made in all the examinees basing on the complex of clinical, case history and device evidence. The diagnosis was morphologically verified in 33.9% patients. Treatment approaches are developed.

[The clinical variability of and approaches to treatment of life-threatening ventricular arrhythmias caused by SCN5A gene mutations].

The reasons for ventricular arrhythmias are variable enough. In many cases the presence and degree of ventricular arrhythmias cannot be explained satisfactorily by the presence of ischemic of inflammatory myocardial lesion. Now that the development of contemporary arrhythmology is associated with active development of molecular-and-genetic research methods, genetic aspects of the pathogenesis of arrhythmias are understood more clearly. Allelic series of diseases that are manifested by arrhythmias that differ clinically but result from mutations in one and the same gene have been described. This paper presents the results of molecular-and-genetic and clinical analysis of diseases caused by mutations in SCN5A gene, which codes the alpha-subunit of the sodium channel Na(v)1.5. Study of clinical manifestations of verified mutations makes it possible to more fully consider possible ways of the development of cardiac rhythm disorders and use the most optimal methods for their treatment.

[Clinical, genealogical and molecular genetic study of Emery-Dreifuss muscular dystrophy].

A search for emerin and lamin A/C (LMNA) mutations was performed in a group of 63 unrelated patients with probable Emery-Dreifuss muscular dystrophy (EDMD) and other MD's with concomitant dilated cardiomyopathy (DCMP). Four different emerin mutations and 7 LMNA mutations were found in unrelated patients. One emerin mutation and 2 LMNA mutations, one of the latter being found twice, have been registered earlier; the rest of the mutations are novel. All the patients with emerin mutations and 3 patients with LMNA mutations represented single cases while 4 LMNA-related cases were familial. De novo origin was proved for one emerin and 3 LMNA mutations. Apart from EDMD phenotypes, varying also in age at onset and severity, 2 cases of limb girdle MD type 1B were diagnosed. One patient with LMNA mutation and severe DCMP had subclinical signs of skeletal myopathy only. There was an overlap between DCMP type 1A and MD's. Autosomal dominant EDMD seems to be more common than "classic" X-linked EDMD. We found neither emerin nor LMNA mutations in a subset of families with EDMD-like phenotypes that may imply an existence of other genes causing similar disorders. Taking into account clinical variability of MD's caused by emerin and LMNA mutations, DNA diagnosis should not confine to the "classic" phenotype. DNA diagnosis of EDMD is important boht for medical genetic counseling and for patients' management: timely diagnosis of the disease allows one to prevent fatal cardiologic complications.