Rendu-Osler-Weber Disease with High Pulmonary Hypertension and Interstitial Lung Disease

A 64-year-old female with a family history of hereditary hemorrhagic telangiectasia (HHT) was hospitalized due to complaints of dyspnea during light physical exertion and leg edema. HHT was diagnosed at 20 y.o., recurrent nasal bleeding started at age 52, bleedings severity was aggravated by not completely compensated hypertension. At the age of 60, after a massive hemorrhage, she noted the onset of dyspnea, edema, ascites. Diuretics and iron preparations improved her well-being, but from that period onward her heart failure worsened after each massive blood loss. The last major bleeding was before the present hospitalization (Hgb 67 g/l), after which heart failure symptoms significantly deteriorated. Echocardiography showed preserved left ventricular ejection fraction, but revealed high pulmonary hypertension (systolic pulmonary artery pressure 69 mmHg). Chest computed tomography (CT) with contrast showed no evidence of pulmonary embolism, but interstitial lung lesions were detected. Pulse therapy with glucocorticosteroids did not result in positive dynamics at the control CT scan, which allowed to reject a separate interstitial lung disease. As a result of cardiotropic and diuretic therapy, as well as correction of anemia, the patient's condition improved. Macitentan was administered, but the patient refused from it because one of possible side effects was anemia. A year later the patient diedfrom acute progression of pulmonary hypertension. According to the literature, pulmonary hypertension in HHT can have a significant impact on the prognosis and requires timely diagnosis and treatment. Interstitial lung lesions are a manifestation of the underlying disease and does not require special treatment

Spectrum of desmosomal gene variations in patients with arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary myocardial disease with a high risk of sudden cardiac death. The most common genetic forms of the disease are associated with desmosomal gene mutations.Aim. To study the prevalence of desmosomal forms of ARVC and to analyze variations in the PKP2, DSG2, DSP, DSC2 and JUP genes in a sample of Russian patients with ARVC.Material and methods. Included patients with ARVC underwent resting electrocardiography (ECG), 24-hour Holter ECG monitoring, echocardiography, chest x-ray, myocardial biopsy (if indicated), contrast-enhanced cardiac magnetic resonance imaging. All patients underwent medical genetic counseling. Mutations in the PKP2, DSG2, DSP, DSC2, and JUP genes was detected using highthroughput sequencing on the IonTorrent platform, followed by Sanger sequencing of uncovered gene regions. The pathogenicity of identified genetic variations was assessed according to modern guidelines.Results. ARVC was established in 80 Russian unrelated patients. More than half of the probands (57%) in the study sample had definite diagnosis of ARVC, while 30% and 13% — borderline and possible ARVC, respectively. A positive family history of heart disease and/or SCD was noted in 30%. Genetic variants of pathogenicity class IV-V were detected in 15 (18,75%) probands in the PKP2, DSG2, DSP genes. The detection of genetic variants of pathogenicity class IV-V was different in the subgroups of patients with varying degrees of diagnosis reliability: 13 probands (28,3%) in the subgroup with definite ARVC and 2 probands (8,3%) in the subgroup with borderline ARVC. No genotype-positive probands were found in the subgroup with possible ARVC. Variations of unknown clinical significance were found in 13 (16,25%) probands.Conclusion. The diagnostic yield of the desmosomal genes PKP2, DSG2, DSP, DSC2, and JUP was 19% with initial diagnosis of ARVC. The detection of mutations was significantly higher in patients with definite ARVC and severe disease manifestations

Noncompact Myocardium with Dilated Phenotype: Manifestations, Treatment and Outcomes in Comparison with Other Forms of Dilated Cardiomyopathy Syndrome

Aim. To study the place of NCM in the structure of DCM, its clinical features and influence on prognosis in comparison with other forms of DCM syndrome.Methods. The NCM registry includes 125 patients, mean age 46.4±15.1 years, 74 men and 51 women, median follow-up 14 [4.0; 41.0] months. The DCM registry included 365 patients, mean age 46.4±15.1 years, 253 men and 112 women, median follow-up 14 [5; 43.75] months. The examination included electrocardiography (ECG), ECG Holter monitoring, echocardiography, blood anti-heart antibody level evaluation, and additionally cardiac computed tomography, magnetic resonance imaging, DNA diagnostics (in the MYH7, MYBPC3, TPM1, TNNI3, TNNT2, ACTC1, TAZ, ZASP (LDB3), MYL2, MYL3, DES, LMNA, EMD, TTR gene panel), coronary angiography, right ventricular endomyocardial biopsy.Results. The proportion of patients with DCM phenotype in the NCM registry was 40% (n=49), another 11% (n=15) had NCM diagnosed simultaneously with acute/subacute myocarditis. Lethality in these subgroups was 12.2% and 33.3%, respectively, and was significantly higher than in asymptomatic, ischemic and arrhythmic variants of NCM. In the DCM registry, the proportion of patients with NСM was 21% (n=78), and increased left ventricular (LV) trabecularity was detected in another 18% (n=64). DCM patients with and without NСM did not differ by baseline echocardiographic parameters, heart failure class, and cardiotropic therapy. Pathogenic mutations were detected in 14% of DCM patients with NCM and only 3% of other patients with DCM (p<0.001). Only in patients without NCM the presence of mutations had a significant effect on lethality. The patients with NCM compared with the others DCM patients showed significantly lower increase in EF in early and late period (from 31.0±10.2 to 34.8±11.0 and 37.1±10.9% [р<0.05] vs from 31.8±9.7 to 38.8±11.3 and 42.3±12.4% [р<0.01] respectively), a greater incidence of premature ventricular   beats (1568 [105;7000] vs 543.5 [77.75; 3194], p<0.05), appropriate defibrillator shocks and sudden deaths (17.9 vs 5.9%, p<0.001), intracardiac thrombosis (21.8 vs 13.5%, p=0.069) despite a greater frequency of anticoagulants (73.1 vs 57.4%, p<0<05). There were no significant differences in death (19.2 vs 18.5%) and transplantation (7.7 vs 3.8%) between patients with and without NCM. There were no cases of NCM regression.Conclusion. NCM is an independent form of DCM syndrome, which is characterized by higher frequency of pathogenic mutations, arrhythmic events, worse response to cardiotropic therapy, higher frequency of intracardiac thrombosis. The absence of mortality differences can be explained by the higher frequency of preventive interventions in this category of patients with DCM (prescription of anticoagulants, defibrillator implantation, heart transplantation)

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

Spectrum of mutations and their phenotypic manifestations in children and adults with long QT syndrome

Aim. To determine the spectrum of mutations in the genes responsible for the long QT syndrome (LQTS) and study their phenotypic manifestations in patients with LQTS in different age groups.Materials and methods. The study included 35 unrelated probands with a clinical diagnosis of LQTS: 23 adults (8 men) and 12 children (9 boys). There were following clinical features: syncope — 54%, positive family history for SCD — 29%, implanted cardioverter defibrillator (ICD) — 46%. All participants underwent 12-lead electrocardiography (ECG), 24-hour Holter monitoring, genealogical analysis, echocardiography and cardiac MRI. The genetic study was performed by nextgeneration sequencing (NGS) using the MiSeq system (Illumina). The quantitative comparison of two unrelated groups was carried out using the nonparametric MannWhitney U-test. The differences were considered significant at p<0,05.Results. In the examined group of 35 probands, 23 genetic variants of pathogenicity class IV and V (hereinafter referred to as) were identified. The molecular genetic variant of the disease was verified in 66% of probands. At the same time, the detection of mutations in the group with early manifestation (children) was significantly higher: 83% (10 out of 12 children) vs 57% in adults (13 out of 23). Rare genetic variants of uncertain significance (VUS, class III pathogenicity) were detected in 4 probands (11%). In the groups of children and adults with LQT1, LQT2 and LQT3, the sex distribution deviated from the 1:1 ratio. Among children, two-thirds were boys, among adults — the same proportion was represented by women. Disease manifestation time, QTc duration and adverse events risk depended on the genetic type of LQTS, intragenic localization of mutations and sex. In children, all 4 missense mutations in the KCNQ1 gene were located in transmembrane domain, and in adults, 4 mutations were in the transmembrane domain and three — in the C-terminal domain of the protein. LQT1 in boys was characterized by early manifestation, while QTc did not exceed 500 ms and there were no adverse outcomes. Two women out of 7 adults with LQT1 with mutations in the transmembrane domain had na ICD (QTc >520 ms). All patients with LQT2 (4 children, 4 adults) had QTc >500 ms. At the same time, 2 children and 3 women had an ICD. LQT3 was diagnosed only in the children subgroup (2 boys, with QTc of 510 ms and QTc of 610 ms); one of them died suddenly despite beta-blocker therapy. Four adult patients, carriers of class III pathogenicity variants, had QTc <500 ms and delayed disease manifestation (after 30 years). Three of them had episodes of clinical death with subsequent resuscitation and implantation of cardioverter defibrillator.Conclusion. The average diagnostic efficiency of mutation identification using NGS in patients with clinically manifest LQTS was 66%. At the same time, mutations were more common in the children’s group. In genotype-positive probands, the risk of adverse outcomes correlated with sex, age and the genetic variant of disease. The greatest number of adverse outcomes was observed in carriers of mutations in both KCNH2 (LQT2) and SCN5A (LQT3) genes. Variants with unknown clinical significance were identified in 4 probands (11%), which potentially allowed to confirm the diagnosis after functional tests

2020 Clinical practice guidelines for Hypertrophic cardiomyopathy

Russian Society of Cardiology (RSC)With the participation: Russian Association of Cardiovascular SurgeonsEndorsed by: Research and Practical Council of the Ministry of Health of the Russian Federation Task Force: Gabrusenko S.A. (Chairman), Gudkova A.Ya.* (Chairman), Koziolova N.A. (Chairman), Alexandrova S.A., Berseneva M.I., Gordeev M.L., Dzemeshkevich S.L., Zaklyazminskaya E.V., Irtyuga O.B., Kaplunova V.Yu., Kostareva A.A., Krutikov A.N., Malenkov D.A., Novikova T.N., Saidova M.A., Sanakoev M.K., Stukalova O.V

Ventricular arrhythmias. Ventricular tachycardias and sudden cardiac death. 2020 Clinical guidelines

Russian Society of Cardiology (RSC).With the participation of Russian Scientific Society of Clinical Electrophysiology, Arrhythmology and Cardiac Pacing, Russian Association of Pediatric Cardiologists, Society for Holter Monitoring and Noninvasive Electrocardiology.Approved by the Scientific and Practical Council of the Russian Ministry of Health

EFFICACY OF CARDIOVERTER-DEFIBRILLATORS IN PREVENTION OF SUDDEN DEATH AND OVERALL MORTALITY DECREASE IN PATIENTS WITH THE SYNDROME OF DILATION CARDIOMYOPATHY: DIFFERENTIAL APPROACH

Aim. To evaluate the exact efficacy of the implantable cardioverter-defibrillators (ICD) and combination devices (CRT-D), and to evaluate their influence on the rate of sudden death and overall mortality in patients with the dilation cardiomyopathy syndrome (DCMP), and to clarify the selection criteria for implantation.Material and methods. Totally, 220 DCMP patients investigated: 66 (30%) of them (mean age 48,5±12,8 y. o., 47 males) underwent implantation of ICD (n=37) and CRT-D (n=29), 154 (70%) patients were in comparison group (mean age 47,1±12,4 y. o., 104 males). In 60 patients (93,9%) the devices were implanted for primary prevention of sudden cardiac death (SCD). Follow-up lasted for 16 [6; 37] months. As primary endpoints, the following parameters were used: “death+transplantation”, mortality, SCD, “SCD+shock” and “death+transplantation+proper shocks of the defibrillators”.Results. Mortality in all DCMP patients was 19,1%, “death+transplantation” — 21,4%, SCD — 2,7%. There were no significant differences by these values in patients with both devices (19,7%; 22,7% and 1,5%), ICD (21,6%; 24,3% and 2,7%), CRT-D (17,2%; 20,7; and 0) and patients with no devices (18,8%; 20,8% and 3,2%). Significantly higher rates by “SCD+shocks” (18,2% v 3,2%, p<0,001) and “death+transplantation+shocks” (36,4% vs 20,8%, p<0,05) in patients with the implanted devices witness for real impact of the defibrillators in equality of overall mortality and SCD parameters. Among the patients with implanted devices, the genetic and mixed (genetic and inflammatory) nature of DCMP predominated (62,1 v 35,7%, p<0,001), there was significantly lower EF (26,3±9,2 v 30,7±10,3%, p<0,01), its end value (31,1±11,0 v 39,2±13,5%, p<0,01), significantly higher end diastolic size of the left ventricle (EDS, LV, 6,8±0,8 v 6,5±0,8 cm, p<0,05) and the grade of mitral regurgitation. In patients with the devices, rate of proper shocks was 18,2%. In isolated myocarditis there were no shocks (35,3±9,1% v 26,8±9,3%, p<0,05), EDS significantly lower (6,2±0,6 cm v 6,9±0,9 cm, p<0,01), ECG signs of LV hypertrophy were more rare (16,7% v 56,3%, p<0,05), but more commonly — the low voltage of QRS (33,3% v 10,6%, p=0,53); there were no differences in the rates of cardiotropic drugs prescription. Main predictors of the shocks were genetic origin of DCMP (isolated or with myocarditis, 25/75%, comparing with 20/33% in patients with no shocks, p<0,01, HR 1,58, OR 10,93, sensitivity 94,1%, negative predictive value 99,2%), and sustained (HR 18,0, sensitivity 98,1%) and non-sustained ventricular tachycardia (HR 1,43, sensitivity and negative predictive value 100%), decrease of QRS voltage and absence of the signs of LV hypertrophy on ECG (negative predictive value 92,8% and 95,6%).Conclusion. In DCMP patients, implanting of ICD/CRT-D was performed with acknowledged additional criteria (genetic or mixed DCMP etiology, lower EF and worse response to treatment); due to more effective ICD therapy, the values of mortality, “death+transplantation” and SCD were not higher than in less severe patients with no such devices. Proper shocks developed in patients with significantly higher EF. As an independent SCD risk factor and a criteria for patients selection to defibrillator implantation, genetic origin of DCMP should be used, especially if comorbid with myocarditis. As the predictors for benign outcome — absence of non-sustained ventricular tachycardia, lower QRS voltage, signs of LV hypertrophy on ECG. An algorithm proposed of DCMP patients selection for ICD treatment

NON-COMPACTION LEFT VENTRICLE MYOCARDIUM: A SYMPTOM, SYNDROME OR DEVELOPMENT VARIATION?

The left ventricle non-compaction myocardium syndrome is relatively new diagnosis entered clinical practice with improvement of the heart visualization methods. There is plenty of studies on genetic heterogeneity of non-compaction myocardium syndrome and its impact on a variety of associated cardiomyopathies. However, there is no single opinion on pathogenesis of non-compaction, as there are no unified diagnostic criteria and no guideline on treatment and management of patients with this syndrome. Current review provides a summary of data on this pathology nature, its genetics, diagnostics and treatment