Ticagrelor in Patients with Stable Coronary Disease and Diabetes.

BACKGROUND: Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear. METHODS: In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. RESULTS: A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02). CONCLUSIONS: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

Circulating miR-499a-5p Is a Potential Biomarker of MYH7-Associated Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited myocardial disease with significant genetic and phenotypic heterogeneity. To search for novel biomarkers, which could increase the accuracy of HCM diagnosis and improve understanding of its phenotype formation, we analyzed the levels of circulating miRNAs­stable non-coding RNAs involved in post-transcriptional gene regulation. Performed high throughput sequencing of miRNAs in plasma of HCM patients and controls pinpointed miR-499a-5p as one of 35 miRNAs dysregulated in HCM. Further investigation on enlarged groups of individuals showed that its level was higher in carriers of pathogenic/likely pathogenic (P/LP) variants in MYH7 gene compared to controls (fold change, FC = 8.9; p < 0.0001). Just as important, carriers of variants in MYH7 gene were defined with higher miRNA levels than carriers of variants in the MYBPC3 gene (FC = 14.1; p = 0.0003) and other patients (FC = 4.1; p = 0.0008). The receiver operating characteristic analysis analysis showed the ability of miR-499a-5p to identify MYH7 variant carriers with the HCM phenotype with area under the curve value of 0.95 (95% confidence interval: 0.88−1.03, p = 0.0004); sensitivity and specificity were 0.86 and 0.91 (cut-off = 0.0014). Therefore, miR-499a-5p could serve as a circulating biomarker of HCM, caused by P/LP variants in MYH7 gene.

Novel Genes Involved in Hypertrophic Cardiomyopathy: Data of Transcriptome and Methylome Profiling.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease; its pathogenesis is still being intensively studied to explain the reasons for the significant genetic and phenotypic heterogeneity of the disease. To search for new genes involved in HCM development, we analyzed gene expression profiles coupled with DNA methylation profiles in the hypertrophied myocardia of HCM patients. The transcriptome analysis identified significant differences in the levels of 193 genes, most of which were underexpressed in HCM. The methylome analysis revealed 1755 nominally significant differentially methylated positions (DMPs), mostly hypomethylated in HCM. Based on gene ontology enrichment analysis, the majority of biological processes, overrepresented by both differentially expressed genes (DEGs) and DMP-containing genes, are involved in the regulation of locomotion and muscle structure development. The intersection of 193 DEGs and 978 DMP-containing genes pinpointed eight common genes, the expressions of which correlated with the methylation levels of the neighboring DMPs. Half of these genes (AUTS2, BRSK2, PRRT1, and SLC17A7), regulated by the mechanism of DNA methylation, were underexpressed in HCM and were involved in neurogenesis and synapse functioning. Our data, suggesting the involvement of innervation-associated genes in HCM, provide additional insights into disease pathogenesis and expand the field of further research.

CYP2C9 and VKORC1 genotyping for the quality of long-standing warfarin treatment in Russian patients.

A total of 263 warfarin naive patients with indications to long-term anticoagulation were included in prospective multicenter study and randomized into Pharmacogenetics and Standard dosing groups. The loading warfarin dose in Pharmacogenetics group was calculated by Gage algorithm and corrected starting on day 5 of treatment according to INR. In Standard dosing group warfarin initial dose was 5 mg and starting on day 3 of treatment it was titrated according to INR. Pharmacogenetics dosing in comparison with prescription of starting dose of 5 mg decreased major bleedings (0 vs. 6, p = 0.031), time to target INR (11 [9-14] vs. 17 [15-24] days, p = 0.046), and frequency of INR fluctuations ≥4.0 (11% vs. 30.9%, p = 0.002). The advantages of the pharmacogenetics dosing were mainly achieved due to the patients with increased warfarin sensitivity.

Late Silent Stent Abscess.

BACKGROUND: Coronary stent infections in general and stent abscesses (SAs) in particular are rare but often deadly complications. Most SAs manifest with fever and chest pain within 30 days after intervention and require antibiotics and stent removal. CASE REPORT: A 45-year-old man with second ST elevated myocardial infarction and cardiogenic shock was admitted to a hospital that had no cardiac catheterization laboratory. The patient underwent fibrinolytic therapy with alteplase but died 1 h later. His medical history revealed posterior myocardial infarction 7 years before, which had been successfully treated with a bare metal stent of the right coronary artery. The post-discharge observation had been unremarkable with no evidence of ischaemia or infection but gross non-compliance. Autopsy revealed complete closure of the left main coronary artery and a surprise additional finding, namely SA; the stented portion of the artery was enveloped by an abscess, and purulent material completely occluded the stent, which was floating in pus. Impressions: Since coronary angioplasty is so common, the incidence of late silent SA is probably higher than expected, especially considering that there is often a lack of clinical manifestations. Clinicians should be cognizant of this complication. More attention may be required to assess the condition of existing stents during repeated interventions. Gross non-compliance and/or early withdrawal from dual anti-platelet therapy may be directly responsible for the development of silent delayed SA.

Diagnosis and Treatment Patterns of Chronic Thromboembolic Pulmonary Hypertension in Russia, Kazakhstan, Turkey, Lebanon, and Saudi Arabia: A Registry Study.

BACKGROUND: Patients with chronic thromboembolic pulmonary hypertension (CTEPH) in countries with limited resources have, to date, been poorly represented in registries. OBJECTIVE: This work assesses the epidemiology, diagnosis, hemodynamic and functional parameters, and treatment of CTEPH in Russia, Kazakhstan, Turkey, Lebanon, and Saudi Arabia. METHODS: A prospective, cohort, phase IV, observational registry with 3-year follow-up (n = 212) in patients aged ≥ 18 years diagnosed with CTEPH was created. Clinical, hemodynamic, and functional parameters were obtained at an initial visit, follow-up visits, and a final visit at the end of 3 years' observation or end of follow-up. Data were recorded on electronic case report forms. Parameters evaluated included 6-minute walking distance (6MWD), use of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), pulmonary hypertension (PH)-targeted therapy, and survival. All statistical analyses were exploratory and descriptive, and were performed in the overall population. RESULTS: The most common symptoms were typical of those expected for CTEPH. Almost 90% of patients underwent right heart catheterization at diagnosis or initial study visit. In total, 66 patients (31%) underwent PEA before the initial visit; 95 patients (45%) were considered operable, 115 (54%) were inoperable, and two (1%) had no operability data. Only 26 patients (12%) had been assessed for BPA at their initial visit. PH-targeted therapy was documented at diagnosis for 77 patients (36%), most commonly a phosphodiesterase type 5 inhibitor (23%). Use of PH-targeted therapy increased to 142 patients (67%) at the initial visit, remaining similar after 3 years. Use of riociguat increased from 6% of patients at diagnosis to 38% at 3 years. Between baseline and end of observation, results for patients with paired data showed an increase in 6MWD. Survival at the end of observation was 88%. CONCLUSIONS: These data highlight the current diagnosis and management of CTEPH in the participating countries. They show that early CTEPH diagnosis remains challenging, and use of off-label PH-targeted therapy is common. CLINICALTRIALS: gov: NCT02637050; registered December 2015.

Hypertrophic Cardiomyopathy in Underrepresented Populations: Clinical and Genetic Landscape Based on a Russian Single-Center Cohort Study.

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder characterized by marked clinical and genetic heterogeneity. Ethnic groups underrepresented in studies may have distinctive characteristics. We sought to evaluate the clinical and genetic landscape of Russian HCM patients. A total of 193 patients (52% male; 95% Eastern Slavic origin; median age 56 years) were clinically evaluated, including genetic testing, and prospectively followed to document outcomes. As a result, 48% had obstructive HCM, 25% had HCM in family, 21% were asymptomatic, and 68% had comorbidities. During 2.8 years of follow-up, the all-cause mortality rate was 2.86%/year. A total of 5.7% received an implantable cardioverter-defibrillator (ICD), and 21% had septal reduction therapy. A sequencing analysis of 176 probands identified 64 causative variants in 66 patients (38%); recurrent variants were MYBPC3 p.Q1233* (8), MYBPC3 p.R346H (2), MYH7 p.A729P (2), TPM1 p.Q210R (3), and FLNC p.H1834Y (2); 10 were multiple variant carriers (5.7%); 5 had non-sarcomeric HCM, ALPK3, TRIM63, and FLNC. Thin filament variant carriers had a worse prognosis for heart failure (HR = 7.9, p = 0.007). In conclusion, in the Russian HCM population, the low use of ICD and relatively high mortality should be noted by clinicians; some distinct recurrent variants are suspected to have a founder effect; and family studies on some rare variants enriched worldwide knowledge in HCM.

A survey of physician opinions in Russia in the field of pharmacogenetics of cardiovascular disease.

Aims: To study the readiness of Russian physicians with experience and younger physicians undergoing clinical residency and postgraduate education to apply pharmacogenetic testing in their clinical practice. Materials & methods: The sociological study involved physicians (n = 378) living in different regions of the Russian Federation, as well as residents and graduate students (n = 185) of the Russian Medical Academy of Continuing Professional Medical Education. The survey consisted of 35 questions, and 23 were created on the online platform of professional surveys, Testograf.ru. Results: Every second respondent was willing to use pharmacogenetic testing in clinical practice to predict the efficacy and safety of medications in patients with cardiovascular disease (p = 0.06). Factors impeding the clinical implementation of pharmacogenetic testing in Russia were identified: physicians' ignorance of pharmacogenetics (p = 0.015), a lack of pharmacogenetic testing in clinical guidelines and treatment standards (p = 0.175) and a lack of economic justification for using pharmacogenetic testing (p = 0.320). Conclusion: Russian physicians have a positive attitude toward pharmacogenetic testing. However, the level of test implementation remains low.

Overlapping Phenotype of Adult-Onset ALPK3-Cardiomyopathy in the Setting of Two Novel Variants.

Inherited cardiomyopathies (CMPs) are fairly common causes of morbidity and mortality, particularly, in young individuals. In substantial number of cases, only morphological diagnostic criteria cannot distinguish one CMP from another because of incomplete penetrance, advanced stage of the disease, or overlapping phenotypes. Genetic testing has become a mandatory tool for definite diagnosis that is required for family screening, individual prognosis, and personalized treatment strategy in routine practice. In parallel, accumulation of genotype-phenotype correlations, especially for rare genes, promotes the deciphering of underling molecular mechanisms and the development of targeting treatment of CMPs. Here we present an adult-onset case comprised morphological features of several CMPs: asymmetric left ventricle (LV) hypertrophy, severe systolic dysfunction, LV hypertrabeculation and restrictive physiology. Using next-generation sequencing, two novel variants (NM_020778.5:c.1958C>G:p.Ser653* and c.3491G>A:p.Arg1164Gln) in alpha-protein kinase 3 (ALPK3) gene were identified and confirmed with Sanger sequencing. The trans-position (location on different alleles) of identified ALPK3 variants was established by plasmid cloning method. The ALPK3 gene, encoding nuclear alpha-protein kinase 3, has only recently been associated with CMPs and there are still few clinical data on ALPK3 variant carriers. To date, only five affected individuals with adult-onset CMPs in the setting of biallelic variants of ALPK3 gene have been reported.

Risk Stratification after an Acute Coronary Syndrome: Significance of Antithrombotic Therapy.

The impact of the de-escalation strategy of antiplatelet therapy (APT) on the life expectancy after acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI) requires an assessment in real clinical practice. Into the Russian multicentral observational trial (ORACLE II ClinicalTrials.gov number, NCT04068909), 1803 patients with ACS and PCI indications were enrolled. During 12 months of follow-up, 228 all-cause deaths have occurred. The analysis of death predictors was carried out by the classification tree method. Age, an option of antithrombotic therapy, a history of chronic heart failure, and uric acid level had the greatest prognostic value. The death prediction model's sensitivity was 82.1% in the training cohort and 79.2% in the test cohort. During the observation period, ticagrelor was replaced with clopidogrel (APT de-escalation) in 357 patients. The groups of patients with different antiplatelet therapy options were adjusted for clinical parameters by the pseudorandomization method. The de-escalation group had the lowerest all-cause death rate. The incidence of bleeding and recurrent nonfatal coronary events in the study groups did not differ significantly. Thus, the APT regimen's advantage of changing from the maximum in the first weeks after ACS to moderate at follow-up has been confirmed. There is an obvious need to study the possibilities of individualizing antiplatelet therapy in patients after acute coronary syndromes.

Advanced age, low left atrial appendage velocity, and factor V promoter sequence variation as predictors of left atrial thrombosis in patients with nonvalvular atrial fibrillation.

Atrial fibrillation (AF) renders individual patients at risk for development of an atrial thrombus. The aim of this study was to determine clinical and echocardiographic factors influencing the risk of left atrial thrombosis (LAT) in patients with persistent nonvalvular AF. Genetic variants encoding haemostatic factors have been also assessed for putative association with LAT. In the cross-sectional study, a total of 212 patients (132 males and 80 females) with nonvalvular persistent AF (duration range 48 h-90 days) have been selected. LAT was visualized by transesophageal echocardiography. The FGB G(-455)A, PAI-1 4G/5G, F5 C(-224)T, and F5 R506Q genetic markers were tested using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. To reveal independent factors contributing to the thromboembolic risk in AF, a multivariate logistic model was applied. LA thrombi were found in 44 out of 212 subjects (21%). LAT was more frequently observed in patients at age >75 years (P < 0.001) and those who had reduced left ventricular ejection fraction <40% (LVEF; P < 0.001) and decreased left atrial appendage velocity <20 cm/s (LAAV; P < 0.001). Logistic regression analysis showed that advanced age (OR = 1.64 per decade P < 0.001), LVEF < 40% (OR = 2.12, P < 0.001), LAAV (OR = 1.56, P = 0.007), and TT genotype of F5 C(-224)T (OR = 2.42, P = 0.041) are associated with higher risk of LAT. Age >75 years, LVEF < 40%, LAAV < 20 cm/s, and Factor V C(-224)T variant independently contribute to the thromboembolic risk in AF.

Association of the CYBA, PPARGC1A, PPARG3, and PPARD gene variants with coronary artery disease and metabolic risk factors of coronary atherosclerosis in a Russian population.

Abnormalities in lipid metabolism and enhanced oxidative stress are considered as major risk factors for coronary atherosclerosis. Functional genetic variations in genes whose products are involved in lipid metabolism and antioxidant defense could therefore modulate risk of coronary artery disease (CAD). In this study, we evaluate whether the PPARGC1A Gly482Ser, PPARG3 (-681)C/G, PPARD +294T/C, and CYBA +242C/T gene variants confer the risk of CAD in a Russian population. A total of 313 CAD patients and 132 controls with no clinical sign of CAD were studied. The polymorphic markers were tested using a TaqMan assay. Allele and genotype frequencies in CAD patients and controls were compared using the Yates chi(2) test. Association of the genetic markers with metabolic risk factors of arterial atherosclerosis was studied using the analysis of variance test and then adjusted for conventional risk factors in the multiple regression analysis. For CYBA +242C/T, both the allele T and genotype T/T showed significant association with higher risk of CAD (odds ratio =1.49 and 3.89, respectively). The allele C and genotype C/C of the +294T/C marker of PPARD were associated with increased risk of CAD providing an odds ratio of 2.12 and 2.78, respectively. The risk variants of CYBA +242C/T and PPARD +294T/C markers were associated with higher low-density lipoprotein cholesterol and increased total serum cholesterol, respectively. In conclusion, the CYBA +242C/T and PPARD +294T/C variants modulate risk of CAD through their associations with atherogenic serum lipid profiles.

Switching of Oral Anticoagulation Therapy After PCI in Patients With Atrial Fibrillation: The RE-DUAL PCI Trial Subanalysis.

OBJECTIVES: The aim of this study was to assess if prior oral anticoagulant agent (OAC) use modifies the lower bleeding risk observed with dabigatran dual therapy (dabigatran twice daily plus a P2Y12 inhibitor) versus warfarin triple therapy (warfarin plus a P2Y12 inhibitor plus aspirin) in patients with atrial fibrillation who underwent percutaneous coronary intervention (PCI). BACKGROUND: In the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial, the primary outcome of major bleeding or clinically relevant nonmajor bleeding was lower with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation who underwent PCI. METHODS: A total of 2,725 patients were randomized to dual therapy with dabigatran (110 or 150 mg twice daily) plus clopidogrel or ticagrelor or triple therapy with warfarin plus aspirin and clopidogrel or ticagrelor. Subgroup analysis compared risk for major bleeding or clinically relevant nonmajor bleeding and a composite thromboembolic endpoint in patients with prior OAC use and in those who were OAC treatment naive. RESULTS: Risk for major bleeding or clinically relevant nonmajor bleeding was reduced with both dabigatran dual therapies compared with warfarin triple therapy in both the prior OAC use group (hazard ratios: 0.58 [95% confidence interval (CI): 0.42 to 0.81] and 0.61 [95% CI: 0.41 to 0.92] with 110 and 150 mg dabigatran, respectively) and the OAC-naive group (hazard ratios: 0.49 [95% CI: 0.38 to 0.63] and 0.76 [95% CI: 0.59 to 0.97] with 110 and 150 mg dabigatran) (p for interaction = 0.42 and 0.37, 110 and 150 mg dabigatran, respectively). The risk for thromboembolic events seemed similar with dabigatran dual therapy (both doses) and warfarin triple therapy across subgroups. CONCLUSIONS: Bleeding risk was reduced with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation after PCI, regardless of whether they were prior OAC users or OAC treatment naive. These results suggest that it is also safe to switch patients on OAC pre-PCI to dabigatran dual therapy post-PCI.

Association of CYP2D6 and ADRB1 genes with hypotensive and antichronotropic action of betaxolol in patients with arterial hypertension.

Betaxolol is a selective antagonist of beta(1)-adrenergic receptors. Personal response to the drug widely varies and depends on its properties and individual features including innate characteristics. Our aim was to study the association between the clinical response to betaxolol in patients with essential hypertension (EH) and polymorphous markers of two genes: beta(1) adrenergic receptor gene (ADRB1) and cytochrome P450 2D6 gene (CYP2D6). Eighty-one patients with EH were selected. Mean age was 52.2 +/- 1.22 years. Betaxolol monotherapy provided effective blood pressure control (BP < 140/90 mmHg) in 68 patients, 56 of them continued treatment with initial dose. The systolic (SBP) and diastolic (DBP) blood pressure declined significantly at the end of the study. We have not found any significant association of rest and exercise BP and heart rate (HR) with polymorphous marker Arg389Gly of ADRB1 gene except the nighttime variability of DBP. But in case of the polymorphous marker Pro34Ser of CYP2D6 gene we have found significant association with response to betaxolol therapy. The rest HR declined more significantly in Ser/Pro genotype carriers (-32.6 +/- 4.77 beats/min and -18.4 +/- 2.01 beats/min, P = 0.023). These patients demonstrated more significant increase of exercise time (4.58 +/- 0.90 and 0.59 +/- 0.58 min, P = 0.045). Maximal exercise HR and DBP were also significantly lower in Ser/Pro genotype carriers in comparison with Ser/Ser genotype carriers. Decline of mean daytime SBP in 24-h ambulatory blood pressure monitoring was more significant in Pro allele carriers (-21.0 +/- 2.55 mmHg vs. -5.2 +/- 2.27 mmHg in patients with Ser/Ser genotype, P = 0.001). Betaxolol effect on HR and BP significantly depends on variability of the gene determining the drug metabolism. The carriers of Pro34 allele of CYP2D6 gene (8.6%) are more sensitive to betaxolol therapy. Because of the relatively small group sizes our data should be considered as preliminary ones. The increase of our groups and the replication in other studies will permit to estimate the contribution of genetic factors to betaxolol effect on HR and BP.