MTNR1A and MTNR1B Gene Variants of the Melatonin Receptor and Arterial Stiffness in Persons without Arterial Hypertension.

A comparative analysis of vascular stiffness indices and the results of blood test was carried out in 85 healthy donors aged 19-64 years, carriers of polymorphic variants of type 1 and type 2 melatonin receptor genes. The associations of polymorphic markers of type 1 MTNR1A (rs34532313) and type 2 MTNR1B (rs10830963) melatonin receptor genes with parameters of vascular stiffness and blood parameters in healthy patients were studied. Genotyping was performed using allele-specific PCR. In all patients, 24-h BP monitoring with assessment of arterial stiffness was performed. Allele C homozygotes of MTNR1A differed significantly from carriers of the major T allele by elevated triglyceride, LDL, and fibrinogen levels. The major allele C of the rs10830963 polymorphic variant of the MTNR1B gene is associated with elevated LDL and triglycerides, as well as with individual differences in the elastic properties of the vascular wall in the examined subjects.

[The impact of BMI on the course of the acute SARS-COV-2 infection and the risks that emerge during the first year after the hospital discharge. Subanalysis evidence of the AKTIV and AKTIV 2 registries].

BACKGROUND: There is enough evidence of the negative impact of excess weight on the formation and progression of res piratory pathology. Given the continuing SARS-CoV-2 pandemic, it is relevant to determine the relationship between body mass index (BMI) and the clinical features of the novel coronavirus infection (NCI). AIM: To study the effect of BMI on the course of the acute SARS-COV-2 infection and the post-covid period. MATERIALS AND METHODS: AKTIV and AKTIV 2 are multicenter non-interventional real-world registers. The АКТИВ registry (n=6396) includes non-overlapping outpatient and inpatient arms with 6 visits in each. The АКТИВ 2 registry (n=2968) collected  the  data  of  hospitalized  patients  and  included  3  visits.  All  subjects  were  divided  into  3  groups:  not  overweight  (n=2139), overweight (n=2931) and obese (n=2666). RESULTS: A higher BMI was significantly associated with a more severe course of the infection in the form of acute kidney injury (p=0.018), cytokine storm (p<0.001), serum C-reactive protein over 100 mg/l (p<0.001), and the need for targeted therapy (p<0.001) in the hospitalized patients. Obesity increased the odds of myocarditis by 1,84 times (95% confidence interval [CI]: 1,13-3,00) and the need for anticytokine therapy by 1,7 times (95% CI: 1,30-2,30).The  patients  with  the  1st  and  2nd  degree  obesity,  undergoing  the  inpatient  treatment,  tended  to  have  a  higher  probability  of  a  mortality  rate.  While  in  case  of  morbid  obesity  patients  this  tendency  is  the  most  significant  (odds  ratio  -  1,78; 95% CI: 1,13-2,70). At the same time, the patients whose chronical diseases first appeared after the convalescence period, and those who had certain complaints missing before SARS-CoV-2 infection, more often had BMI of more than 30 kg/m2 (p<0,001).Additionally, the odds of death increased by 2,23 times (95% CI: 1,05-4,72) within 3 months after recovery in obese people over the age of 60 yearsCONCLUSION.  Overweight  and/or  obesity  is  a  significant  risk  factor  for severe  course  of  the  new  coronavirus  infection  and  the associated cardiovascular and kidney damage Overweight people and patients with the 1st and 2nd degree obesity tend to have a high risk of death of SARS-CoV-2 infection in both acute and post-covid periods. On top of that, in case of morbid obesity patients this tendency is statistically significant. Normalization of body weight is a strategic objective of modern medicine and can contribute to prevention of respiratory conditions, severe course and complications of the new coronavirus infection.

Analysis of Clinical and Biochemical Characteristics of Patients With Genetically Confirmed Familial Hypercholesterolemia in Russian North Western District Residents.

Aim      To compare results of clinical, laboratory, and genetic examination of patients with familial hypercholesterolemia (FHC).Material and methods  112 patients aged 40.2±17.9 years (49 men) were examined. The gene of low-density lipoprotein receptor (LDLR) was analyzed and evaluated using the Dutch Lipid Clinic Network (DLCN) criterion of lipid score ≥6. The LDLR gene mutation was searched for using the conformational polymorphism analysis followed by sequencing of the DNA of isolated LDLR gene exons.Results Mean variables of the blood lipid profile were total cholesterol (C), 10.12±2.32 mmol/l, LDL-C, 7.72±2.3 mmol/l. Corneal arcus was observed in 15 % of patients, tendon xanthomas in 31.8 %, and xanthelasma palpebrarum in 5.3 %. The types of LDLR gene mutations included missense mutations (42.8 %), mutations causing a premature termination of protein synthesis (41.1 %), and frameshift mutations (16.1 %). In the presence of a mutation in exon 4, patients with IHD compared to patients with no IHD had significantly higher levels of total C (10.88±2.08 mmol/l vs. 8.74±1.57 mmol/l, respectively, р=0.001) and LDL-C (8.60±2.14 mmol/l vs. 6.62±1.79 mmol/l, respectively, р=0.005). Patients with IHD compared to patients with no IHD and a mutation in LDLR gene exon 9 had only a higher LDL-C level (8.96±1.53 mmol/l vs. 6.92±1.59 mmol/l, respectively, р=0.022). A differentiated comparison of IHD patients using a logistic regression depending on the identified type of LDLR gene mutation produced formulas for calculating the odds ratio of IHD and myocardial infarction (MI) with adjustments for the patient's age and baseline LDL.Conclusion      The detection rate of the LDLR gene mutations was 42.8 % for missense mutations, 41.1 % for mutations causing a premature termination of protein synthesis, and 16.1 % for frameshift mutations. Blood lipid profiles did not differ between patients from different cities and with different types of LDLR gene mutations. Blood lipid profiles were different in IHD patients depending on the mutation type.

[Case of peripartum cardiomyopathy misdiagnosed as pulmonary changes due to COVID-19].

A 37-year-old female patient was admitted 16 days after delivery in a hospital for infectious diseases with cough, shortness of breath, and infiltrative changes in the lungs that were interpreted as viral pneumonia. Considering the failure of therapy and the history, peripartum cardiomyopathy was suspected. Examination revealed a decrease in left ventricular ejection fraction to 30 %, ultrasonic signs of lung congestion and bilateral hydrothorax. The patient was diagnosed with peripartum cardiomyopathy accompanied by functional class 4 heart failure. A specific feature of this case was fast positive dynamics with complete regression of the clinical picture of congestion and improvement of the left ventricular myocardial function associated with the treatment.

Analysis of influence of background therapy for comorbidities in the period before infection on the risk of the lethal COVID outcome. Data from the international ACTIV SARS-CoV-2 registry («Analysis of chronic non-infectious diseases dynamics after COVID-19 infection in adult patients SARS-CoV-2¼).

Aim      To study the effect of regular drug therapy for cardiovascular and other diseases preceding the COVID-19 infection on severity and outcome of COVID-19 based on data of the ACTIVE (Analysis of dynamics of Comorbidities in paTIents who surVived SARS-CoV-2 infEction) registry.Material and methods  The ACTIVE registry was created at the initiative of the Eurasian Association of Therapists. The registry includes 5 808 male and female patients diagnosed with COVID-19 treated in a hospital or at home with a due protection of patients' privacy (data of nasal and throat smears; antibody titer; typical CT imaging features). The register territory included 7 countries: the Russian Federation, the Republic of Armenia, the Republic of Belarus, the Republic of Kazakhstan, the Kyrgyz Republic, the Republic of Moldova, and the Republic of Uzbekistan. The registry design: a closed, multicenter registry with two nonoverlapping arms (outpatient arm and in-patient arm). The registry scheduled 6 visits, 3 in-person visits during the acute period and 3 virtual visits (telephone calls) at 3, 6, and 12 mos. Patient enrollment started on June 29, 2020 and was completed on October 29, 2020. The registry completion is scheduled for October 29, 2022. The registry ID: ClinicalTrials.gov: NCT04492384. In this fragment of the study of registry data, the work group analyzed the effect of therapy for comorbidities at baseline on severity and outcomes of the novel coronavirus infection. The study population included only the patients who took their medicines on a regular basis while the comparison population consisted of noncompliant patients (irregular drug intake or not taking drugs at all despite indications for the treatment).Results The analysis of the ACTIVE registry database included 5808 patients. The vast majority of patients with COVID-19 had comorbidities with prevalence of cardiovascular diseases. Medicines used for the treatment of COVID-19 comorbidities influenced the course of the infectious disease in different ways. A lower risk of fatal outcome was associated with the statin treatment in patients with ischemic heart disease (IHD); with angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor antagonists and with beta-blockers in patients with IHD, arterial hypertension, chronic heart failure (CHF), and atrial fibrillation; with oral anticoagulants (OAC), primarily direct OAC, clopidogrel/prasugrel/ticagrelor in patients with IHD; with oral antihyperglycemic therapy in patients with type 2 diabetes mellitus (DM); and with long-acting insulins in patients with type 1 DM. A higher risk of fatal outcome was associated with the spironolactone treatment in patients with CHF and with inhaled corticosteroids (iCS) in patients with chronic obstructive pulmonary disease (COPD).Conclusion      In the epoch of COVID-19 pandemic, a lower risk of severe course of the coronavirus infection was observed for patients with chronic noninfectious comorbidities highly compliant with the base treatment of the comorbidity.

[Experience of the use of the PCSK9 inhibitor Alirocumab in patients with extremely high cardiovascular risk].

Aim To study the efficacy and safety of alirocumab in patients with high and very high cardiovascular risk in the Republic of Karelia and to evaluate their compliance with the alirocumab therapy.Materials and methods Study design: observational, noncomparative. The observation group consisted of 9 patients receiving alirocumab (Praluent®) (mean age, 48.6±4.7 years; 7 men). 7 patients had familial hypercholesterolemia of the type diagnosed by DLCN criteria; five patients had MI. Lipid profile, concentrations of transaminases, creatinine, glucose, and lipoprotein a (LP(a)) were measured at 3, 6, 12, and 18 months. Electrocardiography was performed, and the clinical picture (development of acute coronary syndrome, acute cerebrovascular disease, transient ischemic attacks, myocardial revascularization, and cardiovascular death) was evaluated. Efficacy criteria included the absence of these clinical conditions, the proportion of patients who achieved the LDL CS goal, and the decrease in LP(a). Safety was evaluated by clinical and laboratory data, such as levels of transaminases, total bilirubin, creatinine, and blood glucose. The observation lasted for 6 months to 1.5 years.Results LDL CS goals were achieved in 7 (77.8%) patients receiving alirocumab. The mean level of LP(a) decreased from 0.39 to 0.28 g/l; the degree of decrease ranged from 20 to 33 %. No cases of IHD instability (acute coronary syndrome) or new cases of acute cerebrovascular disease and transient ischemic attacks were observed. None of the patients had to stop the alirocumab treatment; adverse effects, including local ones, were not observed.Conclusion LDL CS goals were achieved in 7 (77.8%) patients. The level of LP(a) decreased by 20-33% in patients receiving the PCSK9 inhibitor. In real-life clinical practice, the alirocumab treatment was characterized with high compliance and good tolerability without side effects, including local ones.

[Lipid Lowering Therapy with Statins in Patients with Heterozygous Familial Hypercholesterolemia].

AIM: to analyze adherence of FH patients with familial hypercholesterolemia (FH) to the statin therapy and reveal factors, which influence it; to assess the degree of target level of low-density lipoprotein cholesterol (LDLCH) achievement by FH patients on statin therapy. Materials and methods. We included in this study 203 FH patients aged >18 years (mean age 50.0±1.1 years, 82 men). Definite FH was diagnosed in 96 persons, in the other patients FH was considered possible. For evaluating the adherence to therapy with statins we used the Morisky-Green questionnaire. Results. Among patients with definite FH 57 % were adherent to lipid-lowering therapy, 16 % were partially adherent, and 27 % - not adherent. Target LDLCH levels were achieved in 22.6 % and 12.5 % of patients with definite and possible FH, respectively. Smoking and gender were not associated with adherence to statin therapy. Factors associated with higher adherence were age (p=0.000003), arterial hypertension (odds ratio [OR] 1.90, 95 % confidence interval [CI] 1.02 to 3.55], p=0.044), ischemic heart disease (IHD) (OR=2.99, 95 %CI 1.50 to 5.97, p=0.002), history of myocardial infarction (MI) (OR 5.26, 95 %CI 2.03 to 13.60, p=0.0006), history of myocardial revascularization (OR 20.3, 95 %CI 2.64 to 156.11, p=0.004) and the fact of achieving target LDLCH level (OR 19.93, 95 %CI 7.03 to 56.50, p<0.0001). The main reason for the refuse from statin therapy in 87 % of patients was fear of side effects. Main reasons for stopping of ongoing therapy were: myalgia, an increase in transaminases, skin rashes, and high cost in 12, 35, 12, and 6 % of patients, respectively. The decision to withdraw therapy with statins was made by 29 % of patients by themselves. CONCLUSION: In this study 57 % of patients with definite FH were adherent to statin therapy. Factors associated with increased adherence were age, hypertension, IHD, history of MI, history of myocardial revascularization, achievement of target LDLCH level. Target LDLCH levels were achieved by 22.6 and 12.5 %% of patients with definite and possible FH, respectively.

Cholesterol Levels in Genetically Determined Familial Hypercholesterolaemia in Russian Karelia.

Familial hypercholesterolaemia (FH) is a rare disease that tends to be diagnosed lately. In Russia, the genetic and phenotypic characteristics of the disease are not well defined. We investigated 102 patients with definite FH. In 52 of these patients (50.9%) genetic analysis was performed, revealing pathogenic mutations of the low density lipoprotein (LDL) receptor gene in 22 patients. We report here five mutations of the LDL receptor gene found in the Karelian FH sample for the first time. The detection rate of mutations in definite FH patients was 42.3%. Two groups of patients with a definite diagnosis of FH according to the Dutch Lipid Clinic Network criteria were compared: the first group had putatively functionally important LDL receptor gene mutations, while in the second group LDL receptor gene mutations were excluded by single-strand conformation polymorphism analysis. Total and LDL cholesterol levels were higher in the group with LDL receptor mutations compared to the mutation-free population. The frequency of mutations in patients with LDL cholesterol > 6.5 mmol/L was more than 3 times higher than that in patients with LDL < 6.5 mmol/L. Total and LDL cholesterol levels and the frequency of coronary heart disease and myocardial infarction were higher in the group with definite FH compared to groups with probable and possible FH. Cholesterol figures in FH patients of different age and sex from the Karelian population were comparable.

[The Familial Hypercholesterolemia Caused by a Novel Human Low Density Lipoprotein Receptor Gene Mutation c.1327 T>C (p.W433R)].

During investigation of molecular nature of familial hypercholesterolemia (FH) in Petrozavodsk (Russia) cohort of patients a novel low density lipoprotein (LDL) receptor gene mutation was found. This mutation designated c.1327 T>C (W443R [W422R]) was predicted to cause substitution of arginine for tryptophan residue in the very conservative -propeller domain of the LDL receptor. Inheritance of the new mutation was traced in four generations and its cosegregation with hypercholesterolemia phenotype was observed. Despite the predicted pathogenic effect of the mutation, ischemic heart disease in the pedigree was mild or absent. We consider identification of this mutation in the pedigree extremely helpful to start preventive medical treatment in affected patients.

[CONTRIBUTION OF LIPOPROTEIN(A) TO CARDIOVASCULAR RISK IN PATIENTS UNDER 40 YEARS OF AGE AFTER ACUTE MYOCARDIAL INFARCTION OR ACUTE CEREBRAL CIRCULATION DISORDER].

AIM: To evaluate the importance of lipoprotein(a) for the evaluation of cardiovascular risk in patient under 40 years of age after acute myocardial infarction or acute cerebral circulation disorder. MATERIALS AND METHODS: We analysed the data from two departments of the Regional Vascular Centre for 2013-2015 including 90 case histories of patients of different age (mean 57.8 ± 3.4 yr) and studied standard risk factors, such as age, sex, smoking habits, dyslipidemia, aggravated heredity, arterial hypertension (AH), obesity. Standard examination of 7 patients under 40 years of age was supplemented by measuring lipoprotein(a) by the immunoturbodimetric method regarding the levels over 0.3 g/l as abnormally elevated. RESULTS: The study group was dominated by young and middle-aged men (85.2 and 84% respectively). The key risk factors were increased LDLP level (88%) and smoking (70%) in patients under the age of 40 and AH in middle-aged men (100%, p < 0.004). Arterial hypertension was also diagnosed in 59% of the younger subjects. Increased LDLP levels most frequently occurred in senior patients (90%). The group of patients under 40 yr included 15% of those having a single risk factor. In this group, 22% of the patients were at high risk calculated prior to the development of vascular events, 58% at moderate and 20% at low risk. 42.8% of the patients had elevated lipoprotein(a) levels. CONCLUSION: Based on the relative risk scoring scale, 22% of the patients under 40 years of age were at risk of myocardial infarction or cerebral circulation disorders prior to the development of vascular events. However, these patients like those of other age groups frequently had traditional risk factors, such as smoking (67.5%), AH and dyslipidemia (66.6% each). Total cholesterol was elevated only in 47.6% of the patients while LDLP and LP(a) in 92 and 42.8% respectively.

[Role of assessment of arterial wall stiffness in predicting carotid artery atherosclerosis in patients with abdominal obesity]. / Rol' otsenki zhestkosti arterial'noi stenki pri prognozirovanii ateroskleroza sonnoi arterii u patsientov s abdominal'nym ozhireniem.

AIM: To estimate the possibility of using arterial wall stiffness (AWS) parameters as predictors for carotid artery atherosclerotic plaques (CAAPs) in patients with abdominal obesity (AO). MATERIALS AND METHODS: A total of 132 patients (72% men; mean age, 45.0±5.3 years) with normal blood pressure (BP) and AO, and no cardiovascular diseases (CVD) at a SCORE risk of <5% were examined. The investigators analyzed lipid composition of blood, its levels of glucose, uric acid, and creatinine, by calculating glomerular filtration rate and performed 24-hour BP monitoring, by estimating AWS parameters, and triplex scanning of the brachiocephalic arteries. RESULTS: CAAPs were detected in 20 (15.2%) patients. A subgroup of persons with an aortic pulse wave velocity (PWV) of ≥75th percentile (8.0 m/sec for persons aged 31-45 years; 8.3 m/sec for those aged 46-55 years) showed higher rates of carotid atherosclerosis (CA) (44.1% versus 15.2%; p<0.01). The predictors of CAAPs were aortic PWV, average daily aortic systolic BP, and the blood levels of glucose on an empty stomach and uric acid. CONCLUSION: The analysis of AWS parameters in patients with AO and no CVD at a low SCORE risk may become a potential tool to estimate the likelihood of CAAPs. When the aortic PWV equal or greater than 8.0 m/sec for persons aged 31-45 years and 8.3 m/sec for those aged 46-55 years, CA screening is appropriate for possible further risk reclassification.

[Assessment of arterial wall stiffness by 24-hour blood pressure monitoring]. / Otsenka pokazatelei zhestkosti arterial'noi stenki pri sutochnom monitorirovanii arterial'nogo davleniia.

Arterial wall stiffness is an early marker of cardiovascular diseases. The gold standard for assessment of the stiffness of large vessels is presently pulse wave velocity (PWV). Work is in progress on the study of the reference values of PWV in people of different genders and ages. 24-hour blood pressure (BP) monitoring is not only a procedure that can estimate diurnal BP variability, but also monitor the indicators of vascular wall stiffness in a number of cases over a 24-hour period. The given review highlights the pathophysiology of arterial stiffness, methods for its assessment, and the aspects of use in therapeutic practice.

[Circadian CLOCK Gene Variants, Parameters of Arterial Stiffness and Blood Pressure Levels in Subjects Without Arterial Hypertension].

CLOCK gene polymorphic variants, parameters of arterial stiffness and blood pressure (BP) variability were studied in 115 normotensive Russian patients without cardiovascular diseases (62 men, 53 women; mean age 36.4+/-1.01 years). Examination included ECG, 24h BP monitoring, duplex scan of carotid arteries, registration of vascular stiffness parameters, and genotyping of the following polymorphic markers of CLOCK: 3111T>C (3-untranslated region), 862T>C (exon 9) and 257T>G (promoter region) by PCR-RFLP method. Pulse wave velocity was not significantly different among carriers of various 257T>G, 862T>C, 3111T>C genotypes. Augmentation index (Aix night, Aix max) values were lower in individuals with genotypes allegedly associated with essential hypertension and ischemic heart disease (257GG, 862CC, 3111CC). Arterial stiffness index (ASI) was significantly higher in men having CC genotype of 862T>C. Polymorphic variants 257T>G and 862T>C SNPs of CLOCK gene were found to be associated with parameters reflecting BP variability (morning rise of diastolic BP and rate of BP rise). These results provide a basis for suggestion that the CLOCK gene polymorphism is one of factors determining elastic properties of vascular wall. The suggestion is supported by discussion of possible molecular mechanisms of circadian genes impact on elasticity and rigidity of vessel.

[Visceral Obesity as Risk Factor of Early Vascular Aging].

AIM: to analyze dependence of parameters of vascular remodeling on the presence of visceral obesity (VO) assessed by echocardiographic measurement of epicardial fat thickness (EFT). MATERIAL AND METHODS: We examined 163 asymptomatic normotensive patients (74.8% men, mean age 45.0+/-5.4 years) with low or moderate risk on the SCORE). Examination included echocardiography, triplex ultrasound of brachiocephalic arteries, bifunctional 24-hour blood pressure (BP) monitoring with assessment of arterial stiffness. VO was diagnosed at EFT more or equal 75 percentile which was 4.8 and 3.5, 5.8 and 4.4 mm among patients aged 31-45 and 46-55 years with and without abdominal obesity (AO), respectively. RESULTS: Patients with VO more often had pulse wave velocity (PWV) in the aorta which corresponded to criteria of early vascular aging.