The Prevalence of Heterozygous Familial Hypercholesterolemia in Selected Regions of the Russian Federation: The FH-ESSE-RF Study.

Heterozygous familial hypercholesterolemia (HeFH) is one of the most common genetic conditions but remains substantially underdiagnosed. The aim of our study was to investigate the prevalence of HeFH in the population of 11 different regions of Russia. Individuals were selected from the Epidemiology of Cardiovascular Risk Factors and Diseases in Regions of the Russian Federation Study. All participants who had low-density lipoprotein cholesterol (LDL-C) higher than 4.9 mmol/L, or LDL-C lower than 4.9 mmol/L, but had statin therapy, were additionally examined by FH experts. FH was diagnosed using the Dutch Lipid Clinic Network criteria, incorporating genetic testing. HeFH prevalence was assessed for 18,142 participants. The prevalence of patients with definite or probable HeFH combined was 0.58% (1 in 173). A total of 16.1% of patients with definite or probable HeFH had tendon xanthomas; 36.2% had mutations in one of the three genes; 45.6% of FH patients had coronary artery disease; 63% of HeFH patients received statins; one patient received an additional PCSK9 inhibitor; no patients received ezetimibe. Only 3% of patients reached the LDL-C goal based on 2019 ESC/EAS guidelines. Underdiagnosis and undertreatment of FH in Russia underline the need for the intensification of FH detection with early and aggressive cholesterol-lowering treatment.

Global Differences in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial. METHODS: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region. RESULTS: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction P>0.05). CONCLUSIONS: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.

BACKGROUND: The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS: We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS: There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).

The prevalence of familial hypercholesterolemia in the West Siberian region of the Russian Federation: A substudy of the ESSE-RF.

BACKGROUND: The prevalence of familial hypercholesterolemia (FH) in Russia has not previously been evaluated. The aim of our study was to investigate the prevalence of FH in the population of the West Siberian region of Russia, and then estimate the frequency of coronary artery disease (CAD) and treatment with cholesterol-lowering medication in FH patients. METHODS: The sample of our study consisted of participants from the population-based cohort of The Epidemiology of Cardiovascular Risk Factors and Diseases in Regions of the Russian Federation Study (ESSE-RF), conducted in the Tyumen and Kemerovo regions (1,630 and 1,622 people, respectively, aged 25-64). All participants who had LDL-cholesterol higher than 4.9 mmol/l and who had LDL-cholesterol less than or equal to 4.9 mmol/l but had statin therapy were examined and interviewed by experts in FH. RESULTS: The prevalence of patients with definite FH was 0.24% (one in 407) (95% confidence interval [CI]: 0.06%-0.42%), with probable FH was 0.68% (one in 148) (95% CI: 0.38%-0.98%), and with definite or probable FH combined was 0.92% (one in 108) (95% CI: 0.58%-1.26%). 40% (95% CI: 20.8%-59.2%) of patients with definite or probable FH had CAD. However, only 23% (95% CI: 6.3%-39.7%) of patients with definite or probable FH were on statins. The odds ratios for CAD and myocardial infarction (MI), adjusted for age, gender, region, smoking, hypertension, and diabetes mellitus, were 3.71 (95% CI: 1.58-8.72) (p = 0.003) and 4.06 (95% CI: 0.89-18.55) (р = 0.070) respectively for individuals with definite or probable FH relative to those who were unlikely to have FH. CONCLUSIONS: The prevalence of FH in Russia may be significantly higher than previously estimated. There is underdiagnosis and undertreatment of FH in Russia.

Growth Hormone, Insulin-Like Growth Factor-1, Insulin Resistance, and Leukocyte Telomere Length as Determinants of Arterial Aging in Subjects Free of Cardiovascular Diseases.

Background: Increased arterial stiffness (AS), intima-media thickness (IMT), and the presence of atherosclerotic plaques (PP) have been considered as important aspects of vascular aging. It is well documented that the cardiovascular system is an important target organ for growth hormone (GH) and insulin-like growth factor (IGF)-1 in humans, and GH /IGF-1 deficiency significantly increases the risk for cardiovascular diseases (CVD). The telomere length of peripheral blood leukocytes (LTL) is a biomarker of cellular senescence and that has been proposed as an independent predictor of (CVD). The aim of this study is to determine the role of GH/IGF-1, LTL and their interaction cardiovascular risk factors (CVRF) in the vascular aging. Methods: The study group included 303 ambulatory participants free of known CVD (104 males and 199 females) with a mean age of 51.8 ± 13.3 years. All subjects had one or more CVRF [age, smoking, arterial hypertension, obesity, dyslipidemia, fasting hyperglycemia, insulin resistance-HOMA (homeostatic model assessment) >2.5, or high glycated hemoglobin]. The study sample was divided into the two groups according to age as "younger" (m ≤ 45 years, f ≤ 55 years) and "older" (m > 45 years, f > 55 years). IMT and PP were determined by ultrasonography, AS was determined by measuring the carotid-femoral pulse wave velocity (c-f PWV) using the SphygmoCor system (AtCor Medical). LTL was determined by PCR. Serum IGF-1 and GH concentrations we measured by immunochemiluminescence analysis. Results: Multiple linear regression analysis with adjustment for CVRF indicated that HOMA, GH, IGF-1, and LTL had an independent relationship with all the arterial wall parameters investigated in the younger group. In the model with c-f PWV as a dependent variable, p < 0.001 for HOMA, p = 0.03 for GH, and p = 0.004 for LTL. In the model with IMT as a dependent variable, p = 0.0001 for HOMA, p = 0.044 for GH, and p = 0.004 for IGF-1. In the model with the number of plaques as a dependent variable, p = 0.0001 for HOMA, and p = 0.045 for IGF-1. In the older group, there were no independent significant associations between GH/IGF-1, LTL, HOMA, and arterial wall characteristics. Conclusions: GH/IGF-1, IR, HOMA, and LTL were the important parameters of arterial aging in younger healthy participants.

Carotid and Aortic Stiffness in Patients with Heterozygous Familial Hypercholesterolemia.

BACKGROUND: The role of plasma cholesterol in impairing arterial function and elasticity remains unclear. We evaluated arterial stiffness, measured locally in the common carotid artery by high-resolution echo-tracking, and aortic stiffness, using carotid-femoral pulse wave velocity (PWV) (the "gold-standard" measurement of arterial stiffness), in treatment-naive patients with heterozygous familial hypercholesterolemia (FH). METHODS: The study included 66 patients with FH (10-66 years old) and 57 first-degree relatives without FH (11-61 years old). Carotid-femoral PWV was determined by SphygmoCor (AtCor, Australia). The parameters of carotid stiffness ß-index, Peterson elastic modulus and local PWV were assessed with regard to the common carotid artery at a distance of 1cm from the bifurcation (AlokaProsound Alpha7, Japan). RESULTS: FH patients showed significantly higher ß-index (6.3(4.8-8.2) vs. 5.2(4.2-6.4), p = 0.005), Ep (78(53-111) kPa vs. 62(48-79) kPa, p = 0.006), local PWV (5.4(4.5-6.4) m/c vs. 4.7(4.2-5.4) m/c, p = 0.005), but comparable values of carotid-femoral PWV (6.76(7.0-7.92) m/c vs. 6.48(6.16-7.12) m/c, p = 0.138). Carotid arteries and the aorta stiffened with age in patients with FH, but after 30 years, carotid arteries stiffened more significantly than the aorta. CONCLUSIONS: Our study demonstrated that treatment-naive patients with FH had stiffer carotid arteries than their relatives, but showed no difference in aortic stiffness. We also found out that the rate of reduction of elasticity of the aorta and carotid arteries in FH patients varies: it is observed earlier in carotid arteries than in the aorta.

Association between the gut microbiota and diet: Fetal life, early childhood, and further life.

Gut microbiota establishment and further microbiota shifts are very important for maintaining host health throughout life. There are some factors, including genetics, the mother's health and diet, delivery mode, breast or formula feeding, that may influence the gut microbiota. By the end of approximately the first 3 y of life, the gut microbiota becomes an adult-like stable system. Once established, 60 to 70% of the microbiota composition remains stable throughout life, but 30 to 40% can be altered by changes in the diet and other factors such as physical activity, lifestyle, bacterial infections, and antibiotic or surgical treatment. Diet-related factors that influence the gut microbiota in people of all ages are of great interest. Nutrition may have therapeutic success in gut microbiota correction. This review describes current evidence concerning the links between gut microbiota composition and dietary patterns throughout life.

Russia SimSmoke: the long-term effects of tobacco control policies on smoking prevalence and smoking-attributable deaths in Russia.

BACKGROUND: Russia has high smoking rates and weak tobacco control policies. A simulation model is used to examine the effect of tobacco control policies on past and future smoking prevalence and premature mortality in Russia. METHODS: The Russia model was developed using the SimSmoke tobacco control model previously developed for the USA and other nations. The model inputs population size, birth, death and smoking rates specific to Russia. It assesses, individually and in combination, the effect of seven types of policies consistent with the WHO Framework Convention on Tobacco Control (FCTC): taxes, smoke-free air, mass media campaign, advertising bans, warning labels, cessation treatment and youth access policies. Outcomes are smoking prevalence and the number of smoking-attributable deaths by age and gender from 2009 to 2055. RESULTS: Increasing cigarette taxes to 70% of retail price, stronger smoke-free air laws, a high-intensity media campaign and comprehensive treatment policies are each potent policies to reduce smoking prevalence and smoking-attributable premature deaths in Russia. With the stronger set of policies, the model estimates that, relative to the status quo trend, smoking prevalence can be reduced by as much as 30% by 2020, with a 50% reduction projected by 2055. This translates into 2 684 994 male and 1 011 985 female premature deaths averted from 2015-2055. CONCLUSIONS: SimSmoke results highlight the relative contribution of policies to reducing the tobacco health burden in Russia. Significant inroads to reducing smoking prevalence and premature mortality can be achieved through strengthening tobacco control policies in line with FCTC recommendations.

Ultrasound markers that describe plaques are more sensitive than mean intima-media thickness in patients with familial hypercholesterolemia.

A widely adopted ultrasound surrogate marker for predicting cardiovascular risk is mean intima-medial thickness (mean-IMT). There are, however, certain limitations to this methodology. We compared the severity of carotid atherosclerosis in adult patients with high cardiovascular risk (patients with familial hypercholesterolemia [FH] and without previous statin treatment) and in their adult FH-free first-degree relatives using not only mean-IMT, but also maximum-IMT, plaque number, plaque score and percent area stenosis. Mean-IMT has not differed in both groups (0.64 ± 0.18 mm vs. 0.58 ± 0.13 mm in the control group, p = 0.349). Maximum-IMT (0.99 ± 0.35 vs. 0.76 ± 0.19, p = 0.0057), plaque number (3 ± 3 vs. 1 ± 2, p = 0.0009), plaque score (5.14 ± 4.97 mm vs. 1.58 ± 3.09 mm, p = 0.0009) and percent area stenosis (38% ± 22% vs. 12% ± 20%, p = 0.0004) were significantly higher for FH patients than for their relatives. We have demonstrated that plaque number, plaque score and percent area stenosis markers were more sensitive than mean-IMT for cardiovascular risk estimation in patients with familial hypercholesterolemia.