Blood-Based Epigenetic Age Acceleration and Incident Colorectal Cancer Risk: Findings from a Population-Based Case-Control Study.

This study investigates the association between epigenetic age acceleration (EAA) derived from DNA methylation and the risk of incident colorectal cancer (CRC). We utilized data from a random population sample of 9,360 individuals (men and women, aged 45-69) from the HAPIEE Study who had been followed up for 16 years. A nested case-control design yielded 35 incident CRC cases and 354 matched controls. Six baseline epigenetic age (EA) measures (Horvath, Hannum, PhenoAge, Skin and Blood (SB), BLUP, and Elastic Net (EN)) were calculated along with their respective EAAs. After adjustment, the odds ratios (ORs) for CRC risk per decile increase in EAA ranged from 1.20 (95% CI: 1.04-1.39) to 1.44 (95% CI: 1.21-1.76) for the Horvath, Hannum, PhenoAge, and BLUP measures. Conversely, the SB and EN EAA measures showed borderline inverse associations with ORs of 0.86-0.87 (95% CI: 0.76-0.99). Tertile analysis reinforced a positive association between CRC risk and four EAA measures (Horvath, Hannum, PhenoAge, and BLUP) and a modest inverse relationship with EN EAA. Our findings from a prospective population-based-case-control study indicate a direct association between incident CRC and four markers of accelerated baseline epigenetic age. In contrast, two markers showed a negative association or no association. These results warrant further exploration in larger cohorts and may have implications for CRC risk assessment and prevention.

The Relationship between All-Cause Natural Mortality and Copy Number of Mitochondrial DNA in a 15-Year Follow-Up Study.

We explored the relationship between the copy number of mitochondrial DNA (mtDNA-CN) and all-cause natural mortality. We examined a random population sample in 2003/2005 (n = 9360, men/women, 45-69, the HAPIEE project) and followed up for 15 years. Using a nested case-control design, we selected non-external deaths among those free from baseline cardiovascular diseases (CVD) and cancer (n = 371), and a sex- and age-stratified control (n = 785). The odds ratios (ORs) of death were 1.06 (95%CI 1.01-1.11) per one-decile decrease in mtDNA-CN independent of age, sex, metabolic factors, smoking, alcohol intake and education. The age-sex-adjusted ORs of death in the second and first tertiles of mtDNA-CN vs. the top tertile were 2.35 (95% CI 1.70-3.26) and 1.59 (1.16-2.17); an increased risk was confined to the second tertile after controlling for smoking and metabolic factors. The multivariable-adjusted OR of CVD death was 1.92 (95% CI 1.18-3.15) in tertile 2 vs. the top tertile of mtDNA-CN, and for cancer-related death the ORs were 3.66 (95% CI 2.21-6.05) and 2.29 (95% CI 1.43-3.68) in tertiles 2 and 1 vs. the top tertile. In the Siberian population cohort, the mtDNA-CN was an inverse predictor of the 15-year risk of natural mortality, due to the greatest impact of CVD and cancer-related death. The findings merit attention for exploring further the role of mtDNA in human ageing and the diversity of mortality.

Influence of hypertension on systolic and diastolic left ventricular function including segmental strain and strain rate.

BACKGROUND: Left ventricular (LV) systolic and diastolic functions are important cardiovascular risk predictors in patients with hypertension. However, data on segmental, layer-specific strain, and diastolic strain rates in these patients are limited. The aim of this study was to investigate segmental two-dimensional strain rate imaging (SRI)-derived parameters to characterize LV systolic and diastolic function in hypertensive individuals compared with that in normotensive individuals. METHODS: The study sample comprised 1194 participants from the population-based Know Your Heart study in Arkhangelsk and Novosibirsk, Russia, and 1013 individuals from the Seventh Tromsø Study in Norway. The study population was divided into four subgroups: (A) healthy individuals with normal blood pressure (BP), (B) individuals on antihypertensive medication with normal BP, (C) individuals with systolic BP 140-159 mmHg and/or diastolic BP > 90 mm HG, and (D) individuals with systolic BP ≥160 mmHg. In addition to conventional echocardiographic parameters, global and segmental layer-specific strains and strain rates in early diastole and atrial contraction (SR E, SR A) were extracted. The strain and SR (S/SR) analysis included only segments without strain curve artifacts. RESULTS: With increasing BP, the systolic and diastolic global and segmental S/SR gradually decreased. SR E, a marker of impaired relaxation, showed the most distinctive differences between the groups. In normotensive controls and the three hypertension groups, all segmental parameters displayed apico-basal gradients, with the lowest S/SR in the basal septal and highest in apical segments. Only SR A did not differ between the segmental groups but increased gradually with increasing BP. End-systolic strain showed incremental epi-towards endocardial gradients, irrespective of the study group. CONCLUSION: Arterial hypertension reduces global and segmental systolic and diastolic left ventricular S/SR parameters. Impaired relaxation determined by SR E is the dominant factor of diastolic dysfunction, whereas end-diastolic compliance (by SR A) does not seem to be influenced by different degrees of hypertension. Segmental strain, SR E and SR A provide new insights into the LV cardio mechanics in hypertensive hearts.

Comparing prevalence of chronic kidney disease and its risk factors between population-based surveys in Russia and Norway.

BACKGROUND: Little data exists on the prevalence of chronic kidney disease (CKD) in the Russian population. We aimed to estimate the prevalence of CKD in a population-based study in Russia, compare with a similar study in Norway, and investigate whether differences in risk factors explained between-study differences in CKD. METHODS: We compared age- and sex-standardised prevalence of reduced eGFR (< 60 ml/min/1.73m2 CKD-EPI creatinine equation), albuminuria and or a composite indicator of CKD (one measure of either reduced eGFR or albuminuria) between participants aged 40-69 in the population-based Know Your Heart (KYH) study, Russia (2015-2018 N = 4607) and the seventh Tromsø Study (Tromsø7), Norway (2015-2016 N = 17,646). We assessed the contribution of established CKD risk factors (low education, diabetes, hypertension, antihypertensive use, smoking, obesity) to between-study differences using logistic regression. RESULTS: Prevalence of reduced eGFR or albuminuria was 6.5% (95% Confidence Interval (CI) 5.4, 7.7) in KYH and 4.6% (95% CI 4.0, 5.2) in Tromsø7 standardised for sex and age. Odds of both clinical outcomes were higher in KYH than Tromsø7 (reduced eGFR OR 2.06 95% CI 1.67, 2.54; albuminuria OR 1.54 95% CI 1.16, 2.03) adjusted for sex and age. Risk factor adjustment explained the observed between-study difference in albuminuria (OR 0.92 95% CI 0.68, 1.25) but only partially reduced eGFR (OR 1.42 95% CI 1.11, 1.82). The strongest explanatory factors for the between-study difference was higher use of antihypertensives (Russian sample) for reduced eGFR and mean diastolic blood pressure for albuminuria. CONCLUSIONS: We found evidence of a higher burden of CKD within the sample from the population in Arkhangelsk and Novosibirsk compared to Tromsø, partly explained by between-study population differences in established risk factors. In particular hypertension defined by medication use was an important factor associated with the higher CKD prevalence in the Russian sample.

The Relationship between Epigenetic Age and Myocardial Infarction/Acute Coronary Syndrome in a Population-Based Nested Case-Control Study.

We investigated the relationship between 'epigenetic age' (EA) derived from DNA methylation (DNAm) and myocardial infarction (MI)/acute coronary syndrome (ACS). A random population sample was examined in 2003/2005 (n = 9360, 45-69, the HAPIEE project) and followed up for 15 years. From this cohort, incident MI/ACS (cases, n = 129) and age- and sex-stratified controls (n = 177) were selected for a nested case-control study. Baseline EA (Horvath's, Hannum's, PhenoAge, Skin and Blood) and the differences between EA and chronological age (CA) were calculated (ΔAHr, ΔAHn, ΔAPh, ΔASB). EAs by Horvath's, Hannum's and Skin and Blood were close to CA (median absolute difference, MAD, of 1.08, -1.91 and -2.03 years); PhenoAge had MAD of -9.29 years vs. CA. The adjusted odds ratios (ORs) of MI/ACS per 1-year increments of ΔAHr, ΔAHn, ΔASB and ΔAPh were 1.01 (95% CI 0.95-1.07), 1.01 (95% CI 0.95-1.08), 1.02 (95% CI 0.97-1.06) and 1.01 (0.93-1.09), respectively. When classified into tertiles, only the highest tertile of ΔAPh showed a suggestion of increased risk of MI/ACS with OR 2.09 (1.11-3.94) independent of age and 1.84 (0.99-3.52) in the age- and sex-adjusted model. Metabolic modulation may be the likely mechanism of this association. In conclusion, this case-control study nested in a prospective population-based cohort did not find strong associations between accelerated epigenetic age markers and risk of MI/ACS. Larger cohort studies are needed to re-examine this important research question.

Evaluation of Epigenetic Age Acceleration Scores and Their Associations with CVD-Related Phenotypes in a Population Cohort.

We evaluated associations between nine epigenetic age acceleration (EAA) scores and 18 cardiometabolic phenotypes using an Eastern European ageing population cohort richly annotated for a diverse set of phenotypes (subsample, n = 306; aged 45-69 years). This was implemented by splitting the data into groups with positive and negative EAAs. We observed strong association between all EAA scores and sex, suggesting that any analysis of EAAs should be adjusted by sex. We found that some sex-adjusted EAA scores were significantly associated with several phenotypes such as blood levels of gamma-glutamyl transferase and low-density lipoprotein, smoking status, annual alcohol consumption, multiple carotid plaques, and incident coronary heart disease status (not necessarily the same phenotypes for different EAAs). We demonstrated that even after adjusting EAAs for sex, EAA-phenotype associations remain sex-specific, which should be taken into account in any downstream analysis involving EAAs. The obtained results suggest that in some EAA-phenotype associations, negative EAA scores (i.e., epigenetic age below chronological age) indicated more harmful phenotype values, which is counterintuitive. Among all considered epigenetic clocks, GrimAge was significantly associated with more phenotypes than any other EA scores in this Russian sample.

Novel approach to artefact detection and the definition of normal ranges of segmental strain and strain-rate values.

AIMS: Strain artefacts are known to hamper the correct interpretation of segmental strain and strain-rate (S/SR). Defining the normal ranges of myocardial segmental deformation is important in clinical studies and routine echocardiographic practice. In order to define artefact-free normal ranges for segmental longitudinal S/SR parameters, we investigated the extent to which different types of artefacts and their segmental localisation in the three different myocardial layers created a bias in the results of echocardiographic strain measurements. METHODS: The study included echocardiograms from men and women aged 40-69 years from two population-based studies, namely the Know Your Heart study (Russia) and the Tromsø Study (Norway). Of the 2207 individuals from these studies, 840 had normal results, defined as the absence of hypertension or indicators of any cardiovascular disease. Two-dimensional (2D) global and segmental S/SR of the three myocardial layers were analysed using speckle tracking echocardiography. Artefacts were assessed with two different methods: visual identification of image-artefacts and a novel conceptual approach of 'curve-artefacts' or unphysiological strain-curve formation. RESULTS: Segmental strain values were found to have significantly reduced in the presence of strain-curve artefacts (14.9%±5.8% towards -20.7%±4.9%), and increased with the foreshortening of the 2D image. However, the individual global strain values were not substantially altered by discarding segmental artefacts. Reduction due to artefacts was observed in all segments, layers, systolic and diastolic strain, and SR. Thus, we presented normal ranges for basal-septal, basal, medial and apical segment groups after excluding artefacts. CONCLUSION: Strain-curve artefacts introduce systematic errors, resulting in reduced segmental S/SR values. In terms of artefact-robust global longitudinal strain, the detection of curve-artefacts is crucial for the correct interpretation of segmental S/SR patterns. Intersegmental S/SR gradients and artefacts need to be considered for the correct definition of normalcy and pathology.

Between-study differences in grip strength: a comparison of Norwegian and Russian adults aged 40-69 years.

BACKGROUND: Identifying individuals with low grip strength is an initial step in many operational definitions of sarcopenia. As evidence indicates that contemporaneous Russian populations may have lower mean levels of grip strength than other populations in northern Europe, we aimed to: compare grip strength in Russian and Norwegian populations by age and sex; investigate whether height, body mass index, education, smoking status, alcohol use and health status explain observed differences and; examine implications for case-finding low muscle strength. METHODS: We used harmonized cross-sectional data on grip strength and covariates for participants aged 40-69 years from the Russian Know Your Heart study (KYH) (n = 3833) and the seventh survey of the Norwegian Tromsø Study (n = 5598). Maximum grip strength (kg) was assessed using the same protocol and device in both studies. Grip strength by age, sex and study was modelled using linear regression and between-study differences were predicted from these models. Sex-specific age-standardized differences in grip strength and in prevalence of low muscle strength were estimated using the European population standard of 2013. RESULTS: Normal ranges of maximum grip strength in both studies combined were 33.8 to 67.0 kg in men and 18.7 to 40.1 kg in women. Mean grip strength was higher among Tromsø than KYH study participants and this difference did not vary markedly by age or sex. Adjustment for covariates, most notably height, attenuated between-study differences but these differences were still evident at younger ages. For example, estimated between-study differences in mean grip strength in fully adjusted models were 2.2 kg [95% confidence interval (CI) 1.4, 3.1] at 40 years and 1.0 kg (95% CI 0.5, 1.5) at 65 years in men (age × study interaction P = 0.09) and 1.1 kg (95% CI 0.4, 1.9) at age 40 years and -0.2 kg (95% CI -0.7, 0.3) at 65 years in women (age × study interaction P < 0.01). CONCLUSIONS: We found between-study differences in mean grip strength that are likely to translate into greater future risk of sarcopenia and poorer prospects of healthy ageing for Russian than Norwegian study participants. For example, the average Russian participant had a similar level of grip strength to a Norwegian participant 7 years older. Our findings suggest these differences may have their origins in childhood highlighting the need to consider interventions in early life to prevent sarcopenia.

Heavy alcohol drinking and subclinical echocardiographic abnormalities of structure and function.

OBJECTIVE: The aim of the study is to assess changes in heart structure and function associated with heavy alcohol use by comparing echocardiographic indices in a population-based sample to those in patients admitted to an inpatient facility with severe alcohol problems. METHODS AND RESULTS: We used data from the Know Your Heart study (2015-2017) which is a cross-sectional study that recruited 2479 participants aged 35-69 years from the general population of the city of Arkhangelsk in Northwest Russia and 278 patients from the Arkhangelsk Regional Psychiatric Hospital with a primary diagnosis related to chronic alcohol use (narcology clinic subsample). The drinking patterns of the population-based sample were characterised in detail. We used regression models controlling for age, sex, smoking, education and waist to hip ratio to evaluate the differences in echocardiographic indices in participants with different drinking patterns. The means of left ventricular end-diastolic diameter and indexed left atrial systolic diameter were increased among heavy drinkers (narcology clinic subsample), while mean left ventricular ejection fraction was decreased in this group compared with the population-based sample. In contrast, the harmful and hazardous drinkers in the population-based sample did not differ from non-problem drinkers with respect to echocardiographic indices of systolic and diastolic function. CONCLUSIONS: Extremely heavy drinking is associated with a specific set of structural and functional abnormalities of the heart that may be regarded as precursors of alcohol-related dilated cardiomyopathy.

External validation of a deep learning electrocardiogram algorithm to detect ventricular dysfunction.

OBJECTIVE: To validate a novel artificial-intelligence electrocardiogram algorithm (AI-ECG) to detect left ventricular systolic dysfunction (LVSD) in an external population. BACKGROUND: LVSD, even when asymptomatic, confers increased morbidity and mortality. We recently derived AI-ECG to detect LVSD using ECGs based on a large sample of patients treated at the Mayo Clinic. METHODS: We performed an external validation study with subjects from the Know Your Heart Study, a cross-sectional study of adults aged 35-69 years residing in two cities in Russia, who had undergone both ECG and transthoracic echocardiography. LVSD was defined as left ventricular ejection fraction ≤ 35%. We assessed the performance of the AI-ECG to identify LVSD in this distinct patient population. RESULTS: Among 4277 subjects in this external population-based validation study, 0.6% had LVSD (compared to 7.8% of the original clinical derivation study). The overall performance of the AI-ECG to detect LVSD was robust with an area under the receiver operating curve of 0.82. When using the LVSD probability cut-off of 0.256 from the original derivation study, the sensitivity, specificity, and accuracy in this population were 26.9%, 97.4%, 97.0%, respectively. Other probability cut-offs were analysed for different sensitivity values. CONCLUSIONS: The AI-ECG detected LVSD with robust test performance in a population that was very different from that used to develop the algorithm. Population-specific cut-offs may be necessary for clinical implementation. Differences in population characteristics, ECG and echocardiographic data quality may affect test performance.

Impact and pitfalls of scaling of left ventricular and atrial structure in population-based studies.

BACKGROUND: Several allometric methods for indexing cardiac structures to body size have been proposed but the optimal way for normalization of cardiac structures is still controversial. We aimed to estimate the allometric exponents that best describe the relationships between cardiac dimensions and body size, propose normative values, and analyze how the different scaling metrics influence the prevalence of left ventricular hypertrophy (LVH) and chambers enlargement as well as predictive models for cardiovascular outcome in the community. METHODS: We measured left ventricular end-diastolic dimension, end-diastolic volume, left ventricular mass, and left atrial volume in randomly recruited population cohorts (n = 1509; 52.8% women; mean age, 47.8 years). RESULTS: In a healthy subgroup (n = 656), the allometric exponents that described the relationships between left ventricular end-diastolic dimension and body size were 1, 0.5, and 0.33 for body height, body surface area (BSA), and estimated lean body mass, respectively. With regard to left ventricular end-diastolic volume, left ventricular mass, and left atrial volume the allometric exponents for body height were 2.9, 2.7, and 2.0, respectively; for BSA, they ranged from 1.7 to 1.8; for estimated lean body mass all exponents were around 1. These exponents were used to appropriately scale the cardiac dimensions to body size and derived sex-specific cut-off limits for different indexed cardiac dimensions. The hazard ratios of cardiovascular outcome were highest for LVH defined by left ventricular mass/height. CONCLUSION: Our study resulted in a proposal for thresholds for various indexed cardiac dimensions. Left ventricular mass indexed to height was sensitive in detection of LVH associated with obesity and slightly better predicted outcome.

Left ventricular diastolic function associated with common genetic variation in ATP12A in a general population.

BACKGROUND: Left ventricular (LV) function depends on the activity of transmembrane electrolyte transporters. Failing human myocardium has lower Na(+)/K(+) ATPase expression and higher intracellular sodium concentrations. The ATP12A gene encodes a catalytic subunit of an ATPase that can function as a Na(+)/K(+) pump. We, therefore, investigated the association between LV function and common genetic variants in ATP12A. METHODS: A random sample of 1166 participants (53.7% women; mean age 49.5 years, 44.8% hypertensive) was recruited in Belgium, Poland, Italy and Russia. We measured transmitral early and late diastolic velocities (E and A) by pulsed wave Doppler, and mitral annular velocities (e' and a') by tissue Doppler. Using principal component analysis, we summarized 7 Doppler indexes - namely, E, A, e' and a' velocities, and their ratios (E/A, e'/a', and E/e') - into a single diastolic score. We genotyped 5 tag SNPs (rs963984, rs9553395, rs10507337, rs12872010, rs2071490) in ATP12A. In our analysis we focused on rs10507337 because it is located within a transcription factor binding site. RESULTS: In the population-based analyses while adjusting for covariables and accounting for family clusters and country, rs10507337 C allele carriers had significantly higher E/A (P = 0.003), e' (P = 5.8×10(-5)), e'/a' (P = 0.003) and diastolic score (P = 0.0001) compared to TT homozygotes. Our findings were confirmed in the haplotype analysis and in the family-based analyses in 74 informative offspring. CONCLUSIONS: LV diastolic function as assessed by conventional and tissue Doppler indexes including a composite diastolic score was associated with genetic variation in ATP12A. Further experimental studies are necessary to clarify the role of ATP12A in myocardial relaxation.

Heritability and other determinants of left ventricular diastolic function in the family-based population study.

BACKGROUND: Understanding to what extent genetic factors influence diastolic Doppler indexes is an important issue in view of the relation of left ventricular diastolic dysfunction with outcome. We, therefore, investigated the heritability of left ventricular diastolic traits and the composite diastolic score in nuclear families recruited from the general population. METHODS: In a random sample of 316 nuclear families (452 parents and 600 offspring, mean age, 58.5 and 33.3 years), we measured transmitral early and late diastolic velocities (E and A) by pulsed wave Doppler, and mitral annular velocities (e' and a') by tissue Doppler. Using principal component analysis, we summarized seven Doppler indexes - namely, E, A, e' and a' velocities, and their ratios - into a single diastolic score. To calculate the heritability of diastolic indexes, we used variance decomposition in nuclear families and offspring as implemented in SOLAR and SAS, and the regression slope of offspring on mid-parent residual values. RESULTS: In variance decomposition analyses in nuclear families, the abovementioned traits with adjustment for covariables had moderate heritability ranging from 0.27 to 0.43 (P < 0.0001 for all). The parent-offspring concordances of all diastolic indexes were significant and ranged from 0.17 for A (P = 0.009) to 0.42 for e' (P < 0.0001). In nuclear families and offspring, the heritability estimates of the composite diastolic score were 0.42 and 0.64, respectively (P < 0.0001). CONCLUSION: Our study demonstrated moderate heritability of various indexes reflecting left ventricular diastolic function in nuclear families. The observation highlights the necessity of further research into the genes that affect left ventricular diastolic function.

Prevalence of left ventricular diastolic dysfunction in European populations based on cross-validated diagnostic thresholds.

BACKGROUND: Different diagnostic criteria limit comparisons between populations in the prevalence of diastolic left ventricular (LV) dysfunction. We aimed to compare across populations age-specific echocardiographic criteria for diastolic LV dysfunction as well as their correlates and prevalence. METHODS: We measured the E and A peaks of transmitral blood flow by pulsed wave Doppler and the e' and a' peaks of mitral annular velocities by tissue Doppler imaging (TDI) in 2 cohorts randomly recruited in Belgium (n = 782; 51.4% women; mean age, 51.1 years) and in Italy, Poland and Russia (n = 476; 55.7%; 44.5 years). RESULTS: In stepwise regression, the multivariable-adjusted correlates of the transmitral and TDI diastolic indexes were similar in the 2 cohorts and included sex, age, body mass index, blood pressure and heart rate. Similarly, cut-off limits for the E/A ratio (2.5th percentile) and E/e' ratio (97.5th percentile) in 338 and 185 reference subjects free from cardiovascular risk factors respectively selected from both cohorts were consistent within 0.02 and 0.26 units (median across 5 age groups). The rounded 2.5th percentile of the E/A ratio decreased by ~0.10 per age decade in these apparently healthy subjects. The reference subsample provided age-specific cut-off limits for normal E/A and E/e' ratios. In the 2 cohorts combined, diastolic dysfunction groups 1 (impaired relaxation), 2 (possible elevated LV filling pressure) and 3 (elevated E/e' and abnormally low E/A) encompassed 114 (9.1%), 135 (10.7%), and 40 (3.2%) subjects, respectively. CONCLUSIONS: The age-specific criteria for diastolic LV dysfunction were highly consistent across the study populations with an age-standardized prevalence of 22.4% vs. 25.1%.

Tissue Doppler indexes of left ventricular systolic function in relation to the pulsatile and steady components of blood pressure in a general population.

OBJECTIVES: To our knowledge, no population study described the association of the radial and longitudinal components of left ventricular strain with blood pressure (BP) components in continuous analyses. We therefore investigated these associations in participants randomly recruited from the general population in the framework of the family-based European Project on Genes in Hypertension. METHODS: In 334 participants (55.4% women; mean age, 43.6 year), using tissue Doppler imaging (TDI), we measured the end-systolic longitudinal strain (mean 20.9%) and peak systolic strain rate (1.29 s) from the basal portion of the left ventricular inferior and posterior free walls and radial stain (51.1%) and strain rate (3.40 s) of the left ventricular posterior wall. Models included in addition to covariables and confounders both SBP and DBP or both pulse pressure (PP) and mean arterial pressure (MAP). Effect sizes were expressed per 1-SD increase in BP. RESULTS: Longitudinal strain (-0.62%; P = 0.04 and -0.64%; P = 0.007), but not strain rate, decreased with DBP and MAP. Radial strain (4.0 and -3.4%; P ≤ 0.001) and strain rate (0.38 and -0.18 s; P ≤ 0.04) independently increased with SBP and decreased with DBP. Accordingly, radial strain (2.9%; P < 0.0001) and strain rate (0.22 s; P = 0.0005) increased with higher PP, but were not related to MAP. CONCLUSION: In the general population, BP is an independent determinant of left ventricular systolic function as measured by TDI. Radial function increased with PP, the pulsatile BP component, whereas longitudinal function decreased with the steady component of BP as expressed by MAP or DBP.

Prevalence and predictors of carotid wall triple line pattern in a general population sample.

OBJECTIVE: Carotid intima-media thickness (IMT) and plaques are markers of atherosclerosis and predict cardiovascular events. A specific sonographic triple line pattern (TLP) of the carotid wall has been identified in different conditions, but its origin and clinical significance are unclear. We examined the prevalence and predictors of TLP in a general population. METHODS AND RESULTS: The study was conducted in random sample of the general population of Novosibirsk, Russia, within the international Health, Alcohol and Psychosocial Factors in Eastern Europe project. In a subsample of 418 men (aged 45 to 69), carotid IMT, the presence of atherosclerotic plaques, and the presence of TLP were assessed by ultrasound. The prevalence of TLP was 21%. It was associated with IMT (odds ratio = 9.53 per 1 SD, P<0.001) and the presence of plaques (odds ratio = 2.42, P = 0.002). Other predictors of TLP in multivariate models included age, systolic blood pressure, total cholesterol, and smoking. In addition, infrequent consumption of high amounts of alcohol approximately doubled the risk of triple pattern. CONCLUSIONS: Our findings showed high prevalence of TLP of carotid wall in a general male population sample from a typical Russian city. This sonographic pattern was strongly associated with cardiovascular risk factors and diseases, bioimaging indicators of atherosclerosis, and episodic heavy drinking.

Left ventricular structure in relation to the human SAH gene in the European Project on Genes in Hypertension.

Earlier studies showed association of the human SAH (Spontaneously hypertensive rat-clone A-Hypertension associated) gene with hypertension and obesity. Left ventricular mass index (LVMI) increases with blood pressure and body mass index. In a family-based population study (54.5% women; mean age, 43.1 years), we measured LVMI, mean wall thickness (MWT) and the left ventricular internal diameter (LVID) at end-diastole in 699 non-Slavic and 493 Slavic participants. In multivariable-adjusted analyses, we investigated phenotype-genotype associations (SAH G-1606A and -962ins/del polymorphisms), while accounting for confounders and relatedness. Non-Slavic -1606GG homozygotes had a slightly greater LVID than -1606A allele carriers (48.6 vs. 48.0 mm; P=0.08). However, the between-family component of the variance in LVID was significant (P=0.005), suggesting that population stratification might explain the latter finding. Non-Slavic -962del carriers had higher LVMI (91.1 vs. 88.5 g m(-2); P=0.03) and MWT (9.61 vs. 9.44 mm; P=0.03) than -962ins homozygotes. Transmission of the -962del to non-Slavic offspring was also associated with higher MWT (P=0.03). In Slavic participants, in the absence of population stratification (P>or=0.69), -1606GG homozygotes had lower LVMI (96.5 vs. 102.3 g m(-2); P=0.004) and lower MWT (10.1 vs. 10.5 mm; P=0.003) than -1606A carriers. Sensitivity analyses showed that the latter associations were confined to founders. Transmission of the -962del allele to Slavic offspring was associated with lower MWT (P=0.007). In conclusion, LVMI and MWT, two phenotypes that are jointly influenced by blood pressure and obesity, might be related to variation in the human SAH gene.

Intrafamilial correlations of carotid intima-media thickness and flow-mediated dilation in a Siberian population.

BACKGROUND: Intima-media thickening and impaired endothelium-dependent vasodilation are complex phenotypes determined by genetic and environmental factors. Few studies assessed these phenotypes in the same subjects. The goal of our study was to assess the sex-specific intrafamilial aggregation of ultrasonographic carotid intima-media thickness (IMT) and brachial flow-mediated vasodilation (FMD) in a Siberian population. METHODS: We randomly recruited 81 nuclear families of Caucasian ancestry (129 parents and 157 offspring, mean age 52.4 and 26.3 years) in Novosibirsk, Russia. Carotid artery IMT and brachial artery FMD were assessed by ultrasound. Intraclass correlation coefficients were calculated between first-degree relatives and between unrelated spouse pairs for IMT and FMD in age- adjusted, sex-adjusted, and multivariate-adjusted models. RESULTS: Multivariate-adjusted correlation coefficients in sib-sib pairs were 0.27 (P = .042) for IMT and 0.29 (P = .049) for FMD with heritabilities (h(2)= 2r) of 0.54 and 0.58, respectively. For IMT, the mother-offspring (r = 0.17, P = .051) and mother-daughter correlations (r = 0.28, P = .025) were significant, whereas the father-offspring correlation did not differ from zero (r = 0.11, P = .33). For FMD the father-offspring (r = 0.24, P = .042) and father-son correlations (r = 0.40, P = .051) were significant, whereas the mother-offspring correlation was only -0.09 (P = .39). The P value for the difference in familial aggregation of FMD between father-offspring and mother-offspring pairs was .018. CONCLUSIONS: Our findings confirm that a substantial proportion of the variability of carotid IMT and brachial FMD is attributable to genetic variation. They also suggest that offspring share more genetic or environmental determinants of FMD with fathers than their mothers.

Left ventricular mass in relation to genetic variation in angiotensin II receptors, renin system genes, and sodium excretion.

BACKGROUND: In the European Project On Genes in Hypertension (EPOGH), we investigated in 3 populations to what extent left ventricular mass (LVM) was associated with genetic variation in the angiotensin II receptors type 1 (AGTR1 A1166C) and type 2 (AGTR2 G1675A) while accounting for possible gene-gene interactions with the angiotensin-converting enzyme (ACE D/I) and angiotensinogen (AGT -532C/T) polymorphisms. METHODS AND RESULTS: We randomly recruited 221 nuclear families (384 parents, 431 offspring) in Cracow (Poland), Novosibirsk (Russia), and Mirano (Italy). Echocardiographic LVM was indexed to body surface area, adjusted for covariates, and subjected to multivariate analyses using generalized estimating equations and quantitative transmission disequilibrium tests in a population-based and family-based approach, respectively. For AGTR1 and AGTR2, there was no heterogeneity in the phenotype-genotype relations across populations. LVM index was unrelated to the AGTR1 A1166C polymorphism. In men, in the population- and family-based analyses, the allelic effects of the AGTR2 polymorphism on LVM index differed (P=0.01) according to sodium excretion. In women, this gene-environment interaction did not reach statistical significance. In untreated men, LVM index (4.2 g/m2 per 100 mmol) and left ventricular internal diameter (0.73 mm/100 mmol) increased (P<0.02) with higher sodium excretion in the presence of the G allele with an opposite tendency in A allele carriers. The ACE D/I polymorphism, together with the ACE genotype-by-sodium interaction term, significantly and independently improved the models relating LVM index to the AGTR2 polymorphism and the AGTR2 genotype-by-sodium interaction. CONCLUSIONS: The present findings support the hypothesis that in men the AGTR2 G1675A and the ACE D/I polymorphisms independently influence LVM and that salt intake modulates these genetic effects.

Relationship between left ventricular mass and the ACE D/I polymorphism varies according to sodium intake.

BACKGROUND: In the European Project on Genes in Hypertension (EPOGH), we investigated to what extent left ventricular mass (LVM) in populations and families relates to the angiotensin-converting enzyme (ACE D/I) and aldosterone synthase (CYP11B2 -344C/T) polymorphisms and urinary sodium excretion. METHODS: We recruited 219 nuclear families (382 parents and 436 offspring) randomly in Cracow (Poland), Novosibirsk (Russia) and Mirano (Italy). Echocardiographical LVM was indexed to body surface area, adjusted for covariables, and subjected to multivariate analyses using generalized estimating equations and quantitative transmission disequilibrium tests, in a population-based and family-based approach, respectively. RESULTS: We found significant differences between the two Slavic centres and Mirano in left ventricular mass index (LVMI) (94.9 versus 80.3 g/m2), sodium excretion (229 versus 186 mmol/day), and the prevalence of the ACE D allele (52.1 versus 58.5%). There was significant heterogeneity between Slavic and Italian subjects in the phenotype-genotype relationships with the ACE gene, but not with the aldosterone synthase gene. In the two Slavic centres, ACE II homozygosity was significantly associated with higher LVMI, in population-based as well as in family-based analyses. By contrast, in Mirano, LVMI was slightly higher in DD homozygotes (P = 0.05), but only in the population-based approach. LVMI increased with higher sodium excretion in ACE II homozygous offspring of both Slavic and Italian extraction (+4.2 +/- 2.1 g/m2 per 100 mmol; P = 0.04) and in Slavic (+2.6 +/- 1.1 g/m2 per 100 mmol; P = 0.02), but not Italian (-3.3 +/- 3.2 g/m2 per 100 mmol; P = 0.29) D allele carriers. We did not find any association between LVMI and the aldosterone synthase -344C/T polymorphism. CONCLUSIONS: The relationship between LVMI and the ACE D/I polymorphism differs across populations, possibly as a consequence of intermediate regulatory mechanisms responsive to varying levels of salt intake.