May Measurement Month 2019: an analysis of blood pressure screening results from Slovenia.

Accounting for an estimated 10.4 million deaths each year, arterial hypertension is a worldwide epidemic. However, it is a treatable condition that can be readily recognized with cost-effective blood pressure (BP) measurements. Alongside continuous improvements in BP control and treatment, worldwide strategies aim to achieve a high level of hypertension awareness. May Measurement Month (MMM) is a global campaign initiated by the International Society of Hypertension to raise awareness of high BP. Slovenia began with yearly cost-free BP measurements and awareness campaigns in 2005 when World Hypertension Day was announced by the World Hypertension League and in 2017, we joined the MMM initiative. In May 2019, we performed a cross-sectional survey following the standardized MMM protocol. Healthcare personnel obtained BP measurements in a sample of adult subjects (≥18 years) across all regions of the country, mostly in healthcare facilities and pharmacies. In total, 4974 individuals (61.1% female), with a mean age of 59.6 years, were screened. After multiple imputation for missing data, 3037 (61.1%) participants had hypertension. Of individuals not receiving antihypertensive medication, 973 (33.4%) were hypertensive. Of those who reported receiving antihypertensives, 1110 (53.8%) had uncontrolled BP. MMM19 was the largest BP screening campaign undertaken in Slovenia so far. We again identified a substantial number of participants with possible hypertension and uncontrolled BP despite taking antihypertensive medication, which were then referred to their general practitioners or dedicated hypertension centres for further evaluation and management. Taken together, our findings underline the importance of opportunistic screening programmes.

May Measurement Month 2018: an analysis of blood pressure screening results from Slovenia.

Elevated blood pressure (BP) is a growing burden worldwide, contributing to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative organized by the International Society of Hypertension aimed to raise awareness of high BP. In May 2018, we carried out an opportunistic cross-sectional survey of volunteers from different parts of the country aged ≥18 years. Blood pressure measurement followed the standard MMM protocol and statistical analysis mean of the last 2 of 3 readings was used, where these were unavailable additional imputations were performed. In total, 4883 individuals (61.0% female) were screened during the whole month of May in 91 primary and secondary health facilities, pharmacies and through an online survey. After multiple imputation, 2841 (58.2%) had HTN. Of individuals not receiving antihypertensive medication, 850 (29.4%) were hypertensive. Of those receiving antihypertensive medication, 1025 (51.5%) had uncontrolled BP. MMM18 was the largest BP screening campaign undertaken in Slovenia. A substantial number of people with possible HTN were identified and referred to general practitioners for further management. The high number of individuals with HTN, with newly diagnosed HTN and with uncontrolled BP despite medication, confirms a real need for such screening programmes in our country.

Temporal changes in left ventricular longitudinal strain in general population: Clinical correlates and impact on cardiac remodeling.

BACKGROUND: Recent studies in patients and general population have reported the role of left ventricular (LV) longitudinal strain (LS) as an independent predictor of outcome. However, there are few data on changes in LS over time. We therefore investigated in a general population clinical correlates of temporal changes in LS. We also explored the potential correlation between temporal changes in LV volumes and LS. METHODS AND RESULTS: We measured LV end-systolic (ESV) and end-diastolic (EDV) volumes by conventional echocardiography and LS by 2D speckle tracking in 627 participants (mean age 50.6 years, 51.4% women; 41.3% hypertensives) at baseline and after 4.7 years. For statistical analysis, we used the absolute values of LS. In stepwise regression, the magnitude of the decrease in all LV LS indexes over time was greater in men than in women (P < 0.0001). Higher baseline mean arterial pressure (MAP), a larger longitudinal increase in MAP, and stopping diuretic treatment during follow-up were related to larger decreases in LS indexes. In multivariable-adjusted analysis, we observed an inverse correlation between baseline ESV and LV LS (P ≤ 0.0017). Similarly, lower baseline LS and a larger decrease in LS over time were correlated with a lesser longitudinal decrease in ESV (P ≤ 0.0004). CONCLUSIONS: A significant decrease in LS over time was associated with male sex, higher baseline MAP, ∆MAP, and alteration in antihypertensive treatment. We suggested an interaction between a longitudinal decrease in LV deformation and adverse cardiac remodeling, while underscoring the importance of deformation analysis based on LS assessment in patients at risk.

Relation of Insulin Resistance to Longitudinal Changes in Left Ventricular Structure and Function in a General Population.

BACKGROUND: Population data on the longitudinal changes of left ventricular (LV) structure and function in relation to insulin resistance are sparse. Therefore, we assessed in a general population whether hyperinsulinemia predicts longitudinal changes in LV and arterial characteristics. METHODS AND RESULTS: In 627 participants (mean age 50.7 years, 51.4% women), we assessed echocardiographic indexes of LV structure and function and carotid-femoral pulse wave velocity by applanation tonometry at baseline and after 4.7 years. We regressed longitudinal changes in these indexes on baseline insulin and its change during follow-up, and reported standardized effect sizes as a percentage of the SD of LV changes associated with a doubling of insulin. After adjustment, higher baseline insulin predicted a greater temporal increase in LV mass index (effect size: +15.1%) and E/e' ratio (+22.1%), and a greater decrease in e' peak and longitudinal strain (-11.2% to -17.1%). A greater increase in insulin during follow-up related to a greater increase in LV mass index (+10.7%) and decline in ejection fraction and longitudinal strain (-11.4% to -15.7%). Participants who became or remained insulin resistant during follow-up experienced worse changes in longitudinal strain, E/e', and LV mass index as compared with participants who did not develop or had improved insulin resistance over time (P≤0.033). Moreover, multivariable-adjusted increase in pulse wave velocity was higher in participants with diabetes mellitus than in participants without diabetes mellitus (+1.46 m/s versus +0.71 m/s; P=0.039). CONCLUSIONS: Hyperinsulinemia at baseline and during follow-up predicted worsening of LV function and remodeling over time. Our findings underline the importance of management of insulin resistance.

Doppler indexes of left ventricular systolic and diastolic function in relation to haemodynamic load components in a general population.

BACKGROUND: The contribution of central pulsatility to left ventricular (LV) dysfunction might be mediated by the haemodynamic loads of forward (Pf) and backward (Pb) pulse waves. We investigated the relation between echocardiographic indexes of LV function and pulsatile loads derived by wave separation analysis (WSA). METHODS: In 755 participants, we assessed LV dimensions, transmitral blood flow and mitral annular tissue velocities. We derived central pulse pressure (cPP) from radial tonometric recordings and calculated Pf, Pb and their ratio (reflection magnitude) using an automated, pressure-based WSA algorithm. Despite good quality recordings, WSA failed to derive Pf and Pb in 139 participants (18.4%), in particular in older women with unfavourable haemodynamics. Thus, our analysis included 616 participants (46.1% women; mean age, 49.2 years). RESULTS: Age and age explained most of the variance in cPP (36.9%), Pf (18.6%), Pb (41.5%) and reflection magnitude (36.7%; P < 0.0001) and altered the direct correlation between Pf and Pb (Pint < 0.0001). Haemodynamic loads were independently associated with sex, BMI, heart rate, mean arterial pressure, history of diabetes and use of antihypertensive drugs. In multivariable-adjusted analyses, transmitral velocities and E/e' ratio increased with higher cPP, Pf and Pb in men and women. We also observed an age-dependent association of LV radial strain with cPP, Pf and Pb. CONCLUSION: The commercial WSA algorithm holds limited clinical utility given its low feasibility in older participants with unfavourable haemodynamics. LV function indexes were similarly associated with Pf and Pb, favouring the use of the composite cPP for prediction of LV dysfunction.

Correlation Between Mitochondrial DNA Content Measured in Myocardium and Peripheral Blood of Patients with Non-Ischemic Heart Failure.

BACKGROUND/OBJECTIVES: Heart failure (HF) is associated with disturbances in mitochondrial energy production. This mitochondrial dysfunction is reflected by depletion of mitochondrial DNA (mtDNA) in different tissues. Our aims were to determine if there was a correlation between mtDNA content measured in myocardial tissue and the easily accessible peripheral blood cells of patients with non-ischemic HF; and to determine if there was a correlation between myocardial mtDNA and left ventricular (LV) ejection fraction. METHODS: We prospectively collected paired myocardial tissue and peripheral blood samples from 13 consecutive end-stage non-ischemic HF patients undergoing cardiac transplantation. mtDNA content was assessed with real-time quantitative PCR by calculating the relative ratio of two specific mitochondrial sequences and one nuclear control gene sequence. RESULTS: HF patients with lower myocardial mtDNA content had a significantly lower LV ejection fraction (r = 0.65, p = 0.016). Peripheral blood mtDNA content correlated positively with right ventricular myocardial mtDNA content (r = 0.63, p = 0.021). We also observed that averaged myocardial DNA content tended to correlate with peripheral blood mtDNA content (r = 0.53, p = 0.061). CONCLUSIONS: In non-ischemic HF patients, myocardial mtDNA content is positively correlated with peripheral blood mtDNA content and LV function as assessed by echocardiography.

Peripheral blood mitochondrial DNA content in relation to circulating metabolites and inflammatory markers: A population study.

Mitochondrial DNA (mtDNA) content might undergo significant changes caused by metabolic derangements, oxidative stress and inflammation that lead to development and progression of cardiovascular diseases. We, therefore, investigated in a general population the association of peripheral blood mtDNA content with circulating metabolites and inflammatory markers. We examined 310 subjects (50.6% women; mean age, 53.3 years) randomly selected from a Flemish population. Relative mtDNA content was measured by quantitative real-time PCR in peripheral blood cells. Peak circulating metabolites were quantified using nuclear magnetic resonance spectroscopy. The level of inflammation was assessed via established inflammatory markers. Using Partial Least Squares analysis, we constructed 3 latent factors from the 44 measured metabolites that explained 62.5% and 8.5% of the variance in the contributing metabolites and the mtDNA content, respectively. With adjustments applied, mtDNA content was positively associated with the first latent factor (P = 0.002). We identified 6 metabolites with a major impact on the construction of this latent factor including HDL3 apolipoproteins, tyrosine, fatty acid with αCH2, creatinine, ß-glucose and valine. We summarized them into a single composite metabolite score. We observed a negative association between the composite metabolic score and mtDNA content (P = 0.001). We also found that mtDNA content was inversely associated with inflammatory markers including hs-CRP, hs-IL6, white blood cell and neutrophil counts as well as neutrophil-to-lymphocyte ratio (P≤0.0024). We demonstrated that in a general population relative peripheral blood mtDNA content was associated with circulating metabolites indicative of perturbed lipid metabolism and with inflammatory biomarkers.

Peripheral Blood Mitochondrial DNA and Myocardial Function.

Heart failure is a complex progressive clinical syndrome which is initiated by risk factors (e.g., hypertension, obesity, and diabetes), then proceeds to asymptomatic maladaptive left ventricular remodeling and dysfunction, and finally evolves into clinically overt, symptomatic heart failure, disability, and death. The progression of left ventricular dysfunction is associated with changes in cardiac energy metabolism. Mitochondria play a central role in a variety of cardiomyocytes functions, including oxidative energy production, storage of calcium ions, and programmed cell death. The mitochondrial DNA (mtDNA) content correlates with the size and number of mitochondria, which change under different energy demands and oxidative stress. Experimental studies demonstrated that any genetic manipulation resulting in significantly decreased mtDNA could accelerate the ageing process and cause adverse myocardial remodeling and dysfunction. On the other hand, preservation of the mtDNA copy number in mouse hearts delays the development of heart failure after myocardial infarction. Recent general population study also demonstrated that echocardiographic indexes of left ventricular structure and function are significantly and independently associated with mtDNA content measured at peripheral blood cells in cross-sectional and longitudinal analyses. In this chapter, we will discuss the recent experimental, clinical and epidemiological data of the possible impact of mtDNA content on cardiac structure and function.

Longitudinal Changes in LV Structure and Diastolic Function in Relation to Arterial Properties in General Population.

OBJECTIVES: We assessed to what extent arterial properties measured at baseline and follow-up predict longitudinal alterations in echocardiographic indexes reflecting left ventricular (LV) structure and function. BACKGROUND: Serial imaging studies are needed to clarify the relation of changes in LV structure and function to arterial stiffness. METHODS: In 607 participants (50.7% women; mean age 50.7 years), using echocardiography and Doppler imaging, we measured LV dimensions, transmitral blood flow, and mitral annular tissue velocities at baseline and after 4.7 years. Using applanation tonometry, we assessed central pulse pressure (cPP) and carotid-femoral pulse wave velocity (PWV) at baseline. We regressed longitudinal changes in LV indexes on the arterial stiffness parameters and reported standardized effect sizes as a fraction of SD of LV change. RESULTS: After full adjustment, longitudinal increase in LV septal (standardized effect size: +14.4%; p = 0.0018) and posterior wall (+12.6%; p = 0.0027) thickness was associated with higher baseline PWV, whereas LV internal diameter (-12.4%; p = 0.012) decreased during follow-up with PWV. Consequently, greater increase in relative wall thickness was associated with higher baseline PWV (+17.2%; p <0.0001). Participants with higher baseline PWV had a greater risk to develop or retain LV concentric remodeling during follow-up (odds ratio 1.35; p = 0.028). In addition, in women, baseline cPP predicted a greater increase in LV mass (+22.8%; p = 0.0009) and E/e' ratio (+36.1%; p <0.0001). CONCLUSIONS: Progression to LV concentric remodeling pattern was associated with higher baseline PWV. In women, cPP predicted worsening of LV diastolic function. Our study highlights the importance of arterial properties as mediator of LV concentric remodeling in men and women, and diastolic dysfunction in women.

Additive Prognostic Value of Left Ventricular Systolic Dysfunction in a Population-Based Cohort.

BACKGROUND: Techniques of 2-dimensional speckle tracking enable the measurement of myocardial deformation (strain) during systole. Recent clinical studies explored the prognostic role of left ventricular global longitudinal strain (GLS). However, there are few data on the association between cardiovascular outcome and GLS in the community. Therefore, we hypothesized that GLS contains additive prognostic information over and beyond traditional cardiovascular risk factors in a large, population-based cohort. METHODS AND RESULTS: We measured GLS by 2-dimensional speckle tracking in the apical 4-chamber view in 791 participants (mean age 50.9 years). We calculated multivariable adjusted hazard ratios for midwall, endocardial, and epicardial GLS, while accounting for family cluster and cardiovascular risk factors. Median follow-up was 7.9 years (5th to 95th percentile, 3.7-9.6). In continuous analysis, with adjustments applied for covariables, midwall, endocardial, and epicardial GLS were significant predictors of fatal and nonfatal cardiovascular (n=96; P<0.0001) and cardiac events (n=68; P≤0.001). In the sex-specific low quartile of midwall GLS (<18.8% in women and <17.4% in men), the risk was significantly higher than the average population risk for cardiovascular (128%, P<0.0001) and cardiac (94%, P=0.0007) events. We also noticed that the risk for cardiovascular events increased with increasing number of left ventricular abnormalities, such as low GLS, diastolic dysfunction, and hypertrophy (log-rank P<0.0001). CONCLUSIONS: Low GLS measured by 2-dimensional speckle tracking predicts future cardiovascular events independent of conventional risk factors. Left ventricular midwall strain represents a simple echocardiographic measure, which might be used for assessing cardiovascular risk in a population-based cohort.

Association of left ventricular structure and function with peripheral blood mitochondrial DNA content in a general population.

BACKGROUND/OBJECTIVES: mtDNA content might be an important biomarker in heart disease prediction and to date no population studies are available on the association of mtDNA content with cardiac structure and function. We, therefore, investigated in a general population in cross-sectional and longitudinal studies whether echocardiographic indexes of LV structure and function are associated with mtDNA content measured in peripheral blood cells. METHODS: At baseline we performed echocardiography in 701 randomly selected individuals (50.9% women, mean age, 53.2years) from a Flemish population. Relative mtDNA copy number compared to nuclear DNA was measured by quantitative real-time PCR in peripheral blood cells. RESULTS: With adjustments applied, we observed significant inverse association of LV diastolic and systolic diameters (P≤0.028) and volumes (P=0.013) with mtDNA content. Moreover, for a 1-SD increment in mtDNA (0.37), we found an increase in Tissue Doppler s' velocity by 0.093cm/s (P=0.019) and a decrease in E/e' ratio by 0.18 (P=0.008). In 223 subjects with available echocardiography and mtDNA content at baseline and follow-up, we observed that higher baseline mtDNA content was associated with less increase in 2D LV diastolic volume (P=0.0003), M-mode LV diameter (P=0.046) and LV mass (P=0.003) during the follow-up period. CONCLUSIONS: In the general population, higher mtDNA content was associated with smaller LV diastolic and systolic diameters and volumes and better LV systolic and diastolic function. Moreover, we observed that baseline mtDNA content was a significant predictor of longitudinal changes of LV diastolic volume and dimension, and LV mass.

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.

Doppler indexes of left ventricular systolic and diastolic function in relation to the arterial stiffness in a general population.

BACKGROUND: Late-systolic loading of the left ventricular (LV) is determined by arterial wave reflections and central vascular stiffening. We, therefore, investigated the relationship between various Doppler indexes reflecting LV systolic and diastolic function and arterial stiffness in the framework of a large population study of randomly recruited study participants. METHODS: In 1233 study participants (51.7% women; mean age, 48 years; 41.5% hypertensive), using conventional and tissue Doppler imaging, we measured: the transmitral early (E) and late (A) diastolic velocities; tissue Doppler imaging systolic and early (e') and late diastolic mitral annular velocities; and end-systolic longitudinal and radial strain. Using applanation tonometry, we assessed central pulse pressure (cPP), augmentation pressure and carotid-femoral pulse wave velocity. RESULTS: After full adjustment, transmitral E and A peaks increased with augmentation pressure and cPP (P less than 0.0001) and e' was positively associated with cPP (P = 0.013). The E/e' ratio increased significantly with augmentation pressure (P less than 0.0001), cPP (P less than 0.0001) and pulse wave velocity (P = 0.048). Although accounting for covariables, all arterial indexes were on average significantly higher in the diastolic dysfunction group with elevated filling pressure (n = 171) when compared to participants with normal diastolic function (n = 961; P ≤ 0.0004) or with impaired relaxation (n = 101; P ≤ 0.008). Longitudinal strain decreased independently with mean arterial pressure (P = 0.03). The correlation between radial strain and the arterial indexes shifted from positive at middle age (50-60 years) to negative at older (P less than 0.0001 for interaction). CONCLUSION: Our study underscored the importance of arterial characteristics as a mediator of LV systolic and diastolic dysfunction. We demonstrated an age-dependent relationship between radial strain and indexes of arterial stiffness.

Renal glomerular dysfunction in relation to retinal arteriolar narrowing and high pulse pressure in seniors.

Retinal arteriolar narrowing and high pulse pressure (PP) are associated with macrovascular complications and microvascular renal disease. Few studies addressed whether in seniors (⩾60 years) estimated glomerular filtration rate (eGFR) is independently related to central retinal arteriolar equivalent (CRAE) and PP. In 292 randomly recruited seniors (49.3% women; mean, 68.2 years), we measured PP by standard sphygmomanometry, CRAE (IVAN software), eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) and stage of chronic kidney disease (CKD (Kidney Disease Outcomes Quality Initiative guideline)). Statistical methods included linear and logistic regression. PP, CRAE and eGFR averaged 59.2 mm Hg, 146.3 µm and 79.9 ml min(-1) per 1.73 m(2). Decline in eGFR (-2.27 ml min(-1) per 1.73 m(2) per 15 µm; P=0.011) occurred in parallel with CRAE narrowing. CRAE (effect size per 1-s.d. increment, -1.85 µm; P=0.032) and eGFR (-2.68 ml min(-1) per 1.73 m(2); P=0.003) both declined with higher PP. With PP increasing from 63 to 73 mm Hg (threshold for macrovascular complications), CRAE dropped by -4.70 µm (P⩽0.037). A 70-mm Hg PP threshold corresponded with a 150-µm CRAE cutoff. The risk of CKD (stage ⩾2 vs. 1; n=203 vs. 89) rose with CRAE <150 µm (odds ratio, 2.81; P<0.0001), but not with PP ⩾70 mm Hg (1.47; P=0.20). Additionally, CRAE added to PP increased the area under the curve from 0.58 to 0.64 (P=0.047) for identifying stage ⩾2 CKD. In seniors, CRAE and eGFR decline in parallel with higher PP. CRAE <150 µm identifies early decline in eGFR.

Correlates of Peripheral Blood Mitochondrial DNA Content in a General Population.

Accumulation of mitochondrial DNA (mtDNA) mutations leads to alterations of mitochondrial biogenesis and function that might produce a decrease in mtDNA content within cells. This implies that mtDNA content might be a potential biomarker associated with oxidative stress and inflammation. However, data on correlates of mtDNA content in a general population are sparse. Our goal in the present study was to describe in a randomly recruited population sample the distribution and determinants of peripheral blood mtDNA content. From 2009 to 2013, we examined 689 persons (50.4% women; mean age = 54.4 years) randomly selected from a Flemish population (Flemish Study on Environment, Genes, and Health Outcomes). Relative mtDNA copy number as compared with nuclear DNA was measured by quantitative real-time polymerase chain reaction in peripheral blood. There was a curvilinear relationship between relative mtDNA copy number and age. mtDNA content slightly increased until the fifth decade of life and declined in older subjects (Page (2) = 0.0002). mtDNA content was significantly higher in women (P = 0.007) and increased with platelet count (P < 0.0001), whereas it was inversely associated with white blood cell count (P < 0.0001). We also observed lower mtDNA content in women using estroprogestogens (P = 0.044). This study demonstrated in a general population that peripheral blood mtDNA content is significantly associated with sex and age. Blood mtDNA content is also influenced by platelet and white blood cell counts and estroprogestogen intake. Further studies are required to clarify the impact of chronic inflammation and hormone therapy on mitochondrial function.

Cytokines profile in hypertensive patients with left ventricular remodeling and dysfunction.

There is strong evidence that inflammatory mediators play a key role in the progression to heart failure in patients with systemic hypertension (HTN). The present study aimed to identify a set of cytokines that are associated with early left ventricular (LV) remodeling and dysfunction as captured by echocardiography in patients with HTN in a cross-sectional case-control study nested within the FLEMish study on ENvironment, Genes and Health Outcome. We identified three groups of participants from the cohort: normotensive subjects (normotension; n = 30), HTN with normal LV structure and function (HTN [LV-]; n = 30), and HTN with evidence of adverse LV remodeling (HTN [LV+]; n = 50). We measured cytokines using a 63-plex Luminex platform. Using partial least squares-discriminant analysis, we constructed three latent variables from the measured cytokines that explained 35%-45% of the variance between groups. We identified five common cytokines (interleukin 18, monokine induced by gamma interferon, hepatocyte growth factor, epithelial neutrophil-activating peptide 78, and vascular endothelial growth factor D) with a stable signal which had a major impact on the construction of the latent variables. Among these cytokines, after adjustment for confounders, interleukin 18 remained significantly different between HTN participants with and without LV involvement (P = .02). Moreover, granulocyte-macrophage colony-stimulating factor and leptin showed a consistent upward trend in all HTN patients compared with normotensive subjects. In conclusion, in HTN patients with LV remodeling or/and dysfunction, we identified a set of cytokines strongly associated with LV maladaptation. We also found a distinct profile of inflammatory biomarkers that characterize HTN.

Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

BACKGROUND: In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD). RESULTS: In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25-2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16-3.31), 1.87 (1.20-2.91) and 3.16 (1.41-7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %). CONCLUSIONS: Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.

Longitudinal changes in left ventricular diastolic function in a general population.

BACKGROUND: Data on changes in left ventricular diastolic function (LVDF) over time in the general population are sparse. We, therefore, investigated in the population cohort clinical correlates of longitudinal changes in Doppler diastolic indexes analyzed as continuous measures and assessed factors predictive of the changes in LVDF grades over time. METHODS AND RESULTS: We measured early and late diastolic peak velocities of mitral inflow (E and A) by conventional Doppler, and the mitral annular velocities (e' and a') by tissue Doppler imaging in 650 participants (mean age, 50.7 years) at baseline and after 4.7 years (5th to 95th percentile, 3.7-5.4). In stepwise regression, the multivariable-adjusted correlates of the change in the transmitral and tissue Doppler imaging diastolic indexes included sex, age, baseline serum insulin, blood pressure, and heart rate. During follow-up, LVDF grades remained unchanged in 87.2% (95% confidence interval, 84.6%-89.8%), improved in 3.7% (95% confidence interval, 2.25%-5.15%), and worsened in 9.1% (95% confidence interval, 6.9%-11.3%). Baseline age was a strong predictor of worsening of LVDF from normal/mild grade to more advanced grade (odds ratio, 3.22; P<0.0001). A doubling of baseline insulin was associated with a 184% increase in the odds of worsening of LVDF (P<0.0001). Moreover, baseline diastolic blood pressure and the change in systolic blood pressure over time predicted worsening of LVDF (P≤0.014). CONCLUSIONS: The key findings of this study are that LVDF tended to worsen over time and was associated with advanced age, higher baseline insulin level, and hemodynamic parameters, such as heart rate and blood pressure.

Doppler indexes of left ventricular systolic and diastolic flow and central pulse pressure in relation to renal resistive index.

BACKGROUND: The cardio-renal interaction occurs via hemodynamic and humoral factors. Noninvasive assessment of renal hemodynamics is currently possible by assessment of renal resistive index (RRI) derived from intrarenal Doppler arterial waveforms as ((peak systolic velocity - end-diastolic velocity)/peak systolic velocity). Limited information is available regarding the relationship between RRI and cardiac hemodynamics. We investigated these associations in randomly recruited subjects from a general population. METHODS: In 171 participants (48.5% women; mean age, 52.2 years), using pulsed wave Doppler, we measured RRI (mean, 0.60) and left ventricular outflow tract (LVOT) and transmitral (E and A) blood flow peak velocities and its velocity time integrals (VTI). Using carotid applanation tonometry, we measured central pulse pressure and arterial stiffness indexes such as augmentation pressure and carotid-femoral pulse wave velocity. RESULTS: In stepwise regression analysis, RRI independently and significantly increased with female sex, age, body weight, brachial pulse pressure, and use of ß-blockers, whereas it decreased with body height and mean arterial pressure. In multivariable-adjusted models with central pulse pressure and arterial stiffness indexes as the explanatory variables, we observed a significant and positive correlation of RRI only with central pulse pressure (P < 0.0001). Among the Doppler indexes of left ventricular blood flow, RRI was significantly and positively associated with LVOT and E peak velocities (P ≤ 0.012) and VTIs (P ≤ 0.010). CONCLUSIONS: We demonstrated that in unselected subjects RRI was significantly associated with central pulse pressure and left ventricular systolic and diastolic Doppler blood flow indexes. Our findings imply that in addition to the anthropometric characteristics, cardiac hemodynamic factors influence the intrarenal arterial Doppler waveform patterns.

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.