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Fractal analysis provides a global assessment of vascular networks (e.g., geometric complexity). We examined the association of diastolic left ventricular (LV) function with the retinal microvascular fractal dimension. A lower fractal dimension signifies a sparser retinal microvascular network. In 628 randomly recruited Flemish individuals (51.3% women; mean age, 50.8 years), we measured diastolic LV function by echocardiography and the retinal microvascular fractal dimension by the box-counting method (Singapore I Vessel Assessment software, version 3.6). The left atrial volume index (LAVI), e', E/e' and retinal microvascular fractal dimension averaged (±SD) 24.3 ± 6.2 mL/m 2 , 10.9 ± 3.6 cm/s, 6.96 ± 2.2, and 1.39 ± 0.05, respectively. The LAVI, E, e' and E/e' were associated (P < 0.001) with the retinal microvascular fractal dimension with association sizes (per 1 SD), amounting to -1.49 mL/m 2 (95% confidence interval, -1.98 to -1.01), 2.57 cm/s (1.31-3.84), 1.34 cm/s (1.07-1.60), and -0.74 (-0.91 to -0.57), respectively. With adjustments applied for potential covariables, the associations of E peak and E/e' with the retinal microvascular fractal dimension remained significant (P ≤ 0.020). Over a median follow-up of 5.3 years, 18 deaths occurred. The crude and adjusted hazard ratios expressing the risk of all-cause mortality associated with a 1-SD increment in the retinal microvascular fractal dimension were 0.36 (0.23-0.57; P < 0.001) and 0.57 (0.34-0.96; P = 0.035), respectively. In the general population, a lower retinal microvascular fractal dimension was associated with greater E/e', a measure of LV filling pressure. These observations can potentially be translated into new strategies for the prevention of diastolic LV dysfunction.

Background: Previous studies highlighted the usefulness of integrating left ventricular (LV) deformation (strain) and hemodynamic parameters to quantify LV performance. In a population sample, we investigated the anthropometric and clinical determinants of a novel non-invasive index of LV systolic performance derived from simultaneous registration of LV strain and brachial pressure waveforms., Methods: Three hundred fifty-six randomly recruited subjects (44.7% women; mean age, 53.9 years; 47.5% hypertensive) underwent echocardiographic and arterial data acquisition. We constructed pressure-strain loops from simultaneously recorded two-dimensional LV strain curves and brachial pressure waveforms obtained by finger applanation tonometry. We defined the area of this pressure-strain loop during ejection as LV ejection work density (EWD). We reported effect sizes as EWD changes associated with a 1-SD increase in covariables., Results: In multivariable-adjusted analyses, higher EWD was associated with age, female sex and presence of hypertension (P ≤ 0.0084). In both men and women, EWD increased independently with augmentation pressure (effect size: + 59.1 Pa), central pulse pressure (+ 65.7 Pa) and pulse wave velocity (+ 44.8 Pa; P ≤ 0.0006). In men, EWD decreased with relative wall thickness (- 29.9 Pa) and increased with LV ejection fraction (+ 23.9 Pa; P ≤ 0.040). In women, EWD increased with left atrial (+ 76.2 Pa) and LV end-diastolic (+ 43.8 Pa) volume indexes and with E/e' ratio (+ 51.1 Pa; P ≤ 0.026)., Conclusion: Older age, female sex and hypertension were associated with higher EWD. Integration of the LV pressure-strain loop during ejection might be a useful tool to non-invasively evaluate sex-specific and interdependent effects of preload and afterload on LV myocardial performance.

Background Serial imaging studies in the general population remain important to evaluate the usefulness of pathophysiologically relevant biomarkers in predicting progression of left ventricular (LV) remodeling and dysfunction. Here, we assessed in a general population whether these circulating biomarkers at baseline predict longitudinal changes in LV structure and function. Methods and Results In 592 participants (mean age, 50.8 years; 51.4% women; 40.5% hypertensive), we derived echocardiographic indexes reflecting LV structure and function at baseline and after 4.7 years. At baseline, we measured alkaline phosphatase, markers of collagen turnover (procollagen type I, C-terminal telopeptide, matrix metalloproteinase-1) and high-sensitivity cardiac troponin T. We regressed longitudinal changes in LV indexes on baseline biomarker levels and reported standardized effect sizes as a fraction of the standard deviation of LV change. After full adjustment, a decline in LV longitudinal strain (-14.2%) and increase in E/e' ratio over time (+18.9%; P≤0.019) was associated with higher alkaline phosphatase activity at baseline. Furthermore, longitudinal strain decreased with higher levels of collagen I production and degradation at baseline (procollagen type I, -14.2%; C-terminal telopeptide, -16.4%; P≤0.029). An increase in E/e' ratio over time was borderline associated with lower matrix metalloproteinase-1 (+9.8%) and lower matrix metalloproteinase-1/tissue inhibitor of metalloproteinase-1 ratio (+11.9%; P≤0.041). Higher high-sensitivity cardiac troponin T levels at baseline correlated significantly with an increase in relative wall thickness (+23.1%) and LV mass index (+18.3%) during follow-up ( P≤0.035). Conclusions We identified a set of biomarkers predicting adverse changes in LV structure and function over time. Circulating biomarkers reflecting LV stiffness, injury, and collagen composition might improve the identification of subjects at risk for subclinical cardiac maladaptation.

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.

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., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: No longitudinal study compared associations of echocardiographic indexes of diastolic left ventricular function studies with conventional (CBP) and daytime ambulatory (ABP) blood pressure in the general population., Methods and Results: In 780 Flemish (mean age, 50.2 years; 51.7% women), we measured left atrial volume index (LAVI), peak velocities of the transmitral blood flow (E) and mitral annular movement (e') in early diastole and E/e' 9.6 years (median) after CBP and ABP. In adjusted models including CBP and ABP, we expressed associations per 10/5-mm Hg systolic/diastolic blood pressure increments. LAVI and E/e' were 0.65/0.40 mL/m 2 and 0.17/0.09 greater with higher systolic/diastolic ABP ( P ≤0.028), but not with higher baseline CBP ( P ≥0.086). e' was lower ( P ≤0.032) with higher diastolic CBP (-0.09 cm/s) and ABP (-0.19 cm/s). When we substituted baseline CBP by CBP recorded concurrently with echocardiography, LAVI and E/e' remained 0.45/0.38 mL/m 2 and 0.15/0.08 greater with baseline ABP ( P ≤0.036), while LAVI (+0.53 mL/m 2 ) and E/e' (+0.19) were also greater ( P <0.001) in relation to concurrent systolic CBP. In categorized analyses of baseline data, sustained hypertension or masked hypertension compared with normotension or white-coat hypertension was associated with greater LAVI (24.0 versus 22.6 mL/m 2 ) and E/e' (7.35 versus 6.91) and lower e' (10.7 versus 11.6 cm/s; P ≤0.006 for all) with no differences ( P ≥0.092) between normotension and white-coat hypertension or between masked hypertension and sustained hypertension., Conclusions: ABP is a long-term predictor of diastolic left ventricular function, statistically outperforming distant but not concurrent CBP. Masked hypertension and sustained hypertension carry equal risk for deterioration of diastolic left ventricular function., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

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., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background In view of the increasing heart failure epidemic and awareness of the adverse impact of environmental pollution on human health, we investigated the association of left ventricular structure and function with air pollutants in a general population. Methods In 671 randomly recruited Flemish (51.7% women; mean age, 50.4 years) we echocardiographically assessed left ventricular systolic strain and strain rate and the early and late peak velocities of transmitral blood flow and mitral annular movement (2005-2009). Using subject-level data, left ventricular function was cross-sectionally correlated with residential long-term exposure to air pollutants, including black carbon, PM2.5, PM10 (particulate matter) and nitrogen dioxide (NO2), while accounting for clustering by residential address and confounders. Results Annual exposures to black carbon, PM2.5, PM10 and NO2 averaged 1.19, 13.0, 17.7, and 16.8 µg/m 3 . Systolic left ventricular function was worse ( p ≤ 0.027) with higher black carbon, PM2.5, PM10 and NO2 with association sizes per interquartile interval increment ranging from -0.339 to -0.458% for longitudinal strain and from -0.033 to -0.049 s -1 for longitudinal strain rate. Mitral E and a' peak velocities were lower ( p ≤ 0.021) with higher black carbon, PM2.5 and PM10 with association sizes ranging from -1.727 to -1.947 cm/s and from -0.175 to -0.235 cm/s, respectively. In the geographic analysis, the systolic longitudinal strain sided with gradients in air pollution. The path analysis identified systemic inflammation as a possible mediator of associations with black carbon. Conclusions Long-term low-level air pollution is associated with subclinical impairment of left ventricular performance and might be a risk factor for heart failure.

Background: Experimental studies have demonstrated that lead and cadmium have direct toxic effects on the myocardium, but the few human studies are limited by design, assessment of exposure, and use of heart failure as a late-stage endpoint., Methods and Results: In a prospective population study, we studied the association of left ventricular (LV) function with blood lead (BPb) and 24-hour urinary cadmium (UCd). In 179 participants randomly recruited from a Flemish population (50.3% women; mean age 39.1 years), geometric mean BPb and UCd at enrollment (1985-2000) were 0.20 μmol/L and 6.1 nmol, respectively. We assessed systolic and diastolic LV function 11.9 years (median) later (2005-2010) by using Doppler imaging of the transmitral blood flow and the mitral annular movement and speckle tracking. In multivariable-adjusted linear regression, LV systolic function decreased with BPb. For a doubling of exposure, estimates were -0.392% for global longitudinal strain (P=0.034), -0.618% and -0.113 s -1 for regional longitudinal strain (P=0.028) and strain rate (P=0.008), and -0.056 s -1 for regional radial strain rate (P=0.050). Regional longitudinal strain rate (-0.066 s -1 , P=0.009) and regional radial strain (-2.848%, P=0.015) also decreased with UCd. Models including both exposure indexes did not allow differentiating whether LV dysfunction was predominately related to BPb or UCd. Diastolic LV function was not associated with BPb or UCd (P≥0.159)., Conclusions: Although effect sizes were small, our results suggest that environmental exposure to lead, cadmium, or both might be a risk factor for systolic LV dysfunction, a condition often proceeding to heart failure., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

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., (© 2016 American Heart Association, Inc.)

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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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 β-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., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© 2015 American Heart Association, Inc.)