Measures Of Target Organ Damage Research Articles

Neglected cardiometabolic risk factors and subclinical target organ damage in post-menopausal women with normal glucose tolerance.

Menopausal transition is a crucial step in the women's cardiovascular health, and the risk stratification in apparently health post-menopausal females has been rarely assessed. Heart ultrasonography, unusually performed in such subjects, would be able to detect initial signs of organ damage. We described the cardiovascular risk profile of non-diabetic post-menopausal women, evaluating how easily computed, biochemistry-derived scores were related to ultrasonographic measures of target organ damage. We analyzed the characteristics of a cohort of two-hundred and seventy-three women consecutively referring to a prevention program of Azienda Ospedaliero-Universitaria Pisana (years 2017-2022) who underwent clinical evaluation, complete routine biochemical analyses with proxies of insulin resistance, heart and carotid ultrasonography. The cohort was further divided into four groups according to presence of isolated hypercholesterolemia (HC, 37%), isolated hypertension (HT, 5%), both HC/HT (38%), or none of them. In HC and HC/HT, LDL cholesterol was sharply above the recommended values (149 [134-171] mg/dL and 141 [123-159] mg/dL, respectively). E/e' ratio and left atrium size were augmented in HT women and further worsened in HT/HC, with an independent effect of hypertension (E/e' ß=0.055, P=0.013, left atrium volume ß=0.059, P=0.003). Presence of carotid plaques was independently linked to hypertension (ß=0.474, P=0.003). In HC and HC/HT, the Triglycerides-Glucose Index, a surrogate of insulin resistance, was higher than in the other classes (P=0.0013), and it was associated with E/A in HC and HT/HC, with a significative interaction (P=0.0004) with hypertension. Past hormone replacement therapy did not influence clinical, biochemical or echocardiographic parameters. Postmenopausal women display a high cardiovascular risk burden; a simple clinical and biochemistry screening would be advisable to identify and treat those more at risk. Cardiac ultrasonographic parameters were worse in hypertensive, hypercholesterolemic and insulin-resistant subjects, who may also deserve a deep and early instrumental characterization, especially when these conditions are associated.

Left ventricular hypertrophy and mortality in ethnic minority groups in the UK: e-ECHOES study.

Hypertension is the key modifiable cardiovascular risk factor but is underdiagnosed, and its scale in South Asian and African-Caribbean communities is unknown. Left ventricular hypertrophy (LVH) is a measure of target organ damage in uncontrolled hypertension. The study assesses LVH prevalence in South Asian and African-Caribbean communities and its impact on mortality. This study is based on the large prospective UK community Ethnic-Echocardiographic Heart of England Screening Study (E-ECHOES, age ≥45 years). Left ventricular mass index (LVMI) was calculated using echocardiography to establish LVH. The predictive value of LVH all-cause and cardiovascular mortality was assessed using Cox regression. The study included 3200 South Asians (age 59 ± 10 years, 52% women, 45% had a history of hypertension, 5.8 ± 1.0-year follow-up). LVH was found in 1568 (49%), of whom 45% did not have hypertension diagnosis. On Cox regression, LVH was independently associated with all-cause mortality [hazard ratio 1.38, 95% confidence interval (95% CI) 1.01-1.88], cardiovascular mortality (hazard ratio 2.64, 95% CI 1.21-3.73). The projected overall hypertension prevalence was 82%, undiagnosed hypertension prevalence 37%. The study included 1858 African-Caribbeans (age 62 ± 12, 45% women, 45% had history of hypertension, 5.1 ± 0.9-year follow-up). LVH was found in 1186 (64%), of whom 32% did not have hypertension diagnosis. LVH was borderline associated with all-cause mortality (hazard ratio 1.57, 95% CI 1.01-2.44), but not cardiovascular mortality (hazard ratio 1.82, 95% CI 0.80-4.16). The projected overall hypertension prevalence was 78.5%, and undiagnosed hypertension prevalence was 20.8%. UK South Asians and African-Caribbeans have a high prevalence of hypertension, which is often underdiagnosed and poorly controlled.

SEASONALITY IN NIGHT-TIME BLOOD PRESSURE AND ITS ASSOCIATIONS WITH TARGET ORGAN DAMAGE

Objective: There is some evidence that nighttime blood pressure varies between seasons. And it is unclear if the higher nighttime blood pressure in summer than in other seasons would be associated with target organ damage and if the associations would be different between summer and other seasons. Design and method: In 1054 untreated patients referred for ambulatory blood pressure monitoring, we performed measurements of urinary albumin-to-creatinine ratio (ACR, n = 1044), carotid-femoral pulse wave velocity (cfPWV, n = 1020) and left ventricular mass index (LVMI, n = 622). We investigated seasonality in nighttime blood pressure in our untreated outpatient sample and then its associations with various measures of target organ damage in comparison with those in other seasons. Results: Patients referred in spring (n = 337, 32.0%), summer (n = 210, 19.9%), autumn (n = 196, 18.6%) and winter (n = 311, 29.5%) had similar 24-h ambulatory systolic/diastolic blood pressure (P>0.25). However, both before and after adjustment for confounding factors, nighttime systolic/diastolic blood pressure differed significantly between seasons (P<0.001), being highest in summer and lowest in winter (adjusted mean values 117.0/75.3 mm Hg vs. 111.4/71.1 mm Hg). After adjustment for confounding factors, nighttime systolic/diastolic blood pressure were significantly and positively associated with ACR, cfPWV and LVMI (P<0.006). In season-specific analyses, statistical significance was reached for all the associations of nighttime blood pressure with target organ damage in summer (P<0.02), and for some of the associations in spring, autumn and winter. The association between nighttime systolic blood pressure and ACR was significantly stronger in patients examined in summer than those in winter (standardized beta, 0.31 vs 0.11 mg/mmol, P for interaction = 0.03). Conclusions: There is indeed seasonality in nighttime blood pressure level, as well as in its association with renal injury in terms of urinary albumin excretion.

Association of Blood Pressure-Related Increase in Vascular Stiffness on Other Measures of Target Organ Damage in Youth.

Hypertension-related increased arterial stiffness predicts development of target organ damage (TOD) and cardiovascular disease. We hypothesized that blood pressure (BP)-related increased arterial stiffness is present in youth with elevated BP and is associated with TOD. Participants were stratified by systolic BP into low- (systolic BP <75th percentile, n=155), mid- (systolic BP ≥80th and <90th percentile, n=88), and high-risk BP categories (≥90th percentile, n=139), based on age-, sex- and height-specific pediatric BP cut points. Clinic BP, 24-hour ambulatory BP monitoring, anthropometrics, and laboratory data were obtained. Arterial stiffness measures included carotid-femoral pulse wave velocity and aortic stiffness. Left ventricular mass index, left ventricular systolic and diastolic function, and urine albumin/creatinine were collected. ANOVA with Bonferroni correction was used to evaluate differences in cardiovascular risk factors, pulse wave velocity, and cardiac function across groups. General linear models were used to examine factors associated with arterial stiffness and to determine whether arterial stiffness is associated with TOD after accounting for BP. Pulse wave velocity increased across groups. Aortic distensibility, distensibility coefficient, and compliance were greater in low than in the mid or high group. Significant determinants of arterial stiffness were sex, age, adiposity, BP, and LDL (low-density lipoprotein) cholesterol. Pulse wave velocity and aortic compliance were significantly associated with TOD (systolic and diastolic cardiac function and urine albumin/creatinine ratio) after controlling for BP. Higher arterial stiffness is associated with elevated BP and TOD in youth emphasizing the need for primary prevention of cardiovascular disease.

Cardiovascular Risk Factors and Target Organ Damage in Adolescents: The SHIP AHOY Study.

Development of cardiovascular disease in adults has been directly linked to an adverse metabolic phenotype. While there is evidence that development of these risk factors in childhood persists into adulthood and the development of cardiovascular disease, less is known about whether these risk factors are associated with target organ damage during adolescence. We collected data from 379 adolescents (mean age 15.5, 60% male) with blood pressure between the 75th and 95th percentile to determine if there is a metabolic phenotype that predicts cardiovascular changes (left ventricular mass, systolic and diastolic function, pulse wave velocity, and renal function). We determined the number of risk factors for cardiovascular disease (hypertension, dyslipidemia, obesity, and insulin resistance) present in each participant. Generalized linear models were constructed to determine if the number of cardiovascular risk factors (CVRFs) were associated with measures of target organ damage. The number of CVRFs present were associated with statistically significant differences in increased left ventricular mass index, increased pulse wave velocity, decreased peak longitudinal strain, urine albumin to creatine ratio and echocardiographic parameters of diastolic dysfunction. Generalized linear models showed that dyslipidemia and insulin resistance were independently associated with markers of diastolic dysfunction (P ≤ .05) while increased blood pressure was associated with all makers of target organ damage (P ≤ .03). These data suggest the of the number of CVRFs present is independently associated with early changes in markers of target organ damage during adolescence.

Abstract P033: Higher Ambulatory Sbp Is Associated With Increasing Number Of Target Organ Abnormalities In Youth: The Ship Ahoy Study

Hypertension is associated with elevated left ventricular mass index (LVMI), cardiac dysfunction and increased arterial stiffness in adults which predict cardiovascular (CV) events. The extent to which elevated BP in youth is associated with subclinical CV target organ damage (TOD) is not known. We explored the relation between BP level and number of TOD abnormalities (nTOD). We measured clinic and ambulatory BP (ABP), anthropometrics, and nTOD in 244 adolescents (mean 15.5 + 1.8 years, 67% white, 60% male). Subjects were recruited as low-risk (L=98, SBP%&lt;80 th %), mid-risk (Mid=60, SBP% 80-&lt;90 th %); and high-risk (H=86, SBP% &gt;=90 th %) based on mean of 6 aneroid clinic BPs by age-, sex- and height-specific cut-points. 24-hour ABP was measured with an oscillometric device per pediatric guidelines. Four measures of TOD were: LVMI &gt; 38.6 g/m 2.7 ; LV systolic strain (Strain %) &gt; -18; LV diastolic function (E/e’) &gt; 8; pulse wave velocity (PWV) &gt; 5.8 m/sec. ANOVA was used to evaluate differences in CV risk factors and chi square for differences in nTOD across groups. Logistic regression models were used to determine if clinic and/or ABP was an independent predictor of nTOD after adjustment for age, sex, race, and BMI z-score. BP groups did not differ in BMI z-score. Clinic and ABP systolic and diastolic BP increased across BP groups. The distribution of nTOD was shifted towards higher BP group with most nTOD= 0 (47%) in the L and all (100%) nTOD = 4 in the H group (X 2 = 0.08) and became significant when L (clinic SBP&lt;75 th %) was compared to M+H (clinic SBP &gt; 80 th %; X 2 =0.04). Daytime ABP index (subject daytime systolic ABP/95 th % for daytime systolic ABP) and BMI z-score (both p &lt; 0.003) were significantly associated with nTOD in a model containing clinic SBP, age, sex and race (other covariates NS; full model p &lt; 0.0001, R 2 =0.22). We conclude that higher ABP is associated with a greater number of cardiac and vascular abnormalities in youth. ABP should be applied in youth with elevated BP to evaluate need for intensification of therapy to prevent CV TOD.

Abstract 009: Incremental Predictive Utility Of Subclinical Disease Measures For Cardiovascular Disease Risk

Introduction: The Framingham Risk Score (FRS) has been widely used to predict cardiovascular disease (CVD) risk. However, a comparison of the incremental prognostic utility of different subclinical disease (SubDz) measures is not clear. Methods: We evaluated participants aged 40-79 years (mean age 55 years, 56% women) from the Framingham Offspring (Exam 8, 2005-2008) and Third Generation cohorts (Exam 1, 2002-2005), free of CVD and diabetes, with data on coronary artery calcium (CAC, n=2497), and two measures of target organ damage: urine albumin-to-creatinine ratio (UACR, n=4011) and left ventricular mass (LVM, n=3770). We categorized FRS: &lt;10%, 10-19%, and ≥20% and defined high CAC as CAC≥100, microalbuminuria (MA) as UACR ≥25mg/g in men and ≥35mg/g in women, and left ventricular hypertrophy (LVH) as LVM/body surface area&gt;115 g/m 2 (men) and &gt;95g/m 2 (women). We created 6 cross-classified groups: FRS &lt;10%-No SubDz; FRS &lt;10% + SubDz; FRS 10-19%-No SubDz; FRS 10-19% + SubDz; FRS ≥20%-No SubDz; and FRS ≥20% + SubDz. We related the groups to CVD risk using Cox regression adjusting for age, sex, and cohort and plotted Kaplan-Meier curves to display CVD cumulative incidence by each SubDz cross-classified group. Results: Over a median follow-up of 12 years, 7% of participants developed CVD. Comparing FRS 10-19%-No SubDz and FRS 10-19% + SubDz to FRS &lt;10%-No SubDz (referent), we observed hazards ratios (95% CI) for CVD of 1.68 (0.99-2.83) and 6.50 (3.64-11.61) for high CAC; 1.33 (0.95-1.85) and 2.15 (1.10-4.18) for MA; and 1.43 (0.99-2.07) and 2.18 (1.33-3.57) for LVH. Each SubDz measure predicted CVD risk incrementally over the FRS. In a sub-sample with all three SubDz measures, the model c-statistic with FRS only was 0.725, increasing to 0.773, 0.726, and 0.728 when adding CAC, MA, and LVH, respectively. Conclusion: Presence of a high CAC score outperformed other measures of target organ damage (MA or LVH) for predicting CVD risk, regardless of FRS. Additional studies of larger multi-ethnic samples are warranted to confirm our findings.

Comparing the associations of clinic vs. ambulatory blood pressure with subclinical organ damage in young healthy adults: the African-PREDICT study.

Raised blood pressure (BP) causes pathophysiological cardiovascular changes resulting in target organ damage. Although ambulatory and central BP relate more strongly to outcomes than clinical brachial BP in the elderly population, it is unknown which measure of BP is most strongly associated with markers of organ damage in younger populations. We compared the strength of associations between different BPs and measures of subclinical organ damage and investigated whether ethnic differences exist between these associations. The design was a cross-sectional analysis of the African-PREDICT study, including young black and white men and women (aged 20-30, N = 1202). We obtained clinic, ambulatory, and central BP readings, as well as measures of subclinical organ damage: central retinal arteriolar equivalent (CRAE) from fundus images, echocardiography to determine left ventricular mass index (LVMi), carotid intima media thickness (CIMT), carotid-femoral pulse wave velocity (PWV), and albumin-to-creatinine ratio (ACR) determined from spot urine samples. Overall, weak correlations were evident between CIMT, ACR, and BP, whereas CRAE, LVMi, and PWV correlated strongly with BP. In the total group, clinic brachial BP had stronger associations with CRAE, LVMi, and PWV (all p < 0.001) than ambulatory and central BP. Although the ethnic groups showed similar correlations between CRAE, LVMi, CIMT, and the various BPs, PWV correlated more strongly with ambulatory systolic BP (p < 0.001) in white participants. In young healthy adults, clinic brachial BP correlated more strongly with measures of early target organ damage than central or ambulatory BP. No differences were observed between correlations of BP and measures of target organ damage in the two ethnic groups.

Epigenome-wide association study identifies DNA methylation sites associated with target organ damage in older African Americans

ABSTRACT Target organ damage (TOD) manifests as vascular injuries in the body organ systems associated with long-standing hypertension. DNA methylation in peripheral blood leukocytes can capture inflammatory processes and gene expression changes underlying TOD. We investigated the association between epigenome-wide DNA methylation and five measures of TOD (estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI), relative wall thickness (RWT), and white matter hyperintensity (WMH)) in 961 African Americans from hypertensive sibships. A multivariate (multi-trait) model of eGFR, UACR, LVMI, and RWT identified seven CpGs associated with at least one of the traits (cg21134922, cg04816311 near C7orf50, cg09155024, cg10254690 near OAT, cg07660512, cg12661888 near IFT43, and cg02264946 near CATSPERD) at FDR q < 0.1. Adjusting for blood pressure, body mass index, and type 2 diabetes attenuated the association for four CpGs. DNA methylation was associated with cis-gene expression for some CpGs, but no significant mediation by gene expression was detected. Mendelian randomization analyses suggested causality between three CpGs and eGFR (cg04816311, cg10254690, and cg07660512). We also assessed whether the identified CpGs were associated with TOD in 614 African Americans in the Hypertension Genetic Epidemiology Network (HyperGEN) study. Out of three CpGs available for replication, cg04816311 was significantly associated with eGFR (p = 0.0003), LVMI (p = 0.0003), and RWT (p = 0.002). This study found evidence of an association between DNA methylation and TOD in African Americans and highlights the utility of using a multivariate-based model that leverages information across related traits in epigenome-wide association studies.

Left atrial stiffness index as a marker of early target organ damage in hypertension.

This study aimed to evaluate left atrial (LA) mechanics using two-dimensional speckle-tracking echocardiography (2DSTE) and investigate their correlations with measures of target organ damage (TOD) in hypertension. We enrolled 42 healthy controls (Group I) and 286 hypertension patients: Group II (n = 79) had an LA volume index (LAVI) <28 ml/m2; Group III (n = 92) had an LAVI ≥28 ml/m2; and Group IV (n = 115) had hypertension with left ventricular hypertrophy (LVH). We measured the following parameters: LA reservoir strain and strain rate (LAS-S, LASR-S), LA conduit strain and strain rate (LAS-E and LASR-E), and LA booster strain and strain rate (LAS-A and LASR-A). The LA stiffness index (LASI) was defined as the ratio of early diastolic transmitral flow velocity/lateral mitral annulus myocardial velocity (E/e') to LAS-S. We performed correlation and regression analyses of individual TOD with LA phasic functions, the LASI, and cardiovascular risk factors. Our findings showed that there was a trend toward a gradual increase in the LASI from controls to normal LA and enlarged LA patients and finally to hypertrophic LV patients. The LASI was significantly higher in Group III [0.28 (0.20, 0.38)] than in Group I [0.20 (0.16, 0.23)] and Group II [0.22 (0.18, 0.27)] and was the highest in Group IV [0.33 (0.26, 0.43)]. The LA reservoir and conduit function gradually decreased from Group I to Group IV. Multivariate regression analysis revealed that the LASI was independently correlated with individual TOD. In conclusion, abnormal LA mechanics precede LA enlargement and LVH, and an increased LASI can be used as a marker of early TOD in hypertension.

Abstract MP16: Metabolic Predictors Of Target Organ Damage In Adolescents: The SHIP AHOY Study

The development of cardiovascular disease in adults has been directly linked to a metabolic phenotype that includes hypertension, obesity and dyslipidemia. While there is evidence that the development of these risk factors in childhood is linked with persistence into adulthood and eventual development of cardiovascular disease, less is known about whether these risk factors contribute to target organ damage during childhood. We collected data from 379 otherwise healthy adolescents (mean age 15.5 +/- 1.8, 60% male, 37% Non-White) across the blood pressure spectrum to determine if there is a metabolic phenotype that predicts target organ damage in adolescents. A cardiovascular risk score was calculated (1 point each for: LDL &gt;155 or HDL &lt;40 or TG &gt;150; BMI &gt; 95%; fasting glucose &gt;100; HOMA-IR &gt; 2.5). Generalized linear models were constructed to determine if the cardiovascular risk score was independently associated with measures of target organ damage. Cardiovascular risk score was significantly associated increased left ventricular mass index (β = 1.64, R 2 0.19) , increased pulse wave velocity (β = 0.05, R 2 0.21) and several echocardiographic parameters of diastolic dysfunction (e’/a’: β = -0.07 R 2 0.27; E/A: β = -0.04, R 2 0.11; E/e’: β =0.03, R 2 0.13) after correction for age, sex, race, HR, creatinine, uric acid and log CRP (all models P&lt;0.0009). We found no association with peak longitudinal strain or microalbuminuria. Our study suggests that presence of cardiovascular risk factors in adolescence predicts target organ damage at a young age and could potentially be modified to prevent progression of disease.

Subtypes of masked hypertension and target organ damage in untreated outpatients

Purpose: Masked hypertension (MHT) is characterised as an office normotension in the presence of out-of-office hypertension, and can be further categorised as isolated daytime (dMHT), night-time (nMHT) or day-night MHT (dnMHT) according to the time when hypertension is present. MHT is associated with adverse cardiovascular outcome. However, no previous studies contrasted these MHT subtypes in their associations with target organ damage (TOD).Materials and methods: Consecutive untreated patients referred for ambulatory blood pressure (BP) monitoring to our Hypertension Clinic were recruited. Office and ambulatory BPs were measured using the Omron 7051 and SpaceLabs 90217 monitors, respectively. The BP thresholds of daytime and night-time hypertension were of ≥135/85 mmHg and ≥120/70 mmHg, respectively. We performed various TOD measurements, including carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT), left ventricular mass index (LVMI) and E/E’, estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR).Results: The 1808 participants (mean age, 51 years; women, 52%) included 672 (37.2%) MHT subjects, among whom 123 (18.3%) had dMHT, 78 (11.6%) nMHT, and 471 (70.1%) dnMHT. In all participants as well as patients with office normotension (n = 1222), ambulatory daytime and night-time BPs were similarly associated with all TOD measurements (p ≥ 0.20) after multivariate adjustment. Compared to normotensive subjects (p < 0.05), patients with dMHT had faster cfPWV (7.81 vs. 7.58 m/s) and thicker cIMT (637.6 vs. 610.4 µm), patients with nMHT had thicker cIMT (641.8 vs. 610.4 µm) and increased UACR (0.79 vs. 0.59 mg/mmol), and patients with dnMHT had all worse TOD measures mentioned-above plus elevated eGFR (120.7 vs. 116.8 ml/min/1.73m2).Conclusion: MHT was associated with TOD irrespective of subtype, although TOD varied slightly across these subtypes. The study highlights the importance of controlling both daytime and night-time BP in hypertensive patients.

Intrinsic and extrinsic epigenetic age acceleration are associated with hypertensive target organ damage in older African Americans

BackgroundEpigenetic age acceleration, a measure of biological aging based on DNA methylation, is associated with cardiovascular mortality. However, little is known about its relationship with hypertensive target organ damage to the heart, kidneys, brain, and peripheral arteries.MethodsWe investigated associations between intrinsic (IEAA) or extrinsic (EEAA) epigenetic age acceleration, blood pressure, and six types of organ damage in a primarily hypertensive cohort of 1390 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. DNA methylation from peripheral blood leukocytes was collected at baseline (1996–2000), and measures of target organ damage were assessed in a follow-up visit (2000–2004). Linear regression with generalized estimating equations was used to test for associations between epigenetic age acceleration and target organ damage, as well as effect modification of epigenetic age by blood pressure or sex. Sequential Oligogenic Linkage Analysis Routines (SOLAR) was used to test for evidence of shared genetic and/or environmental effects between epigenetic age acceleration and organ damage pairs that were significantly associated.ResultsAfter adjustment for sex, chronological age, and time between methylation and organ damage measures, higher IEAA was associated with higher urine albumin to creatinine ratio (UACR, p = 0.004), relative wall thickness (RWT, p = 0.022), and left ventricular mass index (LVMI, p = 0.007), and with lower ankle-brachial index (ABI, p = 0.014). EEAA was associated with higher LVMI (p = 0.005). Target organ damage associations for all but IEAA with LVMI remained significant after further adjustment for blood pressure and antihypertensive use (p < 0.05). Further adjustment for diabetes attenuated the IEAA associations with UACR and RWT, and adjustment for smoking attenuated the IEAA association with ABI. No effect modification by age or sex was observed.ConclusionsMeasures of epigenetic age acceleration may help to better characterize the functional mechanisms underlying organ damage from cellular aging and/or hypertension. These measures may act as subclinical biomarkers for damage to the kidney, heart, and peripheral vasculature; however more research is needed to determine whether these relationships remain independent of lifestyle factors and comorbidities.

3044Exploration of biomarkers for subclinical atherosclerosis in an African population using a proteomics chip targeted at inflammation and cardiovascular disease

Abstract Introduction The evolving use of multiplex proteomic platforms provides an excellent tool for investigating associations between multiple proteins and subclinical atherosclerotic disease. In this study, we evaluated the impact of a multiplex protein panel, on carotid intima-media thickness (cIMT) as a marker of subclinical atherosclerosis. Purpose We used a multiplex proteomic platform to identify possible associations between proteins and subclinical carotid atherosclerosis as measured by carotid ultrasound in an African population. Methods In the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study, 92 proteins from the Proseek Multiplex CVD III 96×96 (Olink Bioscience, Sweden) were analyzed in 378 participants (mean age 44.7±9.6 years, 50.6% women, 10.8% with known cardiovascular disease). Carotid ultrasound was performed for measurements of the carotid intima-media thickness (cIMT, mean 0.663±0.127 mm) and calculation of cross-sectional wall area (CSWA, mean 13.5±4.4mm2), a measure of target organ damage. Possible associations between the proteins, and cIMT and CSWA, respectively, were explored using linear regression models. A two-sided Bonferroni corrected P-value of 0.05/92=5.4x10–4 was considered statistically significant in the crude analysis. Results Of 18 proteins (1 standard deviation of change of ln-transformed values) that were Bonferroni-corrected (p≤5.4x10–4) significantly associated with cIMT and/or CWAS in crude analyses, the following remained significant after further adjustment for age, sex, waist circumference, systolic blood pressure, smoking and total cholesterol: growth-differentiation factor-15 (GDF15; β 0.017, p=0.050), E-selectin (SELE; β 0.019, p=0.017), carboxypeptidase A1 (CPA1; β 0.019, p=0.019), C-C motif chemokine 15 (CCL15; β 0.031, p&lt;0.001), chitinase-3-like protein 1 (CHI3L1; β 0.021, p=0.007), the hemoglobin scavenger receptor (CD163; β 0.021, p=0.008) and osteoprotegerin (OPG; β 0.022, p=0.004). As for target-organ damage defined by CSWA, SELE (β 0.459, p=0.018), CCL15 (β 0.398; p=0.032) and CD163 (β 0.541, p=0.005) showed multivariate adjusted significant associations. Conclusion In an African population, we could confirm five proteins (GDF15, SELE, CHI3L1, CD163 and OPG) associated with cIMT, but in addition identified two proteins (CPA1 and CCL15) with novel associations with cIMT and/or CSWA. Acknowledgement/Funding North-West University; National Research Foundation (NRF); Medical Research Council (MRC-SA); Department of Education North-West Province; ROCHE

Abstract 057: Epigenome Wide Association Study Identifies DNA Methylation Sites Associated With Target Organ Damage in Elderly African Americans

Introduction: Epigenetic mechanisms, including DNA methylation, influence gene expression and mediate responses to the environment over the lifecourse. Previous research has identified a number of DNA methylation sites (CpGs) associated with arteriosclerosis and its risk factors. Given the underlying role of immunological and inflammatory processes in arteriosclerosis and the potential of pleiotropic effects of individual CpG sites across organ systems influenced by arteriosclerosis, we investigated the DNA methylation profiles of peripheral blood leukocytes from a cohort of African American (AA) hypertensive sibships to explore their association with measures of target organ damage (TOD), analyzed using both single and multi-trait (multivariate) models. Methods: Using the Genome-wide Efficient Mixed Model Association algorithm (GEMMA), we assessed the association between ~790,000 CpGs across the genome and 4 TOD traits: Estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI) and relative wall thickness (RWT) in 961 subjects with mean baseline age of 57.5 years (SD: 10.3). DNA methylation was measured at baseline using the Infinium MethylationEPIC BeadChip and TOD was assessed 5 years later. Results: Single trait models adjusting for age, sex, blood cell proportions, genetic principal components, and time difference between the measures identified a single CpG site associated with UACR (cg04816311), LVMI (cg21134922) and RWT (cg03042953, all FDR &lt; 0.1). Pleiotropic (multivariate) models identified 8 CpGs associated with at least one of the traits in the CATSPERD, C7orf50, ALDH1L1, IFT43 and OAT genes. After adjusting for SBP, DBP and antihypertensive medication use, 6 CpGs remained significant and 1 additional CpG (cg21447579 in SNORD116 gene cluster) was identified. After further adjustment for BMI, T2DM and smoking, two CpGs (cg02264946 in CATSPERD and cg12661888 in IFT43) remained significant. Conclusions: The study highlights the role of specific epigenetic sites in risk of TOD in an African American population. Additionally, it highlights the utility of using a pleiotropy-based analysis to identify CpG sites by leveraging information across related traits.

Clinical Implications

HomeHypertensionVol. 74, No. 3Clinical Implications Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBClinical Implications Originally published7 Aug 2019https://doi.org/10.1161/HYPERTENSIONAHA.119.13545Hypertension. 2019;74:431is related toProcedural and Anatomical Determinants of Multielectrode Renal Denervation EfficacyAssociation of Blood Pressure Level With Left Ventricular Mass in AdolescentsEdoxaban Versus Warfarin Stratified by Average Blood Pressure in 19 679 Patients With Atrial Fibrillation and a History of Hypertension in the ENGAGE AF-TIMI 48 TrialDeterminants of Biomarker Reduction in Denervation (page 546)Download figureDownload PowerPointCatheter-based radiofrequency renal denervation reduces sympathetic activity and blood pressure with variable success. Among the reasons cited for variability in response was suboptimal procedural performance with incomplete nerve ablation. Further optimization of renal denervation systems and understanding of the dependence of efficacy on the pattern of ablations is necessary. The coupling of quantitative preclinical experiments and computational models provided a comprehensive understanding of the procedural dependence of renal norepinephrine reduction as a biomarker of efficacy. Biomarker effects were shown to track with the percentage of affected nerves in the treated artery segment, such that half-maximal norepinephrine reduction was achieved when >46% of nerves were affected. For 15 W/30 s treatments, threshold effects were only attained when ≥4 electrodes were powered. The total fractions of ablation area and annular coverage were the prime determinants of renal denervation efficacy. Hence, all else being equal, efficacy decreased with increasing vessel diameter owing to an increase in the target area, or when radiofrequency electrodes directed their energy at blood vessels owing to efficient heat clearance and reduced ablation area. Design of new renal denervation therapies should focus on strategies for maximizing total ablation area and arc rather than depth of ablation. In particular, strategies for delivering multiple helically staggered ablations and abrogating the heat clearance effects of periarterial blood vessels seem promising.Association of BP With LV Mass in Adolescents (page 590)Download figureDownload PowerPointHypertension is associated with left ventricular hypertrophy, a risk factor for cardiovascular events. The current guidelines on management of blood pressure (BP) in children recommend evaluation for left ventricular hypertrophy at the time of starting medication to treat hypertension, usually when BP is persistently above the 95th percentile of the normal BP distribution in healthy children. However, the optimal BP percentile associated with left ventricular hypertrophy in youth is unknown. In this multicenter study of 303 adolescents, we found that the 90th percentile for systolic BP resulted in the best balance between sensitivity and specificity for predicting left ventricular hypertrophy. Therefore, our findings indicate that many youths with lower levels of BP than currently recommended for medication treatment may be at risk for BP-related target organ damage. Validation of our findings in other cohorts and examination of other measures of target organ damage are needed to provide additional evidence to inform future BP guidelines on pediatrics.BP and Anticoagulation in Atrial Fibrillation (page 597)Download figureDownload PowerPointHypertension is the most common comorbid condition with atrial fibrillation and is associated with increased risks of stroke and bleeding. Because uncontrolled hypertension is a known risk factor for stroke, cardiovascular mortality, and bleeding in anticoagulated patients, there are concerns that the benefits of direct oral anticoagulants may be modified by blood pressure (BP). Although direct oral anticoagulants compare favorably to warfarin in preventing cardiovascular events and reducing the risk of major bleeding, including intracranial hemorrhage, the relationship between on-treatment BP and the efficacy and safety of direct oral anticoagulants is not fully known. In this post hoc analysis of the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48), we examined the efficacy and safety of edoxaban relative to warfarin stratified by average BP during the trial among 19 679 patients with atrial fibrillation, a history of hypertension, and elevated stroke risk. The efficacy and safety of high dose edoxaban relative to warfarin were consistent across the full range of average systolic BP. Further, the superior safety of edoxaban was most pronounced among patients with elevated diastolic BP. As direct oral anticoagulants continue to be underused in patients with atrial fibrillation perceived to be at elevated bleeding risk, including those with uncontrolled hypertension, these findings emphasize the importance of this class of medications in the management of this high-risk patient population. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesProcedural and Anatomical Determinants of Multielectrode Renal Denervation EfficacyAbraham R. Tzafriri, et al. Hypertension. 2019;74:546-554Association of Blood Pressure Level With Left Ventricular Mass in AdolescentsElaine M. Urbina, et al. Hypertension. 2019;74:590-596Edoxaban Versus Warfarin Stratified by Average Blood Pressure in 19 679 Patients With Atrial Fibrillation and a History of Hypertension in the ENGAGE AF-TIMI 48 TrialSungha Park, et al. Hypertension. 2019;74:597-605 September 2019Vol 74, Issue 3 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.119.13545 Originally publishedAugust 7, 2019 PDF download Advertisement

C‐Reactive Protein Levels and Blood Pressure Loads with Training

Blood pressure (BP) load is the percentage of BP readings above a particular threshold within a given period. Elevated BP loads translate to organ exposures to high pressures for greater amounts of time. Because of this, BP load was heralded as a strong predictor of target organ damage (TOD). However, recent evidence has not confirmed its prognostic value above 24 hr ambulatory blood pressure monitoring (ABPM). Although questioned, it is incorporated in AHA ABPM guidelines for children and adolescents. Newer evidence in chronic kidney disease and untreated hypertensives has shown an independent association of BP load with various measures of TOD. Additionally, a marker of systemic inflammation (neutrophil‐to‐lymphocyte ratio) has been shown to correlate with BP load.ObjectiveThis analysis investigated the relationship between classic inflammatory biomarker C‐Reactive Protein (CRP) and debated measure BP Load in a high‐risk population for cardiovascular diseases (CVD).MethodsSedentary, middle‐to‐older age African Americans free of disease underwent aerobic exercise training (AEXT) 3x/week for 24 weeks. Intensity targets progressed to sustain 60% VO2 max. Because of the strong relationship between BMI and BP, participants were required to maintain a constant weight. ABPM was conducted before and after training, and BP loads determined. Fasted blood draws were utilized at these times to measure circulating CRP and categorize future CVD risks based on baseline CRP levels. Slightly less conservative thresholds for BP readings were used because of this known high‐risk population.ResultsWith training, daytime SBP and DBP loads decreased for those only in the low risk CRP group (p=.047 and p=.036, respectively). Nighttime values, however, did not change for either CRP group with training. For daytime values at baseline and final, there was no difference in SBP load (&gt;124 mmHg) for those classified as at low (&lt;1mg/L), average (1–3mg/L) or high (&gt;3mg/L) risk for CVD based on CRP levels. When a more conservative threshold was utilized (SBP &gt;139 mmHg) there was a difference between CRP groups after training (p&lt;.05). There was a similar trend for DBP load (DBP&gt;74 mmHg), with a difference appearing after training (p&lt;.05). Nighttime DBP load did not differ between groups either before or after training. SBP load, however, differed between CRP groups at baseline when a more (&gt;119 mmHg, p&lt;.05), but not less (&gt;104 mmHg) conservative threshold was used. Groups after training showed no SBP load difference.ConclusionsCRP levels may contribute to BP loads and resultant TOD. These may be a specific indicator of the response to AEXT, especially in those considered low‐risk. Because nighttime BP load did not change with training in either category, but daytime values did decrease, the reasons for this need to be further examined. It is possible that a different stimulus may be necessary to cause changes in nighttime values. This is especially important since recent evidence has shown nighttime values to be a greater indicator of clinical events and cardiovascular outcomes than daytime BP values. Additionally, BP load thresholds may need to be adjusted for various populations. Future studies are needed to confirm the independent effect of BP load in this high‐risk population, and its relationship to inflammation.Support or Funding InformationNIH Grant #R01 HL085497‐01A1 Systolic (&gt;139 mmHg) and Diastolic (&gt;74 mmHg) Blood Pressure load decreased after training in low‐risk subjects. SBP Load showed between group differences only after, but not before training.* p&lt;.05 within groups. # p&lt;.05 between groupsimageSystolic (&gt;139 mmHg) and Diastolic (&gt;74 mmHg) Blood Pressure load decreased after training in low‐risk subjects. SBP Load showed between group differences only after, but not before training.* p&lt;.05 within groups. # p&lt;.05 between groups Neither Systolic (&gt;104 mmHg) nor Diastolic (&gt;64 mmHg) Blood Pressure load decreased after training for subjects. SBP (&gt;119) Load showed between group differences before, but not after training. # p&lt;.05 between groupsimageNeither Systolic (&gt;104 mmHg) nor Diastolic (&gt;64 mmHg) Blood Pressure load decreased after training for subjects. SBP (&gt;119) Load showed between group differences before, but not after training. # p&lt;.05 between groupsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A13549 Which measures of target organ damage best predict cardiovascular events?

Objectives: We aimed to compare various measures of target organ damage (TOD) in predicting cardiovascular events. Methods: In 4,327 subjects with cardiovascular risk factors, positive predictive values (PPV) of carotid IMT ≧ 1.1 mm, carotid plaque, left ventricular hypertrophy (LVH, defined by F ≧ 110, M ≧ 134 g/m2), brachial-ankle pulse wave velocity (baPWV), ankle-brachial index (ABI), urinary albumin excretion ratio (UACR), and eGFR in predicting cardiovascular events. The mean follow up period was 3.9 ± 2.1yrs. Results: The PPV of UACR >300 mg/g?cr was highest, followed by abnormal ABI and LVH. However, PPV of carotid plaque and carotid IMT were not good predictors of cardiovascular events (Figure). Conclusion: In evaluating TOD, presence of macroalbumiuria, abnormal ABI, and LVH are particularly cautioned.

A2328 The associations of target organ damage with morning hypertension by various definitions

Objectives: Morning Hypertension (MHT) can be defined based on ambulatory blood pressure (BP) monitoring (ABPM) or home BP monitoring (HBPM). In which definition MHT is more associated with cardiovascular outcome remains unknown. Methods: From 2010–2015, we consecutively recruited untreated outpatients from our Hypertension Clinic. MHT was an average BP≥135/85 mmHg in the morning defined either based on HBPM, or the diary (the first 2 h after awakening) or short-clock time interval (6–10 AM) on the day of ABPM, irrespective of the BP levels at other time windows. We assessed carotid-femoral pulse wave velocity (cfPWV) by SphygmoCor system, left ventricular mass index (LVMI) and carotid intima-media thickness (IMT) by ultrasonography, and urinary albumin/creatinine ratio (ACR) as measures of target organ damage. Results: In the 1085 untreated patients (age 51.2 years), the prevalence of MHT were 63.7%, 65.1% and 48.7% based on the ABPM diary, short-clock time interval and HBPM, respectively. After adjustment for age, sex, and other cardiovascular risk factors, patients with MHT compared to normotensives had significantly (P < 0.001) increased cfPWV, urinary ACR and carotid IMT, irrespective of the definitions. In multivariate-adjusted continuous analyses, target organ measures were all positively associated with morning systolic BP recorded by ABPM and HBPM (P < 0.002), except for that of LVMI with home BP. After further including the systolic BP at other time windows in the models, morning systolic BP during 6–10 AM remained significantly associated with cfPWV (β = 0.019, P < 0.001), and home morning systolic BP was associated with cfPWV (β = 0.024, P < 0.001) and urinary ACR (β = 0.012, P = 0.003). Conclusion: Irrespective of the definitions based on ABPM or HBPM, morning hypertension was associated with target organ measures.

Clinical Implications of the Revised AAP Pediatric Hypertension Guidelines.

New pediatric hypertension definitions were recently published in a clinical practice guideline (CPG). We evaluated the impact of the CPG, compared with the previous guideline ("Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents"), on the prevalence of hypertension and associations with target organ damage (TOD) in high-risk youth. Participants (10-18 years old) undergoing an evaluation of the cardiovascular effects of obesity and type 2 diabetes mellitus in youth were studied. Blood pressure was categorized according to the 2 guidelines as normal, elevated, and hypertension (stages 1 and 2). Measures of TOD (carotid artery intima-media thickness, pulse wave velocity, left ventricular mass, and diastolic function) were obtained. Associations between blood pressure categories and TOD and the sensitivity of hypertension classification in identifying TOD were evaluated. Data were available for 364 participants (65% female sex; 15.1 ± 2.1 years of age). Hypertension was identified in 8% and 13% as defined in the Fourth Report and CPG, respectively (P = .007). The 2 guidelines revealed similar associations with TOD; however, the CPG demonstrated improved sensitivity of TOD detection in hypertensive participants. For example, the proportion of participants with an abnormal left ventricular mass categorized as hypertensive increased from 20% to 31% as defined in the Fourth Report and CPG, respectively (P < .001). Incorporation of the CPG increased the prevalence of pediatric hypertension in a population of high-risk youth and improved the sensitivity of TOD identification in hypertensive participants.