Generalizability of SPRINT Results to the U.S. Adult Population

Background In SPRINT (Systolic Blood Pressure Intervention Trial), a systolic blood pressure (SBP) goal of <120 mm Hg resulted in lower cardiovascular disease (CVD) risk compared with an SBP goal of <140 mm Hg. Objectives The purpose of this study was to estimate the prevalence, number, and characteristics of U.S. adults meeting SPRINT eligibility criteria and determine the broader population to whom SPRINT could be generalized. Methods We conducted a cross-sectional, population-based study using data from the National Health and Nutrition Examination Survey, 2007 to 2012. The SPRINT inclusion criteria were age ≥50 years, SBP 130 to 180 mm Hg depending on the number of antihypertensive medication classes being taken, and high CVD risk (history of coronary heart disease, estimated glomerular filtration rate of 20 to 59 ml/min/1.73 m2, 10-year CVD risk ≥15%, or age ≥75 years). Exclusion criteria were diabetes, history of stroke, >1 g in 24 h of proteinuria daily, heart failure, estimated glomerular filtration rate <20 ml/min/1.73 m2, or receiving dialysis. Treated hypertension was defined by self-reported use of medication to lower blood pressure with ≥1 class of antihypertensive medication identified through a pill bottle review. Results Overall, 7.6% (95% confidence interval [CI]: 7.0% to 8.3%) or 16.8 million (95% CI: 15.7 to 17.8 million) U.S. adults, and 16.7% (95% CI: 15.2% to 18.3%) or 8.2 million (95% CI: 7.6 to 8.8 million) adults with treated hypertension met the SPRINT eligibility criteria. Among both the overall U.S. population and adults with treated hypertension, the percentage meeting SPRINT eligibility criteria increased with older age, was higher among males than females, and was higher among non-Hispanic whites compared with non-Hispanic blacks or Hispanics. Of U.S. adults eligible for SPRINT, 51.0% (95% CI: 47.8% to 54.1%) or 8.6 million (95% CI: 8.0 to 9.1 million) were not treated for hypertension. Conclusions A substantial percentage of U.S. adults meet the eligibility criteria for SPRINT

Association between 24-hour blood pressure variability and chronic kidney disease: a cross-sectional analysis of African Americans participating in the Jackson heart study

Background Studies suggest 24-h blood pressure (BP) variability has prognostic value for cardiovascular disease. Several factors associated with high 24-h BP variability are also common among individuals with chronic kidney disease (CKD). We hypothesized 24-h BP variability would be higher for individuals with versus without CKD. Methods We analyzed 1,022 Jackson Heart Study participants who underwent ambulatory blood pressure monitoring (ABPM). Twenty-four hour BP variability was defined by two metrics: day-night standard deviation (SDdn) and average real variability (ARV). CKD was defined as ACR ≥30 mg/g or eGFR <60 mL/min/1.73 m2. Results The mean SDdn of systolic BP (SBP) was 10.2 ± 0.2 and 9.1 ± 0.1 mmHg and the mean ARV of SBP was 9.2 ± 0.2 and 8.6 ± 0.1 mmHg for those with and without CKD, respectively (each p ≤ 0.001). After adjustment for age and sex, SDdn and ARV were 0.98 mmHg (95 % CI 0.59, 1.38) and 0.52 mmHg (95 % CI 0.18, 0.86), respectively, higher among participants with versus without CKD. These differences were not statistically significant after further multivariable adjustment including 24-h mean SBP. Older age, and higher total cholesterol and 24-h mean SBP were associated with higher SDdn and ARV of SBP among participants with CKD. Mean SDdn and ARV of diastolic BP (DBP) were higher for participants with versus without CKD but these associations were not present after multivariable adjustment. Conclusion Data from the current study suggest that CKD is associated with higher 24-h BP variability, but the association is primarily explained by higher mean BP among those with CKD

Visit-to-Visit Variability of Blood Pressure and Cardiovascular Disease and All-Cause Mortality: A Systematic Review and Meta-Analysis

Visit-to-visit variability of blood pressure (BP) has been associated with cardiovascular disease (CVD) and mortality in some but not all studies. We conducted a systematic review and meta-analysis to examine the association between visit-to-visit variability of BP and CVD and all-cause mortality. Medical databases were searched through June 4, 2014, for studies meeting the following eligibility criteria: adult participants; BP measurements at ≥3 visits; follow-up for CVD, coronary heart disease, stroke, or mortality outcomes; events confirmed via database, death certificate, or event ascertainment committee; and adjustment for confounders. Data were extracted by 2 reviewers and pooled using a random-effects model. Overall, 8870 abstracts were identified of which 37 studies, representing 41 separate cohorts, met inclusion criteria. Across studies, visit-to-visit variability of systolic BP and diastolic BP showed significant associations with outcomes in 181 of 312 (58.0%) and 61 of 188 (32.4%) analyses, respectively. Few studies provided sufficient data for pooling risk estimates. For each 5 mm Hg higher SD of systolic BP, the pooled hazard ratio for stroke across 7 cohorts was 1.17 (95% confidence interval [CI], 1.07–1.28), for coronary heart disease across 4 cohorts was 1.27 (95% CI, 1.07–1.51), for CVD across 5 cohorts was 1.12 (95% CI, 0.98–1.28), for CVD mortality across 5 cohorts was 1.22 (95% CI, 1.09–1.35), and for all-cause mortality across 4 cohorts was 1.20 (95% CI, 1.05–1.36). In summary, modest associations between visit-to-visit variability of BP and CVD and all-cause mortality are present in published studies. However, these findings are limited by the small amount of data available for meta-analysis

Genetic Contributors of Incident Stroke in 10,700 African Americans with Hypertension: A Meta-Analysis from the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies

Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals. Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs aiming to evaluate cross-ethnic performance. Results: We identified 10 statistically significant (p \u3c 5.00E-08) and 90 additional suggestive (p \u3c 1.00E-06) variants associated with incident stroke in the meta-analysis. Six of the top 10 variants were located in an intergenic region on chromosome 18 (LINC01443-LOC644669). Additional variants of interest were located in or near the COL12A1, SNTG1, PCDH7, TMTC1, and NTM genes. Replication was conducted in the Warfarin Pharmacogenomics Cohort (WPC), and while none of the variants were directly validated, seven intronic variants of NTM proximal to our target variants, had a p-value \u3c5.00E-04 in the WPC. The inclusion of the PRS did not improve the prediction accuracy compared to a reference model adjusting for age, sex, and genetic ancestry in either study and had lower predictive accuracy compared to models accounting for established stroke risk factors. These results demonstrate the necessity for PRS derivation in AAs, particularly for diseases that affect AAs disproportionately. Conclusion: This study highlights biologically plausible genetic determinants for incident stroke in hypertensive AAs. Ultimately, a better understanding of genetic risk factors for stroke in AAs may give new insight into stroke burden and potential clinical tools for those among the highest at risk

The association between vitamin B12, albuminuria and reduced kidney function: an observational cohort study

Background: Variants in CUBN, the gene encoding cubilin, a proximal tubular transport protein, have been associated with albuminuria and vitamin B12 (B12) deficiency. We hypothesized that low levels of B12 would be associated with albuminuria in a population-based cohort. Methods: We analyzed participants from the Framingham Heart Study (n = 2965, mean age 58 years, 53% female) who provided samples for plasma B12. Logistic regression models adjusted for covariates including homocysteine were constructed to test the association between B12 and prevalent albuminuria (UACR ≥17 mg/g [men] and ≥25 mg/g [women]) and reduced kidney function (defined as an eGFR < 60 ml/min/1.73 m2, RKF). Because of a significant interaction between B12 and homocysteine in the prevalent RKF model (p = 0.005), the model was stratified by the median homocysteine levels. Logistic regression models were constructed to test the association between B12 and incident albuminuria and RKF. The results were replicated in 4445 participants from NHANES 2003–2004. Results: Baseline B12 levels ranged from 50-1690 pg/ml. Elevated B12 was associated with prevalent albuminuria (OR 1.44 per 1 SD increase, 95% CI 1.10-1.87) and RKF (OR 1.83, 95% CI 1.30-2.60). However after stratifying by median homocysteine levels, this relationship remained only in the higher homocysteine stratum. There was no association between B12 and incident albuminuria (OR 1.17, 95% CI 0.79 – 1.73) or RKF (OR 1.45, 95% CI 0.97 – 1.88). In the NHANES cohort, elevated B12 was associated with RKF after full covariate adjustment (OR 3.06, 95% CI 2.30-4.08). There was no association with albuminuria. Conclusion: In participants with high baseline homocysteine levels, increased plasma B12 was associated with RKF

Genomics of Postprandial Lipidomics in the Genetics of Lipid-Lowering Drugs and Diet Network Study

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry. A total of 413 unique lipids were identified. Heritable and responsive lipid species were examined for association with single-nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array. The most statistically significant SNP findings were replicated in the Amish Heredity and Phenotype Intervention (HAPI) Heart Study. We further followed up findings from GOLDN with a regional analysis of cytosine-phosphate-guanine (CpGs) sites measured on the Illumina HumanMethylation450 array. A total of 132 lipids were both responsive to the meal challenge and heritable in the GOLDN study. After correction for multiple testing of 132 lipids (α = 5 × 10−8/132 = 4 × 10−10), no SNP was statistically significantly associated with any lipid response. Four SNPs in the region of a known lipid locus (fatty acid desaturase 1 and 2/FADS1 and FADS2) on chromosome 11 had p \u3c 8.0 × 10−7 for arachidonic acid FA(20:4). Those SNPs replicated in HAPI Heart with p \u3c 3.3 × 10−3. CpGs around the FADS1/2 region were associated with arachidonic acid and the relationship of one SNP was partially mediated by a CpG (p = 0.005). Both SNPs and CpGs from the fatty acid desaturase region on chromosome 11 contribute jointly and independently to the diet response to a high-fat meal

Associations of Blood Pressure Dipping Patterns With Left Ventricular Mass and Left Ventricular Hypertrophy in Blacks: The Jackson Heart Study

Background: Abnormal diurnal blood pressure (BP), including nondipping patterns, assessed using ambulatory BP monitoring, have been associated with increased cardiovascular risk among white and Asian adults. We examined the associations of BP dipping patterns (dipping, nondipping, and reverse dipping) with cardiovascular target organ damage (left ventricular mass index and left ventricular hypertrophy), among participants from the Jackson Heart Study, an exclusively black population–based cohort. Methods and Results: Analyses included 1015 participants who completed ambulatory BP monitoring and had echocardiography data from the baseline visit. Participants were categorized based on the nighttime to daytime systolic BP ratio into 3 patterns: dipping pattern (≤0.90), nondipping pattern (>0.90 to ≤1.00), and reverse dipping pattern (>1.00). The prevalence of dipping, nondipping, and reverse dipping patterns was 33.6%, 48.2%, and 18.2%, respectively. In a fully adjusted model, which included antihypertensive medication use and clinic and daytime systolic BP, the mean differences in left ventricular mass index between reverse dipping pattern versus dipping pattern was 8.3±2.1 g/m2 (P<0.001) and between nondipping pattern versus dipping pattern was −1.0±1.6 g/m2 (P=0.536). Compared with participants with a dipping pattern, the prevalence ratio for having left ventricular hypertrophy was 1.65 (95% CI, 1.05–2.58) and 0.96 (95% CI, 0.63–1.97) for those with a reverse dipping pattern and nondipping pattern, respectively. Conclusions: In this population‐based study of blacks, a reverse dipping pattern was associated with increased left ventricular mass index and a higher prevalence of left ventricular hypertrophy. Identification of a reverse dipping pattern on ambulatory BP monitoring may help identify black at increased risk for cardiovascular target organ damage

Pharmacogenetic Associations of MMP9 and MMP12 Variants with Cardiovascular Disease in Patients with Hypertension

MMP-9 and -12 function in tissue remodeling and may play roles in cardiovascular disease (CVD). We assessed associations of four MMP polymorphisms and three antihypertensive drugs with cardiovascular outcomes.Hypertensives (n = 42,418) from a double-blind, randomized, clinical trial were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatment (mean follow up, 4.9 years). The primary outcome was coronary heart disease (CHD). Secondary outcomes included combined CHD, all CVD outcomes combined, stroke, heart failure (HF), and mortality. Genotype-treatment interactions were tested. = 0.015). for CHD and composite CVD. The data suggest that these genes may provide useful clinical information with respect to treatment decisions

Genome wide association study of apparent treatment resistant hypertension in the CHARGE consortium: the CHARGE pharmacogenetics working group

Background: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. Methods: We conducted a case–control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP &lt; 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (&lt;140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case–control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. Results: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10−8) and in the race-combined analysis (P = 1.5 × 10−9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6–0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. Conclusion: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus