Association Between Sleep Apnea and Blood Pressure Control Among Blacks.

BACKGROUND: Blacks have a high prevalence of hypertension and uncontrolled blood pressure (BP), each of which may be partially explained by untreated sleep apnea. We investigated the association of sleep apnea with uncontrolled BP and resistant hypertension in blacks. METHODS: Between 2012 and 2016, Jackson Heart Sleep Study participants (N=913) underwent an in-home Type 3 sleep apnea study, clinic BP measurements, and anthropometry. Moderate or severe obstructive sleep apnea (OSA) was defined as a respiratory event index ≥15, and nocturnal hypoxemia was quantified as percent sleep time with <90% oxyhemoglobin saturation. Prevalent hypertension was defined as either a systolic BP ≥130 mm Hg or diastolic BP >80mm Hg, use of antihypertensive medication, or self-report of a diagnosis of hypertension. Controlled BP was defined as systolic BP <130 mm Hg and diastolic BP <80 mm Hg; uncontrolled BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with use of 1 to 2 classes of antihypertensive medication; and resistant BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with the use of ≥3 classes of antihypertensive medication (including a diuretic) or use of ≥4 classes of antihypertensive medication regardless of BP level. Multinomial logistic regression models were fit to determine the association between OSA severity and uncontrolled BP or resistant hypertension (versus controlled BP) after multivariable adjustment. RESULTS: The analytic sample with hypertension (N=664) had a mean age of 64.0 (SD,10.6) years, and were predominately female (69.1%), obese (58.6%), and college educated (51.3%). Among the sample, 25.7% had OSA, which was untreated in 94% of participants. Overall, 48% of participants had uncontrolled hypertension and 14% had resistant hypertension. After adjustment for confounders, participants with moderate or severe OSA had a 2.0 times higher odds of resistant hypertension (95% confidence interval [CI], 1.14-3.67). Each standard deviation higher than <90% oxyhemoglobin saturation was associated with an adjusted odds ratio for resistant hypertension of 1.25 (95% CI 1.01-1.55). OSA and <90% oxyhemoglobin saturation were not associated with uncontrolled BP. CONCLUSION: Untreated moderate or severe OSA is associated with increased odds of resistant hypertension. These results suggest that untreated OSA may contribute to inadequate BP control in blacks.

Black-White Differences in Cardiovascular Disease Mortality: A Prospective US Study, 2003-2017.

Objectives. To determine factors that explain the higher Black:White cardiovascular disease (CVD) mortality rates among US adults.Methods. We analyzed data from the Reasons for Geographic and Racial Differences in Stroke study from 2003 to 2017 to estimate Black:White hazard ratios (HRs) for CVD mortality within subgroups younger than 65 years and aged 65 years or older.Results. Among 29 054 participants, 41.0% who were Black and 54.9% who were women, 1549 CVD deaths occurred. Among participants younger than 65 years, the demographic-adjusted Black:White CVD mortality HR was 2.23 (95% confidence interval [CI] = 1.87, 2.65) and 1.21 (95% CI = 1.00, 1.47) after full adjustment. Among participants aged 65 years or older, the demographic-adjusted Black:White CVD mortality HR was 1.58 (95% CI = 1.39, 1.79) and 1.12 (95% CI = 0.97, 1.29) after full adjustment. When we used mediation analysis, socioeconomic status explained 21.2% (95% CI = 13.6%, 31.4%) and 38.0% (95% CI = 20.9%, 61.7%) of the Black:White CVD mortality risk difference among participants younger than 65 years and aged 65 years or older, respectively. CVD risk factors explained 56.6% (95% CI = 42.0%, 77.2%) and 41.3% (95% CI = 22.9%, 65.3%) of the Black:White CVD mortality difference for participants younger than 65 years and aged 65 years or older, respectively.Conclusions. The higher Black:White CVD mortality risk is primarily explained by racial differences in socioeconomic status and CVD risk factors.

Incident Cardiovascular Disease Among Adults With Blood Pressure <140/90 mm Hg.

BACKGROUND: Data from before the 2000s indicate that the majority of incident cardiovascular disease (CVD) events occur among US adults with systolic and diastolic blood pressure (SBP/DBP) ≥140/90 mm Hg. Over the past several decades, BP has declined and hypertension control has improved. METHODS: We estimated the percentage of incident CVD events that occur at SBP/DBP <140/90 mm Hg in a pooled analysis of 3 contemporary US cohorts: the REGARDS study (Reasons for Geographic and Racial Differences in Stroke), the MESA (Multi-Ethnic Study of Atherosclerosis), and the JHS (Jackson Heart Study) (n=31 856; REGARDS=21 208; MESA=6779; JHS=3869). Baseline study visits were conducted in 2003 to 2007 for REGARDS, 2000 to 2002 for MESA, and 2000 to 2004 for JHS. BP was measured by trained staff using standardized methods. Antihypertensive medication use was self-reported. The primary outcome was incident CVD, defined by the first occurrence of fatal or nonfatal stroke, nonfatal myocardial infarction, fatal coronary heart disease, or heart failure. Events were adjudicated in each study. RESULTS: Over a mean follow-up of 7.7 years, 2584 participants had incident CVD events. Overall, 63.0% (95% confidence interval [CI], 54.9-71.1) of events occurred in participants with SBP/DBP <140/90 mm Hg; 58.4% (95% CI, 47.7-69.2) and 68.1% (95% CI, 60.1-76.0) among those taking and not taking antihypertensive medication, respectively. The majority of events occurred in participants with SBP/DBP <140/90 mm Hg among those <65 years of age (66.7%; 95% CI, 60.5-73.0) and ≥65 years of age (60.3%; 95% CI, 51.0-69.5), women (61.4%; 95% CI, 49.9-72.9) and men (63.8%; 95% CI, 58.4-69.1), and for whites (68.7%; 95% CI, 66.1-71.3), blacks (59.0%; 95% CI, 49.5-68.6), Hispanics (52.7%; 95% CI, 45.1-60.4), and Chinese-Americans (58.5%; 95% CI, 45.2-71.8). Among participants taking antihypertensive medication with SBP/DBP <140/90 mm Hg, 76.6% (95% CI, 75.8-77.5) were eligible for statin treatment, but only 33.2% (95% CI, 32.1-34.3) were taking one, and 19.5% (95% CI, 18.5-20.5) met the SPRINT (Systolic Blood Pressure Intervention Trial) eligibility criteria and may benefit from a SBP target goal of 120 mm Hg. CONCLUSIONS: Although higher BP levels are associated with increased CVD risk, in the modern era, the majority of incident CVD events occur in US adults with SBP/DBP <140/90 mm Hg. While absolute risk and cost-effectiveness should be considered, additional CVD risk-reduction measures for adults with SBP/DBP <140/90 mm Hg at high risk for CVD may be warranted.

Primary Care Physician Perspectives on Barriers to Statin Treatment.

PURPOSE: Discontinuation of statin therapy represents a major challenge for effective cardiovascular disease prevention. It is unclear how often primary care physicians (PCPs) re-initiate statins and what barriers they encounter. We aimed to identify PCP perspectives on factors influencing statin re-initiation. METHODS: We conducted six nominal group discussions with 23 PCPs from the Deep South Continuing Medical Education network. PCPs answered questions about statin side effects, reasons their patients reported for discontinuing statins, how they respond when discontinuation is reported, and barriers they encounter in getting their patients to re-initiate statin therapy. Each group generated a list of responses in round-robin fashion. Then, each PCP independently ranked their top three responses to each question. For each PCP, the most important reason was given a weight of 3 votes, and the second and third most important reasons were given weights of 2 and 1, respectively. We categorized the individual responses into themes and determined the relative importance of each theme using a "percent of available votes" metric. RESULTS: PCPs reported that side effects, especially muscle/joint-related symptoms, were the most common reason patients reported for statin discontinuation (47% of available votes). PCPs reported statin re-challenge as their most common response when a patient discontinues statin use (31% of available votes). Patients' fear of side effects was ranked as the biggest challenge PCPs encounter in getting their patients to re-initiate statin therapy (70% of available votes). CONCLUSION: PCPs face challenges getting their patients to re-initiate statins, particularly after a patient reports side effects.

Waist Circumference, Body Mass Index, and ESRD in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study.

BACKGROUND: The association between waist circumference and end-stage renal disease (ESRD) remains poorly explored. STUDY DESIGN: Longitudinal population-based cohort. SETTING & PARTICIPANTS: Participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study (n=30,239) with information for body mass index (BMI), waist circumference, spot urine albumin-creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR; n=26,960). PREDICTOR: Elevated waist circumference or BMI. OUTCOMES & MEASUREMENTS: Incident cases of ESRD were identified through linkage of REGARDS participants with the US Renal Data System. RESULTS: Mean baseline age was 64.8 years, 45.8% were men, and 40.3% were black. Overall, 297 (1.1%) individuals developed ESRD during a median of 6.3 years. After adjustment for all covariates including waist circumference, no significant association was noted between BMI categories and ESRD incidence compared to BMI of 18.5 to 24.9 kg/m2 (referent). Higher waist circumference categories showed significantly increased hazard rates of ESRD, with waist circumference ≥ 108 cm in women and ≥122 cm in men (highest category) showing a 3.97-fold higher hazard rate (95% CI, 2.10-6.86) for ESRD compared to waist circumference < 80 cm in women and <94 cm in men (referent) after adjusting for demographic factors and BMI. However, no significant association was noted between any waist circumference category and ESRD incidence after adjustment for obesity-associated comorbid conditions and baseline ACR and eGFR. LIMITATIONS: Short follow-up period (6.3 years) to assess ESRD risk among adults with eGFRs>60 mL/min/1.73 m2. CONCLUSIONS: In this cohort of older adults, obesity as measured by waist circumference is associated with higher ESRD risk even with adjustment for BMI, whereas obesity as measured by BMI is not associated with higher ESRD risk after adjustment for waist circumference. However, no significant association is noted between increased waist circumference and ESRD risk after adjustment for obesity-related comorbid conditions, eGFR, and ACR.

Addressing Stroke Risk Factors in Black and White Americans: Findings from the National Health and Nutrition Examination Survey, 2009-2010.

OBJECTIVE: Recurrent stroke affects 5%-15% of stroke survivors, is higher among Blacks, and preventable with secondary stroke prevention medications. Our study aimed to examine racial differences in risk factors being addressed (defined as either on active treatment or within guideline levels) among stroke survivors and those at risk for stroke. METHODS: A cross-sectional study using NHANES 2009-2010 standardized interviews of Whites and Blacks aged ≥18 years. Risk factors were defined as being addressed if: 1) for hypertension, SBP <140, DBP <90 (SBP<130, DBP<80 for diabetics) or using BP-lowering medications; 2) for current smoking, using cessation medications; and 3) for hyperlipidemia, LDL<100 (LDL<70 for stroke survivors) or using lipid-lowering medications. Participants were stratified by stroke history. Prevalence of addressed risk factors was compared by race. RESULTS: Among 4005 participants (mean age 48, 52% women, 15% Black), 4% reported a history of stroke. Among stroke survivors, there were no statistically significant differences in Blacks and Whites having their hypertension or hyperlipidemia addressed. Among stroke naïve participants, the prevalence of addressed hypertension (P<.01) and hyperlipidemia (P<.01) was lower in Blacks compared with Whites. CONCLUSIONS: We found that addressed hypertension and hyperlipidemia in stroke naïve participants were significantly lower in Blacks than Whites. Our observations call attention to areas that require further investigation, such as why Black Americans may not be receiving evidence-based pharmacologic therapy for hypertension and hyperlipidemia or why Black Americans are not at goal blood pressure or goal LDL. A better understanding of this information is critical to preventing stroke and other vascular diseases.

Contrasting Cholesterol Management Guidelines for Adults with CKD.

The Kidney Disease Improving Global Outcomes Lipid Work Group recommends statins for adults ≥50 years old with CKD. The American College of Cardiology/American Heart Association endorses statins for adults with atherosclerotic cardiovascular disease, adults with LDL cholesterol≥190 mg/dl, and adults 40-79 years old with LDL cholesterol=70-189 mg/dl and diabetes or a 10-year predicted risk for atherosclerotic cardiovascular disease ≥7.5% estimated using the Pooled Cohort risk equations. Using data from the Reasons for Geographic and Racial Differences in Stroke Study, we calculated the agreement for statin treatment between these two guidelines for adults 50-79 years old with CKD (eGFR<60 ml/min per 1.73 m(2) or albuminuria≥30 mg/g) not on dialysis. We assessed the validity of the Pooled Cohort risk equations in individuals with CKD. Study participants were enrolled between 2003 and 2007, and we report incident cardiovascular disease events (stroke and coronary heart disease) through December of 2010. Among 4726 participants with CKD, 2366 (50%) were taking statins, and 1984 (42%) were recommended statins by the American College of Cardiology/American Heart Association guideline but not taking them. Overall, 376 (8%) participants did not meet the American College of Cardiology/American Heart Association criteria for initiating statin treatment. Cardiovascular disease incidence was low (3.0/1000 person-years; 95% confidence interval, 0.1 to 5.9) among these participants. The Pooled Cohort risk equations were well calibrated (Hosmer-Lemeshow chi-squared=2.7, P=0.45) with moderately good discrimination (C index, 0.71; 95% confidence interval, 0.65 to 0.77). In conclusion, these guidelines show high concordance for statin treatment for adults with CKD.

Obesity, metabolic health, and the risk of end-stage renal disease.

Obesity is associated with chronic kidney disease progression. Whether metabolic risk factors modify this association is unclear. Here we examined associations of body mass index (BMI) and metabolic health with risk of end-stage renal disease (ESRD) in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Among 21,840 participants eligible for analysis, 247 developed ESRD (mean follow-up of 6.3 years). Metabolic health significantly modified the association of BMI with ESRD. In models stratified by the presence or absence of the metabolic syndrome and adjusted for demographic, lifestyle, and clinical factors, higher BMI was associated with lower risk of ESRD in those without (hazard ratio per 5 kg/m2 increase in BMI 0.70, 95% CI 0.52, 0.95) but not those with (hazard ratio, 1.06) the metabolic syndrome. In models stratified by weight and metabolic health, compared with normal weight (BMI 18.5-24.9 kg/m2) participants without the metabolic syndrome the overweight individuals (BMI 25-29.9) and obese individuals (BMI of 30 or more) with the metabolic syndrome had greater risk of ESRD (hazard ratios of 2.03 and 2.29, respectively), whereas obesity without the metabolic syndrome was associated with lower risk of ESRD (hazard ratio 0.47). Thus, higher BMI is associated with lower ESRD risk in those without but not those with the metabolic syndrome.

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 m(2). 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.

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 m(2), 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.

Validation of an Albuminuria Self-assessment Tool in the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: We previously developed an 8-item self-assessment tool to identify individuals with a high probability of having albuminuria. This tool was developed and externally validated among non-Hispanic Whites and non-Hispanic Blacks. We sought to validate it in a multi-ethnic cohort that also included Hispanics and Chinese Americans. DESIGN: This is a cross-sectional study. SETTING: Data were collected using standardized questionnaires and spot urine samples at a baseline examination in 2000-2002. The 8 items in the self-assessment tool include age, race, gender, current cigarette smoking, history of diabetes, hypertension, or stroke, and self-rated health. PARTICIPANTS: Of 6,814 community-dwelling adults aged 45-84 years participating in the Multi-Ethnic Study of Atherosclerosis (MESA), 6,542 were included in the primary analysis. MAIN OUTCOME MEASURES: Albuminuria was defined as urine albumin-to-creatinine ratio ≥ 30 mg/g at baseline. RESULTS: Among non-Hispanic Whites, non-Hispanic Blacks, Hispanics, and Chinese Americans, the prevalence of albuminuria was 6.0%, 11.3%, 11.6%, and 10.8%, respectively. The c-statistic for discriminating participants with and without albuminuria was .731 (95% CI: .692, .771), .728 (95% CI: .687, .761), .747 (95% CI: .709, .784), and .761 (95% CI: .699, .814) for non-Hispanic Whites, non-Hispanic Blacks, Hispanics, and Chinese Americans, respectively. The self-assessment tool over-estimated the probability of albuminuria for non-Hispanic Whites and Blacks, but was well-calibrated for Hispanics and Chinese Americans. CONCLUSIONS: The albuminuria self-assessment tool maintained good test characteristics in this large multi-ethnic cohort, suggesting it may be helpful for increasing awareness of albuminuria in an ethnically diverse population.

Incident ESRD and treatment-resistant hypertension: the reasons for geographic and racial differences in stroke (REGARDS) study.

BACKGROUND: Studies suggest that treatment-resistant hypertension is common and increasing in prevalence among US adults. Although hypertension is a risk factor for end-stage renal disease (ESRD), few data are available for the association between treatment-resistant hypertension and ESRD risk. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We analyzed data from 9,974 REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study participants treated for hypertension without ESRD at baseline. PREDICTOR: Treatment-resistant hypertension was defined as uncontrolled blood pressure (BP) with concurrent use of 3 antihypertensive medication classes including a diuretic or use of 4 or more antihypertensive medication classes including a diuretic regardless of BP. OUTCOME: Incident ESRD was identified by linkage of REGARDS Study participants with the US Renal Data System. MEASUREMENTS: During a baseline in-home study visit, BP was measured twice and classes of antihypertensive medication being taken were determined by pill bottle inspection. RESULTS: During a median follow-up of 6.4 years, there were 152 incident cases of ESRD (110 ESRD cases among 2,147 with treatment-resistant hypertension and 42 ESRD cases among 7,827 without treatment-resistant hypertension). The incidence of ESRD per 1,000 person-years for hypertensive participants with and without treatment-resistant hypertension was 8.86 (95% CI, 7.35-10.68) and 0.88 (95% CI, 0.65-1.19), respectively. After multivariable adjustment, the HR for ESRD comparing hypertensive participants with versus without treatment-resistant hypertension was 6.32 (95% CI, 4.30-9.30). Of participants who developed incident ESRD during follow-up, 72% had treatment-resistant hypertension at baseline. LIMITATIONS: BP, estimated glomerular filtration rate, and albuminuria assessed at a single time. CONCLUSIONS: Individuals with treatment-resistant hypertension are at increased risk for ESRD. Appropriate clinical management strategies are needed to treat treatment-resistant hypertension in order to preserve kidney function in this high-risk group.

Geographic variation in CKD prevalence and ESRD incidence in the United States: results from the reasons for geographic and racial differences in stroke (REGARDS) study.

BACKGROUND: It is not known whether geographic differences in the prevalence of chronic kidney disease exist and are associated with end-stage renal disease (ESRD) incidence rates across the United States. STUDY DESIGN: Cross-sectional and ecologic. SETTING & PARTICIPANTS: White (n = 16,410) and black (n = 11,109) participants from across the continental United States in the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. PREDICTOR: Geographic region, defined by the 18 networks of the US ESRD Network Program. OUTCOMES & MEASUREMENTS: Albuminuria, defined as albumin-creatinine ratio ≥30 mg/g, and decreased estimated glomerular filtration rate (eGFR), defined as <60 mL/min/1.73 m(2), were measured in the REGARDS Study. ESRD incidence rates were obtained from the US Renal Data System. RESULTS: For whites, the network-specific prevalence of albuminuria ranged from 8.4% (95% CI, 3.3%-13.5%) in Network 15 to 14.8% (95% CI, 8.0%-21.6%) in Network 3, and decreased eGFR ranged from 4.3% (95% CI, 2.0%-6.6%) in Network 4 to 16.7% (95% CI, 12.7%-20.7%) in Network 7. For blacks, the prevalence of albuminuria ranged from 12.1% (95% CI, 8.7%-15.5%) in Network 5 to 26.5% (95% CI, 16.7%-36.3%) in Network 4, and decreased eGFR ranged from 6.7% (95% CI, 5.0%-8.4%) in Network 17/18 to 13.4% (95% CI, 7.8%-19.1%) in Network 12. Spearman correlation coefficients for the prevalence of albuminuria and decreased eGFR with network-specific ESRD incidence rates were 0.49 and 0.24, respectively, for whites and 0.29 and 0.25, respectively, for blacks. LIMITATIONS: There were few cases of albuminuria and decreased eGFR in some geographic regions. CONCLUSIONS: In the United States, substantial geographic variations in the prevalence of albuminuria and decreased eGFR exist, but were correlated only modestly with ESRD incidence, suggesting the chronic kidney disease burden may not explain the geographic variation in ESRD incidence.

Hypertension severity, apparent treatment resistant hypertension and hyperuricemia in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study.

BACKGROUND: Prior studies have identified an association between hypertension and hyperuricemia; however, there has been limited research on the association between hypertension severity and hyperuricemia. METHOD: We studied 997 Black and white adults with serum urate data from the reasons for geographic and racial differences in stroke (REGARDS) study. Hypertension was defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg or self-reported use of antihypertensive medication. Apparent treatment-resistant hypertension (aTRH) was defined as a SBP ≥ 140 mmHg or DBP ≥ 90 mmHg with concurrent use of three classes of antihypertensive medications, or taking four or more classes of antihypertensive medication regardless of BP level. Controlled BP was defined as SBP <140 mmHg and DBP <90 mmHg. RESULTS: Overall 5.9% of participants had aTRH and 36.6% had hyperuricemia, defined as serum urate >7.0 mg/dl for men and >6.0 mg/dl for women. After full multivariable adjustment, the odds ratio (OR) for hyperuricemia associated with hypertension was 1.60 [95% confidence interval (95% CI): 1.06-2.40]. Compared to participants not taking antihypertensive medication, the ORs for hyperuricemia for participants taking one, two and three classes of antihypertensive medication without aTRH were 1.98 (95% CI: 1.23-3.20), 2.08 (95% CI: 1.25-3.43), 4.31 (95% CI: 2.07-8.97), respectively, and 3.96 (95% CI: 1.75-8.96) for aTRH. Compared to participants without hypertension, the odds ratios for hyperuricemia were 1.67 (95% CI: 1.08-2.58) and 1.46 (95% CI: 0.88-2.44) among those with hypertension with and without controlled BP, respectively. Diuretic use was associated with a higher odds of hyperuricemia. CONCLUSION: This study suggests that individuals taking more classes of antihypertensive medication may benefit from monitoring for hyperuricemia.

The predominant PAR4 variant in individuals of African ancestry worsens murine and human stroke outcomes.

Protease-activated receptor 4 (PAR4) (gene F2RL3) harbors a functional dimorphism, rs773902 A/G (encoding Thr120/Ala120, respectively) and is associated with greater platelet aggregation. The A allele frequency is more common in Black individuals, and Black individuals have a higher incidence of ischemic stroke than White individuals. However, it is not known whether the A allele is responsible for worse stroke outcomes. To directly test the in vivo effect of this variant on stroke, we generated mice in which F2rl3 was replaced by F2RL3, thereby expressing human PAR4 (hPAR4) with either Thr120 or Ala120. Compared with hPAR4 Ala120 mice, hPAR4 Thr120 mice had worse stroke outcomes, mediated in part by enhanced platelet activation and platelet-neutrophil interactions. Analyses of 7,620 Black subjects with 487 incident ischemic strokes demonstrated the AA genotype was a risk for incident ischemic stroke and worse functional outcomes. In humanized mice, ticagrelor with or without aspirin improved stroke outcomes in hPAR4 Ala120 mice, but not in hPAR4 Thr120 mice. P selectin blockade improved stroke outcomes and reduced platelet-neutrophil interactions in hPAR4 Thr120 mice. Our results may explain some of the racial disparity in stroke and support the need for studies of nonstandard antiplatelet therapies for patients expressing PAR4 Thr120.

Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.

Introduction: Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Methods: Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP (n = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg (n = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg (n = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). Results: One variant in the known HTN locus, KCNK3, was a top finding in the multi-ethnic analysis (p = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes AGTPBP, MYL4, PDCD4, BBS9, ERG, and IER3. Discussion: Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

Epidemiology of obesity, the metabolic syndrome, and chronic kidney disease.

The prevalence of obesity and metabolic syndrome (MetS) has increased over the past several decades and is expected to continue to increase. Although the individual components of MetS have previously been associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD), until recently there were few data on the relationship between MetS itself and incident CKD and ESRD. A recent meta-analysis demonstrated an association between MetS and CKD. When pooling 10 prospective cohort studies, MetS was associated with an increased odds ratio for an estimated glomerular filtration rate (eGFR) less than 60 mL/ min per 1.73 m2 (OR, 1.55; 95% CI, 1.34-1.80). Additionally, published data suggest an association between MetS and albuminuria. Evidence suggests that lifestyle modifications such as weight reduction, reduced dietary fat intake and cholesterol, and pharmacologic treatments may reduce the burden of MetS and thus the risk for CKD, albuminuria, and ESRD.

Genetic Contributors of Efficacy and Adverse Metabolic Effects of Chlorthalidone in African Americans from the Genetics of Hypertension Associated Treatments (GenHAT) Study.

Hypertension is a leading risk factor for cardiovascular disease mortality. African Americans (AAs) have the highest prevalence of hypertension in the United States, and to alleviate the burden of hypertension in this population, better control of blood pressure (BP) is needed. Previous studies have shown considerable interpersonal differences in BP response to antihypertensive treatment, suggesting a genetic component. Utilizing data from 4297 AA participants randomized to chlorthalidone from the Genetics of Hypertension Associated Treatments (GenHAT) study, we aimed to identify variants associated with the efficacy of chlorthalidone. An additional aim was to find variants that contributed to changes in fasting glucose (FG) in these individuals. We performed genome-wide association analyses on the change of systolic and diastolic BP (SBP and DBP) over six months and FG levels over 24 months of treatment. We sought replication in the International Consortia of Pharmacogenomics Studies. We identified eight variants statistically associated with BP response and nine variants associated with FG response. One suggestive LINC02211-CDH9 intergenic variant was marginally replicated with the same direction of effect. Given the impact of hypertension in AAs, this study implies that understanding the genetic background for BP control and glucose changes during chlorthalidone treatment may help prevent adverse cardiovascular events in this population.

Stress and Depression Are Associated With Life's Simple 7 Among African Americans With Hypertension: Findings From the Jackson Heart Study.

BACKGROUND: The American Heart Association created the Life's Simple 7 (LS7) metrics to promote cardiovascular health (CVH) by achieving optimal levels of blood pressure, cholesterol, blood sugar, physical activity, diet, weight, and smoking status. The degree to which psychosocial factors such as stress and depression impact one's ability to achieve optimal CVH is unclear, particularly among hypertensive African Americans. METHODS: Cross-sectional analyses included 1,819 African Americans with hypertension participating in the Jackson Heart Study (2000-2004). Outcomes were LS7 composite and individual component scores (defined as poor, intermediate, ideal). High perceived chronic stress was defined as the top quartile of Weekly Stress Inventory scores. High depressive symptoms were defined as Center for Epidemiologic Studies Depression scale scores of ≥16. We compared 4 groups: high stress alone; high depressive symptoms alone; high stress and high depressive symptoms; low stress and low depressive symptoms (reference) using linear regression for total LS7 scores and logistic regression for LS7 components. RESULTS: Participants with both high stress and depressive symptoms had lower composite LS7 scores (B [95% confidence interval] = -0.34 [-0.65 to -0.02]) than those with low stress and depressive symptoms in unadjusted and age/sex-adjusted models. They also had poorer health status for smoking (odds ratio [95% confidence interval] = 0.52 [0.35-0.78]) and physical activity (odds ratio [95% confidence interval] = 0.71 [0.52-0.95]) after full covariate adjustment. CONCLUSIONS: The combination of high stress and high depressive symptoms was associated with poorer LS7 metrics in hypertensive African Americans. Psychosocial interventions may increase the likelihood of engaging in behaviors that promote optimal CVH.

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 < 5.00E-08) and 90 additional suggestive (p < 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 <5.00E-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.