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INTRODUCTION: African-Americans (blacks) have higher risk of stroke and coronary heart disease (CHD) - collectively referred to here as cardiovascular disease (CVD), than Caucasian-Americans (whites). Though partly explained by traditional cardiovascular risk factors, half of the excess risk in blacks is not explained by known risk factors. Recent data suggest increased risk of CVD and mortality in individuals with clonal hematopoiesis, which often presents as cytopenia. Using peripheral blood cytopenia as a marker of clonal hematopoiesis, we examined the association between cytopenia and risk of CVD and mortality in blacks and whites. METHODS: The REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study enrolled 30,239 US black and white adults between 2003 and 2007 (41% black). Socio-demographics and medical history were obtained by telephone interview, and laboratory studies (including complete blood count [CBC]) and physical exam from an in-home visit at baseline. Participants or their proxies were contacted every 6 months to ascertain CVD events, hospitalizations or deaths, and medical records were reviewed to confirm these events. Cytopenia was defined using thresholds in Table 1 as presence of 2 or more of the following: i) hemoglobin in age-, sex-, and race-specific lowest 5th percentile; ii) white cell count in race-specific lowest 5th percentile; iii) platelet count in lowest 5th percentile, and iv) macrocytosis (MCV >98fL). Participants with pre-baseline history of stroke (for analyses including stroke or CVD mortality) or CHD (for analyses including CHD or CVD mortality) and those with missing CBC were excluded. Cox proportional hazards models were used to calculate hazard ratios (HRs) of incident CVD and mortality associated with cytopenia. Models adjusted for socio-demographics (Model 1), Framingham stroke or CHD risk factors (Model 2), and estimated glomerular filtration rate and C-reactive protein (Model 3) were used. Differences in the association of cytopenia with outcomes by race were tested using cross-product interaction terms, using a p of <0.1 for interaction. RESULTS: The study included 19,544 participants who were followed for a median of ~9 years. There were 798 (4.3% of those at risk) incident stroke cases and 727 (4.3%) incident CHD cases; 1033 (5.3%) died of CVD, and 3933 (20.1%) died of all-causes. Cytopenia was present in 378 (1.9%) participants, ranging from 0.9% to 3.5% in blacks, 1.4 to 3.9% in whites, 1.6 to 3.9% in men, and 0.9 to 1.8% in women, with increasing prevalence by age. There was no association between cytopenia and stroke or CHD risk in any model. However, cytopenia was associated with increased risk of all-cause mortality (HR=1.73, 95%CI: 1.34-2.22), and CVD mortality (HR=1.56, 95% CI: 1.11-2.19) in the extended risk factor Model 3 and also in CVD risk factor adjusted model (Model 2), with little evidence of confounding (Table 2). While the race by cytopenia interaction term was not significant in any model for incident CHD or mortality, the interaction for cytopenia by race for stroke was statistically significant (p-interaction=0.08) in Model 2. The HR of stroke for cytopenia in blacks was 0.86 (95%CI: 0.46-1.61), and for whites was 1.96 (95%CI: 1.0-3.82). CONCLUSION: In this large biracial cohort, cytopenia was associated with increased all-cause and CVD mortality. Cytopenia was a race-specific risk factor for stroke affecting white Americans but not black Americans. With growing knowledge on the role of clonal hematopoiesis in CVD risk and mortality, further work is needed to determine if our phenotype of cytopenia is accurate in classifying clonal hematopoiesis and for determining the mortality risk. Given these findings, assessing clonal hematopoiesis and outcomes related to clonal hematopoiesis in diverse populations is critical to understanding the interactions between somatic mutations in hematopoietic cells and CVD/mortality risk. Disclosures Safford: Amgen: Research Funding.

Biospecimens acquired during routine medical practice are the primary sources of molecular information about patients and their diseases that underlies precision medicine and translational research. In cancer care, molecular analysis of biospecimens is especially common because it often determines treatment choices and may be used to monitor therapy in real time. However, patient specimens are collected, handled, and processed according to routine clinical procedures during which they are subjected to factors that may alter their molecular quality and composition. Such artefactual alteration may skew data from molecular analyses, render analysis data uninterpretable, or even preclude analysis altogether if the integrity of a specimen is severely compromised. As a result, patient care and safety may be affected, and medical research dependent on patient samples may be compromised. Despite these issues, there is currently no requirement to control or record preanalytical variables in clinical practice with the single exception of breast cancer tissue handled according to the guideline jointly developed by the American Society of Clinical Oncology and College of American Pathologists (CAP) and enforced through the CAP Laboratory Accreditation Program. Recognizing the importance of molecular data derived from patient specimens, the CAP Personalized Healthcare Committee established the Preanalytics for Precision Medicine Project Team to develop a basic set of evidence-based recommendations for key preanalytics for tissue and blood specimens. If used for biospecimens from patients, these preanalytical recommendations would ensure the fitness of those specimens for molecular analysis and help to assure the quality and reliability of the analysis data.

Background Blood pressure ( BP ) varies over time within individual patients and across different BP measurement techniques. The effect of different BP targets on concordance between BP measurements is unknown. The goals of this analysis are to evaluate concordance between (1) clinic and ambulatory BP , (2) clinic visit‐to‐visit variability and ambulatory BP variability, and (3) first and second ambulatory BP and to evaluate whether different clinic targets affect these relationships. Methods and Results The SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP monitoring ancillary study obtained ambulatory BP readings in 897 participants at the 27‐month follow‐up visit and obtained a second reading in 203 participants 293±84 days afterward. There was considerable lack of agreement between clinic and daytime ambulatory systolic BP with wide limits of agreement in Bland‐Altman plots of −21 to 34 mm Hg in the intensive‐treatment group and −26 to 32 mm Hg in the standard‐treatment group. Overall, there was poor agreement between clinic visit‐to‐visit variability and ambulatory BP variability with correlation coefficients for systolic and diastolic BP all <0.16. We observed a high correlation between first and second ambulatory BP ; however, the limits of agreement were wide in both the intensive group (−27 to 21 mm Hg) and the standard group (−23 to 20 mm Hg). Conclusions We found low concordance in BP and BP variability between clinic and ambulatory BP and second ambulatory BP . Results did not differ by treatment arm. These results reinforce the need for multiple BP measurements before clinical decision making.

Blood pressure (BP) varies over time within individual patients and across different BP measurement techniques. The effect of different BP targets on the concordance between BP measurements is unknown. The goal of this analysis was to evaluate concordance in: 1) clinic BP and ambulatory BP, 2) clinic visit-to-visit variability and ambulatory BP variability and 3) initial and repeat ambulatory BP. We also sought to evaluate whether treatment assignment of intensive vs standard BP target affected these relationships. The Systolic Blood Pressure Intervention Trial (SPRINT) ambulatory blood pressure monitoring ancillary study obtained ambulatory BP readings in 897 SPRINT participants at the 27 month follow up visit and 203 consecutive repeat ambulatory BP readings taken an average of 9.8 months later. There was poor agreement between clinic systolic BP and daytime ambulatory systolic BP (limits of agreement in Bland-Altman plots of -21 to 34 mm Hg in the intensive treatment group and -26 to 32 mm Hg in the standard treatment group). There was poor agreement between clinic visit-to-visit variability (coefficient of variation) and ambulatory BP variability (coefficient of variation of a 24 hr ambulatory BP) with correlation coefficients for systolic BP <0.16. While there was a high correlation between ambulatory BP at 27 months and repeat ambulatory BP (r ~0.56), there was significant variability between repeat ambulatory BP assessments (limits of agreement of -27 to 21 mm Hg in the intensive group and -23 to 20 mm Hg in the standard group). In conclusion, irrespective of treatment target, we found low concordance in BP and BP variability between clinic BP and ambulatory BP, and additionally between repeat ambulatory BP assessments. These results reinforce the need for multiple guideline adherent BP measurements prior to clinical decision making.

Background and Purpose— White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods— In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results— At 17q25, we confirmed the association of multiple common variants in TRIM65 , FBF1 , and ACOX1 ( P <6×10 −7 ). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P EA =4.5×10 −8 ) partially independent of known common signal ( P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1 , CARF , and WDR12 (lead, rs2351524; P all =1.9×10 −10 ). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P rs34136221 =2.8×10 −8 ). Conclusions— Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

Intensive systolic blood pressure (SBP) control improved outcomes in SPRINT (Systolic Blood Pressure Intervention Trial). Our objective was to expand on reported findings by analysis of baseline characteristics, primary outcomes, adverse events, follow-up blood pressure, and medication use differences by baseline SBP (tertile 1 [T1], <132; tertile 2 [T2], 132–145; and tertile 3 [T3], >145 mm Hg). Participants with higher baseline SBP tertile were more often women and older, had higher cardiovascular risk, and lower utilization of antihypertensive medications, statins, and aspirin. Achieved SBP in both treatment arms was slightly higher in T2 and T3 compared with T1 and fewer in the T3 groups achieved SBP targets compared with T1 and T2 groups. The primary composite outcome with intensive versus standard SBP treatment was reduced by 30% in T1, 23% in T2, and 17% in T3 with no evidence of an interaction ( P =0.77). Event rates were lower in the intensive arm, and there was no evidence that this benefit differed by SBP tertile. There was no difference in the hazard for serious adverse events in any of the 3 tertiles. Medication utilization differed across the SBP tertiles at baseline with a lesser percentage of diuretics and angiotensin-converting enzyme inhibitors/angiotensin receptor blocker drugs in the higher tertiles—a finding that reversed during the trial. The beneficial effects of intensive SBP lowering were not modified by the level of baseline SBP. Within the parameters of this population, these findings add support for clinicians to treat blood pressure to goal irrespective of baseline SBP.

Background: In individuals with a low diastolic blood pressure (DBP), the potential benefits or risks of intensive systolic blood pressure (SBP) lowering are unclear. Methods: SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized controlled trial that compared the effects of intensive (target <120 mm Hg) and standard (target <140 mm Hg) SBP control in 9361 older adults with high blood pressure at increased risk of cardiovascular disease. The primary outcome was a composite of cardiovascular disease events. All-cause death and incident chronic kidney disease were secondary outcomes. This post hoc analysis examined whether the effects of the SBP intervention differed by baseline DBP. Results: Mean baseline SBP and DBP were 139.7±15.6 and 78.1±11.9 mm Hg, respectively. Regardless of the randomized treatment, baseline DBP had a U-shaped association with the hazard of the primary cardiovascular disease outcome. However, the effects of the intensive SBP intervention on the primary outcome were not influenced by baseline DBP level ( P for interaction=0.83). The primary outcome hazard ratio for intensive versus standard treatment was 0.78 (95% confidence interval, 0.57–1.07) in the lowest DBP quintile (mean baseline DBP, 61±5 mm Hg) and 0.74 (95% confidence interval, 0.61–0.90) in the upper 4 DBP quintiles (mean baseline DBP, 82±9 mm Hg), with an interaction P value of 0.78. Results were similar for all-cause death and kidney events. Conclusions: Low baseline DBP was associated with increased risk of cardiovascular disease events, but there was no evidence that the benefit of the intensive SBP lowering differed by baseline DBP. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01206062.

The appropriate target for BP in patients with CKD and hypertension remains uncertain. We report prespecified subgroup analyses of outcomes in participants with baseline CKD in the Systolic Blood Pressure Intervention Trial. We randomly assigned participants to a systolic BP target of <120 mm Hg (intensive group; n =1330) or <140 mm Hg (standard group; n =1316). After a median follow-up of 3.3 years, the primary composite cardiovascular outcome occurred in 112 intensive group and 131 standard group CKD participants (hazard ratio [HR], 0.81; 95% confidence interval [95% CI], 0.63 to 1.05). The intensive group also had a lower rate of all-cause death (HR, 0.72; 95% CI, 0.53 to 0.99). Treatment effects did not differ between participants with and without CKD ( P values for interactions ≥0.30). The prespecified main kidney outcome, defined as the composite of ≥50% decrease in eGFR from baseline or ESRD, occurred in 15 intensive group and 16 standard group participants (HR, 0.90; 95% CI, 0.44 to 1.83). After the initial 6 months, the intensive group had a slightly higher rate of change in eGFR (−0.47 versus −0.32 ml/min per 1.73 m 2 per year; P <0.03). The overall rate of serious adverse events did not differ between treatment groups, although some specific adverse events occurred more often in the intensive group. Thus, among patients with CKD and hypertension without diabetes, targeting an SBP<120 mm Hg compared with <140 mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcome.