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Context: Although authoritative bodies have promulgated guidelines for donation after cardiac death (DCD) and the Joint Commission requires hospitals to address DCD, little is known about actual hospital policies.Objective: To characterize DCD policies in children's hospitals and evaluate variation among policies.Design, Setting, and Participants: Mixed-methods analysis of policies collected between November 2007 and January 2008 from hospitals in the United States, Puerto Rico, and Canada in 2 membership categories of the National Association of Children's Hospitals and Related Institutions.Main Outcome Measures: Status of DCD policy development and content of the policies based on coding categories developed in part from authoritative statements.Results: One hundred five of 124 eligible hospitals responded, a response rate of 85%. Seventy-six institutions (72%; 95% confidence interval [CI], 64%-82%) had DCD policies, 20 (19%; 95% CI, 12%-28%) were developing policies; and 7 (7%; 95% CI, 3%-14%) neither had nor were developing policies. We received and analyzed 73 unique, approved policies. Sixty-one policies (84%; 95% CI, 73%-91%) specify criteria or tests for declaring death. Four policies require total waiting periods prior to organ recovery at variance with professional guidelines: 1 less than 2 minutes and 3 longer than 5 minutes. Sixty-four policies (88%; 95% CI, 78%-94%) preclude transplant personnel from declaring death and 37 (51%; 95% CI, 39%-63%) prohibit them from involvement in premortem management. While 65 policies (89%; 95% CI, 80%-95%) indicate the importance of palliative care, only 5 (7%; 95% CI, 2%-15%) recommend or require palliative care consultation. Of 68 policies that indicate where withdrawal of life-sustaining treatment can or should take place, 37 policies (54%; 95% CI, 42%-67%) require it to occur in the operating room and 3 policies (4%; 95% CI, 1%-12%) require it to occur in the intensive care unit.Conclusions: Most children's hospitals have developed or are developing DCD policies. There is, however, considerable variation among policies. [ABSTRACT FROM AUTHOR]

The presence of calcified coronary artery plaque has shown variable association with clinical coronary heart disease (CHD), particularly after adjustment for other risk factors. From 2002 to 2004, as part of the National Heart, Lung, and Blood Institute's Family Heart Study, coronary artery calcium (CAC) scans by 4-slice multidetector computed tomography were performed in 3,359 subjects, including 389 with clinically diagnosed CHD. Among these was a cohort of 2,254 patients who had been asymptomatic at an initial examination 7 to 9 years previously (1994 to 1996), with 111 who had developed newly diagnosed, nonfatal CHD since the initial examination. In cross-sectional analyses, we examined associations between CAC and CHD in the entire group and in the subgroup seen at the initial examination. In the 2 sets of analyses, odds ratios for CHD ranged from approximately 4 in those with CAC scores of 100 to 199 (p <0.01) to >20 in those with CAC scores >/=1,000 (p <0.0001) compared with those with no measurable CAC. This steep gradient of risk persisted after adjustment for risk factors. A quantitative CHD family history score was significantly associated with CHD even after adjusting for all standard risk factors and including CAC in the model. In conclusion, CAC was strongly associated with CHD even after adjustment for standard risk factors and family history contributed independently to CHD risk. [ABSTRACT FROM AUTHOR]

Objective: Metabolic syndrome-related traits (obesity, glucose intolerance/insulin resistance, dyslipidemia, and hypertension) have been shown to be genetically correlated. It is less clear, however, if the genetic correlation extends to novel risk factors associated with inflammation, impaired fibrinolytic activity, and hyperuricemia. We present a bivariate genetic analysis of MetS-related traits including both traditional and novel risk factors.Research Design and Methods: Genetic correlations were estimated using a variance components procedure in 1,940 nondiabetic white individuals from 445 families in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Twelve MetS-related traits, including BMI, waist circumference, blood pressure, white blood cell count, fasting serum triglycerides, HDL cholesterol, insulin, glucose, plasminogen activator inhibitor-1 antigen, uric acid, and C-reactive protein, were measured and adjusted for covariates, including lifestyle variables.Results: Significant genetic correlations were detected among BMI, waist circumference, HDL cholesterol, triglycerides, insulin, and plasminogen activator inhibitor-1 antigen and between uric acid and all of the above variables except insulin. C-reactive protein and white blood cell count were genetically correlated with each other, and both showed significant genetic correlations with waist circumference and insulin. Fasting glucose was not significantly genetically correlated with any of the other traits.Conclusions: These results suggest that pleiotropic effects of genes or shared family environment contribute to the familial clustering of MetS-related traits. [ABSTRACT FROM AUTHOR]

Defects in the lipoprotein lipase (LPL) gene are associated with dyslipidemia in the general population. Several rare mutations in the gene, as well as two common coding region polymorphisms, D9N and N291S, exhibit deleterious effects on circulating lipid levels. Using a linkage-based approach, we have identified a large Utah kindred segregating the D9N variant in the LPL gene. The kindred was ascertained for premature coronary heart disease and was expanded based on familial dyslipidemia. A genomic scan identified a region of linkage including LPL, and mutation screening identified the segregating variant. In the kindred, the variant shows high penetrance for a hypoalphalipoproteinemia phenotype, but is also associated with hypertriglyceridemia and elevated insulin levels. The strength of linkage was dependent on the combination of phenotype definition and model parameters, favoring the use of a MOD score approach. Most other studies of LPL have proceeded by mutation screening of randomly chosen individuals or selected affected probands; this is the first example identifying a segregating LPL mutation using direct linkage. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We sought to estimate the optimal time to deliver uncomplicated monochorionic-diamnionic (MCDA) twins. STUDY DESIGN: Data were retrospectively obtained from twin pregnancies from 2000 through 2009. The gestational week-specific prospective perinatal mortality risk was calculated. A cohort of MCDA twins with nonindicated deliveries was analyzed separately. Neonatal outcomes and costs were compared between MCDA twins with nonindicated deliveries born at specific weeks of gestation, and those born the subsequent week. RESULTS: There were 5894 dichorionic-diamnionic twins and 1704 MCDA twins. After 28 weeks, the gestational week-specific prospective risk of perinatal mortality did not differ between groups. There were 948 MCDA twins with nonindicated deliveries. Until 37 weeks, the risk of severe neonatal morbidity, perinatal mortality, and hospital costs were greater for fetuses delivered compared to fetuses born in a subsequent week. CONCLUSION: To optimize neonatal outcome and decrease hospital costs, MCDA twins should not be delivered <37 weeks unless medically indicated. [ABSTRACT FROM AUTHOR]

Detailed medical family history data have been proposed to be effective in identifying high-risk families for targeted intervention. With use of a validated and standardized quantitative family risk score (FRS), the degree of familial aggregation of coronary heart disease (CHD), stroke, hypertension, and diabetes was obtained from 122,155 Utah families and 6,578 Texas families in the large, population-based Health Family Tree Study, and 1,442 families in the NHLBI Family Heart Study in Massachusetts, Minnesota, North Carolina, and Utah. Utah families with a positive family history of CHD (FRS > or =0.5) represented only 14% of the general population but accounted for 72% of persons with early CHD (men before age 55 years, women before age 65 years) and 48% of CHD at all ages. For strokes, 11% of families with FRS > or =0.5 accounted for 86% of early strokes (<75 years) and 68% of all strokes. Analyses of >5,000 families sampled each year in Utah for 14 years demonstrated a gradual decrease in the frequency of a strong positive family history of CHD (-26%/decade) and stroke (-15%/decade) that paralleled a decrease in incidence rates (r = 0.86, p <0.001 for CHD; r = 0.66, p <0.01 for stroke). Because of the collaboration of schools, health departments, and medical schools, the Health Family Tree Study proved to be a highly cost-efficient method for identifying 17,064 CHD-prone families and 13,106 stroke-prone families (at a cost of about $27 per high-risk family) in whom well-established preventive measures can be encouraged. We conclude that most early cardiovascular events in a population occur in families with a positive family history of cardiovascular disease. Family history collection is a validated and relatively inexpensive tool for family-based preventive medicine and medical research. [ABSTRACT FROM AUTHOR]

Lifestyle modification including exercise training is often the first line of defense in the treatment of obesity and hypertension (HTN), however, little is known regarding how these potentially compounding disease states impact vasodilatory and hemodynamic responses at baseline and exercise. Therefore, this study sought to compare the impact of obesity on vascular function and hemodynamics at baseline and during handgrip (HG) exercise among individuals with HTN. Non-obese (13M/7F, 56 ± 16 yr, 25 ± 4 kg/m 2 ) and obese (17M/4F, 50 ± 7 yr, 35 ± 4 kg/m 2 ) middle-aged individuals with HTN forwent antihypertensive medication use for ≥2 wk before assessment of vascular function by brachial artery flow-mediated dilation (FMD) and exercise hemodynamics during progressive HG exercise at 15-30-45% maximal voluntary contraction (MVC). FMD was not different between Non-Obese (4.1 ± 1.7%) and Obese (5.2 ± 1.9%, P = 0.11). Systolic blood pressure (SBP) was elevated by ∼15% during the supine baseline and during HG exercise in the obese group. The blood flow response to HG exercise at 30% and 45% MVC was ∼20% greater ( P < 0.05) in the obese group but not different after normalizing for the higher, albeit, nonsignificant differences in workloads (MVC: obese: 24 ± 5 kg, non-obese: 21 ± 5 kg, P = 0.11). Vascular conductance and the brachial artery shear-induced vasodilatory response during HG were not different between groups ( P > 0.05). Taken together, despite elevated SBP during HG exercise, obesity does not lead to additional impairments in vascular function and peripheral exercising hemodynamics in patients with HTN. Obesity may not be a contraindication when prescribing exercise for the treatment of HTN among middle-aged adults, however, the elevated SBP should be appropriately monitored. NEW & NOTEWORTHY This study examined vascular function and handgrip exercise hemodynamics in obese and nonobese individuals with hypertension. Obesity, when combined with hypertension, was neither associated with additional vascular function impairments at baseline nor peripheral hemodynamics and vasodilation during exercise compared with nonobese hypertension. Interestingly, systolic blood pressure and pulse pressure were greater in the obese group during supine baseline and exercise. These findings should not be ignored and may be particularly important for rehabilitation strategies.

Background: High dietary salt confers a risk of elevating blood pressure (BP) and the development of hypertension. BP to salt intake may be determined in part by individual genetic predisposition. Identifying these genetic underpinnings will enhance our understanding of the biological mechanisms of BP regulation. This study aims to assess the genetic association with salt sensitivity of BP (SSBP) within two well-phenotyped multinational cohorts., Methods: A total of 720 white participants from the HyperPATH consortium program were selected and genotyped using a multiethnic genotyping array. Individuals consumed two study diets containing high (>200 mEq/day) and low (<10 mEq/day) sodium content, after which SSBP, aldosterone, and plasma renin activity (PRA) were assessed in a controlled inpatient research setting., Results: A top signal (rs10887801; beta = 4.57, P  = 5.03E - 07) at the renalase gene ( RNLS ) region was significantly associated with SSBP. We also identified seven single nucleotide variants with linkage disequilibrium to the top signal at this region that comprised a significant haplotype (TCTTAGTT, P  = 0.00081). Homozygous carriers of the T-risk allele of the key single nucleotide variant had higher SSBP ( P  ≤ 0.00001) and lower PRA ( P  = 0.0076) compared with the nonrisk allele., Conclusion: We identified significant associations between genetic variants of the RNLS gene and BP responses to dietary salt intervention and PRA that suggest susceptibility to volume-driven hypertension. These findings may contribute to a better understanding of the genetic mechanisms underlying BP regulation, support the role of RNLS in the pathogenesis of SSBP, and identify individuals who may be at risk from excess dietary salt intake., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Vascular dysfunction, an independent risk factor for cardiovascular disease, often persists in patients with hypertension, despite improvements in blood pressure control induced by antihypertensive medications., Methods: As some of these medications may directly affect vascular function, this study sought to comprehensively examine the impact of reducing blood pressure, by a nonpharmacological approach (5 days of sodium restriction), on vascular function in 22 hypertensive individuals (14 men/8 women, 50 ± 10 years). Following a 2-week withdrawal of antihypertensive medications, two 5-day dietary phases, liberal sodium (liberal sodium, 200 mmol/day) followed by restricted sodium (restricted sodium, 10 mmol/day), were completed. Resting blood pressure was assessed and vascular function, at both the conduit and microvascular levels, was evaluated by brachial artery flow-mediated dilation (FMD), reactive hyperemia, progressive handgrip exercise, and passive leg movement (PLM)., Results: Despite a sodium restriction-induced fall in blood pressure (liberal sodium: 141 ± 14/85 ± 9; restricted sodium 124 ± 12/79 ± 9 mmHg, P < 0.01 for both SBP and DBP), FMD (liberal sodium: 4.6 ± 1.8%; restricted sodium: 5.1 ± 2.1%, P = 0.27), and reactive hyperemia (liberal sodium: 548 ± 201; restricted sodium: 615 ± 206 ml, P = 0.08) were not altered. Similarly, brachial artery vasodilation during handgrip exercise was not different between conditions (liberal sodium: Δ0.36 ± 0.19 mm; restricted sodium: Δ0.42 ± 0.18 mm, P = 0.16). Lastly, PLM-induced changes in peak blood flow (liberal sodium: 5.3 ± 2.5; restricted sodium: 5.8 ± 3.6 ml/min per mmHg, P = 0.30) and the total vasodilatory response [liberal sodium: 2 (0.9-2.5) vs. restricted sodium: 1.7 (1.1-2.6) ml/min per mmHg; P = 0.5] were also not different between conditions., Conclusion: Thus vascular dysfunction, at both the conduit and microvascular levels, persists in patients with hypertension even when blood pressure is acutely reduced by a nonpharmacological approach., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Context: Salt sensitivity of blood pressure (SSBP) is associated with increased cardiovascular risk, especially in individuals of African descent, although the underlying mechanisms remain obscure. Lysine-specific demethylase 1 (LSD1) is a salt-sensitive epigenetic regulator associated with SSBP and aldosterone dysfunction. An LSD1 risk allele in humans is associated with SSBP and lower aldosterone levels in hypertensive individuals of African but not European descent. Heterozygous knockout LSD1 mice display SSBP and aldosterone dysregulation, but this effect is modified by age and biological sex. This might explain differences in cardiovascular risk with aging and biological sex in humans., Objective: This work aims to determine if LSD1 risk allele (rs587618) carriers of African descent display a sex-by-age interaction with SSBP and aldosterone regulation., Methods: We analyzed 297 individuals of African and European descent from the HyperPATH cohort. We performed multiple regression analyses for outcome variables related to SSBP and aldosterone., Results: LSD1 risk allele carriers of African (but not European) descent had greater SSBP than nonrisk homozygotes. Female LSD1 risk allele carriers of African descent had greater SSBP, mainly relationship-driven by women with low estrogen (postmenopausal). There was a statistically significant LSD1 genotype-sex interaction in aldosterone response to angiotensin II stimulation in individuals aged 50 years or younger, with female carriers displaying decreased aldosterone responsiveness., Conclusion: SSBP associated with LSD1 risk allele status is driven by women with a depleted estrogen state. Mechanisms related to a resistance to develop SSBP in females are uncertain but may relate to an estrogen-modulating effect on mineralocorticoid receptor (MR) activation and/or LSD1 epigenetic regulation of the MR., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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Context: There are well-established interactions between the thyroid and the kidney. Thyroid hypofunction is associated with reduced renal plasma flow (RPF), and hypothyroidism is highly prevalent in chronic kidney disease; however, less is known about the thyroid-kidney axis in the euthyroid state., Objective: This work aimed to study the association of thyroid function with renovascular parameters in a well-phenotyped cohort of euthyroid normotensive and hypertensive individuals., Methods: This cross-sectional, multicenter study of the HyperPATH Consortium took place in 5 US and European academic institutions. A total of 789 individuals, aged 18 to 65 years, with serum thyrotropin (TSH) 0.4 to 5.5 mIU/L, participated; individuals with uncontrolled or secondary hypertension or on medication affecting the hypothalamus-pituitary-thyroid axis were excluded. Hemodynamic parameters including RPF, thyroid function testing, and the Thr92Ala deiodinase 2 (D2) polymorphism were assessed in the setting of a liberal and restricted salt diet. We searched for associations between thyroid function and renovascular parameters and accounted for confounding factors, such as older age, hypertension, and diabetes., Results: Serum TSH was inversely associated with RPF assessed in the setting both of liberal and restricted salt diets. This association remained significant and independent when accounting for confounding factors, whereas free thyroxine index (fTI) and the Thr92Ala polymorphism, associated with lower D2 catalytic activity and disrupted thyroid hormone tissue availability, were not independently associated with RPF. Serum TSH remained an independent predictor of RPF on a liberal salt diet when the analysis was restricted to healthy young individuals., Conclusion: Serum TSH levels, but not fTI nor the Thr92Ala D2 polymorphism, were independently inversely associated with RPF in individuals of the HyperPATH Consortium. These findings suggest a direct interconnection between TSH and renovascular dynamics even with TSH within reference range, warranting further investigation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Genome-wide association studies have identified associations between a common single nucleotide polymorphism (SNP; rs267738) in CERS2, a gene that encodes a (dihydro)ceramide synthase that is involved in the biosynthesis of very-long-chain sphingolipids (eg, C20-C26) and indices of metabolic dysfunction (eg, impaired glucose homeostasis). However, the biological consequences of this mutation on enzyme activity and its causal roles in metabolic disease are unresolved., Objective: The studies described herein aimed to characterize the effects of rs267738 on CERS2 enzyme activity, sphingolipid profiles, and metabolic outcomes., Design: We performed in-depth lipidomic and metabolic characterization of a novel CRISPR knock-in mouse modeling the rs267738 variant. In parallel, we conducted mass spectrometry-based, targeted lipidomics on 567 serum samples collected through the Utah Coronary Artery Disease study, which included 185 patients harboring 1 (n = 163) or both (n = 22) rs267738 alleles., Results: In-silico analysis of the amino acid substitution within CERS2 caused by the rs267738 mutation suggested that rs267738 is deleterious for enzyme function. Homozygous knock-in mice had reduced liver CERS2 activity and enhanced diet-induced glucose intolerance and hepatic steatosis. However, human serum sphingolipids and a ceramide-based cardiac event risk test 1 score of cardiovascular disease were not significantly affected by rs267738 allele count., Conclusions: The rs267738 SNP leads to a partial loss-of-function of CERS2, which worsened metabolic parameters in knock-in mice. However, rs267738 was insufficient to effect changes in serum sphingolipid profiles in subjects from the Utah Coronary Artery Disease Study., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although the contribution of noncardiac complications to the pathophysiology of heart failure with preserved ejection fraction (HFpEF) have been increasingly recognized, disease-related changes in peripheral vascular control remain poorly understood. We utilized small muscle mass handgrip exercise to concomitantly evaluate exercising muscle blood flow and conduit vessel endothelium-dependent vasodilation in individuals with HFpEF ( n = 25) compared with hypertensive controls (HTN) ( n = 25). Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), brachial artery blood velocity, and brachial artery diameter were assessed during progressive intermittent handgrip (HG) exercise [15-30-45% maximal voluntary contraction (MVC)]. Forearm blood flow (FBF) and vascular conductance (FVC) were determined to quantify the peripheral hemodynamic response to HG exercise, and changes in brachial artery diameter were evaluated to assess endothelium-dependent vasodilation. HR, SV, and CO were not different between groups across exercise intensities. However, although FBF was not different between groups at the lowest exercise intensity, FBF was significantly lower (20-40%) in individuals with HFpEF at the two higher exercise intensities (30% MVC: 229 ± 8 versus 274 ± 23 ml/min; 45% MVC: 283 ± 17 versus 399 ± 34 ml/min, HFpEF versus HTN). FVC was not different between groups at 15 and 30% MVC but was ∼20% lower in HFpEF at the highest exercise intensity. Brachial artery diameter increased across exercise intensities in both HFpEF and HTN, with no difference between groups. These findings demonstrate an attenuation in muscle blood flow during exercise in HFpEF in the absence of disease-related changes in central hemodynamics or endothelial function. NEW & NOTEWORTHY The current study identified, for the first time, an attenuation in exercising muscle blood flow during handgrip exercise in individuals with heart failure with preserved ejection fraction (HFpEF) compared with overweight individuals with hypertension, two of the most common comorbidities associated with HFpEF. These decrements in exercise hyperemia cannot be attributed to disease-related changes in central hemodynamics or endothelial function, providing additional evidence for disease-related vascular dysregulation, which may be a predominant contributor to exercise intolerance in individuals with HFpEF.

Background: Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitine palmitoyltransferase-1A (CPT1A) gene to be associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome), but the mechanism underlying these associations is unknown., Objectives: We aimed to elucidate whether carbohydrate and fat intakes modulate cg00574958 methylation and the risk of metabolic diseases., Methods: We examined associations between carbohydrate (CHO) and fat (FAT) intake, as percentages of total diet energy, and the CHO/FAT ratio with CPT1A-cg00574958, and the risk of metabolic diseases in 3 populations (Genetics of Lipid Lowering Drugs and Diet Network, n = 978; Framingham Heart Study, n = 2331; and REgistre GIroní del COR study, n = 645) while adjusting for confounding factors. To understand possible causal effects of dietary intake on the risk of metabolic diseases, we performed meta-analysis, CPT1A transcription analysis, and mediation analysis with CHO and FAT intakes as exposures and cg00574958 methylation as the mediator., Results: We confirmed strong associations of cg00574958 methylation with metabolic phenotypes (BMI, triglyceride, glucose) and diseases in all 3 populations. Our results showed that CHO intake and CHO/FAT ratio were positively associated with cg00574958 methylation, whereas FAT intake was negatively correlated with cg00574958 methylation. Meta-analysis further confirmed this strong correlation, with β = 58.4 ± 7.27, P = 8.98 x 10-16 for CHO intake; β = -36.4 ± 5.95, P = 9.96 x 10-10 for FAT intake; and β = 3.30 ± 0.49, P = 1.48 x 10-11 for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively associated with FAT intake, and metabolic phenotypes. Mediation analysis supports the hypothesis that CHO intake induces CPT1A methylation, hence reducing the risk of metabolic diseases, whereas FAT intake inhibits CPT1A methylation, thereby increasing the risk of metabolic diseases., Conclusions: Our results suggest that the proportion of total energy supplied by CHO and FAT can have a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A.Study registration at https://www.clinicaltrials.gov/: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)-NCT01023750; and the Framingham Heart Study (FHS)-NCT00005121., (Published by Oxford University Press on behalf of the American Society for Nutrition 2020.)

Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statin's aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1-43.2) lower aldosterone level ( P =0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels ( P =0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant ( P =0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statin's aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation.

Background: Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease., Objective: To characterize the prevalence of nonsuppressible renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure., Design: Cross-sectional study., Setting: 4 U.S. academic medical centers., Participants: Participants with normotension ( n  = 289), stage 1 hypertension ( n  = 115), stage 2 hypertension ( n  = 203), and resistant hypertension ( n  = 408)., Measurements: Participants completed an oral sodium suppression test, regardless of aldosterone or renin levels, as a confirmatory diagnostic for primary aldosteronism and to quantify the magnitude of renin-independent aldosterone production. Urinary aldosterone was measured in participants in high sodium balance with suppressed renin activity. Biochemically overt primary aldosteronism was diagnosed when urinary aldosterone levels were higher than 12 μg/24 h., Results: Every blood pressure category had a continuum of renin-independent aldosterone production, where greater severity of production was associated with higher blood pressure, kaliuresis, and lower serum potassium levels. Mean adjusted levels of urinary aldosterone were 6.5 μg/24 h (95% CI, 5.2 to 7.7 μg/24 h) in normotension, 7.3 μg/24 h (CI, 5.6 to 8.9 μg/24 h) in stage 1 hypertension, 9.5 μg/24 h (CI, 8.2 to 10.8 μg/24 h) in stage 2 hypertension, and 14.6 μg/24 h (CI, 12.9 to 16.2 μg/24 h) in resistant hypertension; corresponding adjusted prevalence estimates for biochemically overt primary aldosteronism were 11.3% (CI, 5.9% to 16.8%), 15.7% (CI, 8.6% to 22.9%), 21.6% (CI, 16.1% to 27.0%), and 22.0% (CI, 17.2% to 26.8%). The aldosterone-renin ratio had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism., Limitation: Prevalence estimates rely on arbitrary and conventional thresholds, and the study population may not represent nationwide demographics., Conclusion: The prevalence of primary aldosteronism is high and largely unrecognized. Beyond this categorical definition of primary aldosteronism, there is a prevalent continuum of renin-independent aldosterone production that parallels the severity of hypertension. These findings redefine the primary aldosteronism syndrome and implicate it in the pathogenesis of "essential" hypertension., Primary Funding Source: National Institutes of Health.

Background: Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain., Methods: We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk., Results: We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR., Conclusions: We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age., (Published by Oxford University Press on behalf of the American Association for Clinical Chemistry 2020. This work is written by US Government employees and is in the public domain in the US.)

Autosomal dominant hypercholesterolemia results from mutations affecting the low-density lipoprotein receptor pathway, including proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GoFm) and apolipoprotein B (APOB) loss-of-function mutations (LoFm). This study examined the long-term efficacy and safety of alirocumab in patients with PCSK9 GoFm and APOB LoFm who participated in the open-label extension to a Phase 2 double-blind study (NCT01604824). Of the 23 patients who completed the 14-week double-blind period and 8-week follow-up, 21 opted to continue in the open-label extension (PCSK9 GoFm, n = 15; APOB LoFm, n = 6). Patients received alirocumab 150 mg every 2 weeks from week 32 up to 3 years for PCSK9 GoFm and 2 years for APOB LoFm. Mean duration of alirocumab exposure was 129 weeks (median: 144 weeks). After initiation of alirocumab treatment, low-density lipoprotein cholesterol (LDL-C) decreased in both groups. At week 80, mean percent reduction in LDL-C from baseline was 58.0% and 47.1% for PCSK9 GoFm and APOB LoFm groups, respectively. Treatment-emergent adverse events were reported in 19 patients (90.5%); no patients discontinued treatment due to treatment-emergent adverse events. In patients with autosomal dominant hypercholesterolemia and elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapies, alirocumab 150 mg every 2 weeks resulted in clinically meaningful reductions in LDL-C, sustained through to 3 years and 2 years for patients with PCSK9 GoFm and APOB LoFm, respectively. Alirocumab was generally well tolerated with no unexpected safety concerns., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

BACKGROUNDCeramides are sphingolipids that play causative roles in diabetes and heart disease, with their serum levels measured clinically as biomarkers of cardiovascular disease (CVD).METHODSWe performed targeted lipidomics on serum samples from individuals with familial coronary artery disease (CAD) (n = 462) and population-based controls (n = 212) to explore the relationship between serum sphingolipids and CAD, using unbiased machine learning to identify sphingolipid species positively associated with CAD.RESULTSNearly every sphingolipid measured (n = 30 of 32) was significantly elevated in subjects with CAD compared with measurements in population controls. We generated a novel sphingolipid-inclusive CAD risk score, termed SIC, that demarcates patients with CAD independently and more effectively than conventional clinical CVD biomarkers including serum LDL cholesterol and triglycerides. This new metric comprises several minor lipids that likely serve as measures of flux through the ceramide biosynthesis pathway rather than the abundant deleterious ceramide species that are included in other ceramide-based scores.CONCLUSIONThis study validates serum ceramides as candidate biomarkers of CVD and suggests that comprehensive sphingolipid panels should be considered as measures of CVD.FUNDINGThe NIH (DK112826, DK108833, DK115824, DK116888, and DK116450); the Juvenile Diabetes Research Foundation (JDRF 3-SRA-2019-768-A-B); the American Diabetes Association; the American Heart Association; the Margolis Foundation; the National Cancer Institute, NIH (5R00CA218694-03); and the Huntsman Cancer Institute Cancer Center Support Grant (P30CA040214).

Dietary salt restriction is a well-established approach to lower blood pressure and reduce cardiovascular disease risk in hypertensive individuals. However, little is currently known regarding the effects of salt restriction on central and peripheral hemodynamic responses to exercise in those with hypertension. Therefore, this study sought to determine the impact of salt restriction on the central and peripheral hemodynamic responses to static-intermittent handgrip (HG) and dynamic single-leg knee extension (KE) exercise in individuals with hypertension. Twenty-two subjects (14 men and 8 women, 51 ± 10 yr, 173 ± 11 cm, 99 ± 23 kg) forewent their antihypertensive medication use for at least 2 wk before embarking on a 5-day liberal salt (LS: 200 mmol/day) diet followed by a 5-day restricted salt (RS: 10 mmol/day) diet. Subjects were studied at rest and during static intermittent HG exercise at 15, 30, and 45% of maximal voluntary contraction and KE exercise at 40, 60, and 80% of maximum KE work rate. Salt restriction lowered resting systolic blood pressure (supine: -12 ± 12 mmHg, seated: -17 ± 12 mmHg) and diastolic blood pressure (supine: -3 ± 9 mmHg, seated: -5 ± 7 mmHg, P < 0.05). Despite an ~8 mmHg lower mean arterial blood pressure during both HG and KE exercise following salt restriction, neither central nor peripheral hemodynamics were altered. Therefore, salt restriction can lower blood pressure during exercise in subjects with hypertension, reducing the risk of cardiovascular events, without impacting central and peripheral hemodynamics during either arm or leg exercise. NEW & NOTEWORTHY This is the first study to examine the potential blood pressure-lowering benefit of a salt-restrictive diet in individuals with hypertension without any deleterious effects of exercising blood flow. While mean arterial pressure decreased by ~8 mmHg following salt restriction, these findings provide evidence for salt restriction to provide protective effects of reducing blood pressure without inhibiting central or peripheral hemodynamics required to sustain arm or leg exercise in subjects with hypertension.

Background: Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm)., Objective: The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm., Methods: Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22., Results: At Week 8, mean ± standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 ± 1.81 vs 16.74 ± 2.53 mg/L). APOB LOFm carriers had higher mean ± SE total PCSK9 (6.56 ± 0.73 mg/L) and lower mean ± SE free PCSK9 (0.025 ± 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 ± 0.35 and 0.11 ± 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean ± SE percent LDL-C reduction was lower in APOB LOFm (55.3 ± 1.0%) compared with PCSK9 GOFm carriers (73.1 ± 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group., Conclusions: Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm., Clinical Trial Registration: NCT01604824; clinicaltrials.gov., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background Heart fats (epicardial and paracardial adipose tissue [PAT]) are greater after menopause. Endogenous estrogen may regulate these fat depots. We evaluated the differential effects of hormone therapy formulations on heart fat accumulations and their associations with coronary artery calcification (CAC) progression in recently menopausal women from KEEPS (Kronos Early Estrogen Prevention Study). Methods and Results KEEPS was a multicenter, randomized, placebo-controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens and 50 µg/d transdermal 17β-estradiol, compared with placebo, on 48-month progression of subclinical atherosclerosis among 727 early menopausal women. CAC progression was defined if baseline CAC score was 0 and 48-month CAC score was >0 or if baseline CAC score was >0 and <100 and annualized change in CAC score was ≥10. Of 727 KEEPS participants, 474 (mean age: 52.7 [SD: 2.6]; 78.1% white) had computed tomography-based heart fat and CAC measures at both baseline and 48 months. Compared with women on placebo, women on oral conjugated equine estrogens were less likely to have any increase in epicardial adipose tissue (odds ratio for oral conjugated equine estrogens versus placebo: 0.62 [95% CI, 0.40-0.97]; P =0.03). PAT did not change in any group. Changes in epicardial adipose tissue and PAT did not differ by treatment group. CAC increased in 14% of participants. The assigned treatment modified the association between PAT changes and CAC progression ( P =0.02) such that PAT increases were associated with CAC increases only in the transdermal 17β-estradiol group. Conclusions In recently menopausal women, oral conjugated equine estrogens may slow epicardial adipose tissue accumulation, whereas transdermal 17β-estradiol may increase progression of CAC associated with PAT accumulation. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00154180.

There are conflicting data on whether variations of physiologic cortisol levels associated with cardiovascular risk. We hypothesize that prior discordant findings are related to problems associated with varying sample size, techniques for assessing cardiovascular risk and failure to adequately account for environmental factors. To address these issues, we utilized a large sample size, selected the Framingham risk score to compute cardiovascular risk and performed the study in a highly controlled setting. We had two main objectives: determine whether higher, yet physiologic, cortisol levels associated with increased cardiovascular risk and determine whether caveolin-1 (rs926198) risk allele carriers associated with increased cardiovascular risk. This was a cross-sectional study of 574 non-diabetic individuals who completed a common protocol. Data collection included fasting blood samples, blood pressure measurements and a 24-h urine-free cortisol collection. Five hundred seventeen of these participants also completed caveolin-1 genotyping. Subjects were classified as belonging to either the low-mode or high-mode urine-free cortisol groups, based on the bimodal distribution of urine-free cortisol. In multivariate analysis, Framingham risk score was statistically higher in the high-mode cortisol group (10.22 (mean) ± 0.43 (s.e.m.)) compared to the low-mode cortisol group (7.73 ± 0.34), P < 0.001. Framingham risk score was also statistically higher in the caveolin-1 risk allele carriers (8.91 ± 0.37) compared to caveolin-1 non-risk allele carriers (7.59 ± 0.48), P = 0.034. Overall, the estimated effect on Framingham risk score of carrying the caveolin-1 risk allele was 1.33 ± 0.61, P = 0.029. Both urinary cortisol and caveolin-1 risk allele status are independent predictors of Framingham risk score.

Background: Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants. Results: We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ITGA7 ) was associated with fasting triglyceride levels ( P = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ITGA7 ( P = 1.77E-07) and SLCO2A1 ( P = 7.18E-07) and triglycerides, as well as between POT1 ( P = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved P -values of 0.04 ( ITGA7 ), 0.08 ( SLCO2A1 ), and 0.02 ( POT1 ). In GOLDN, gene transcript levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides ( P = 0.07 and P = 0.02), highlighting functional relevance of our findings. Conclusion: In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.

Key Points: Insulin sensitivity (as determined by a hyperinsulinaemic-euglyceamic clamp) decreased 15% after reduced activity. Despite not fully returning to baseline physical activity levels, insulin sensitivity unexpectedly, rebounded above that recorded before 2 weeks of reduced physical activity by 14% after the recovery period. Changes in insulin sensitivity in response to reduced activity were primarily driven by men but, not women. There were modest changes in ceramides (nuclear/myofibrillar fraction and serum) following reduced activity and recovery but, in the absence of major changes to body composition (i.e. fat mass), ceramides were not related to changes in inactivity-induced insulin sensitivity in healthy older adults., Abstract: Older adults are at risk of physical inactivity as they encounter debilitating life events. It is not known how insulin sensitivity is affected by modest short-term physical inactivity and recovery in healthy older adults, nor how insulin sensitivity is related to changes in serum and muscle ceramide content. Healthy older adults (aged 64-82 years, five females, seven males) were assessed before (PRE), after 2 weeks of reduced physical activity (RA) and following 2 weeks of recovery (REC). Insulin sensitivity (hyperinsulinaemic-euglyceamic clamp), lean mass, muscle function, skeletal muscle subfraction, fibre-specific, and serum ceramide content and indices of skeletal muscle inflammation were assessed. Insulin sensitivity decreased by 15 ± 6% at RA (driven by men) but rebounded above PRE by 14 ± 5% at REC. Mid-plantar flexor muscle area and leg strength decreased with RA, although only muscle size returned to baseline levels following REC. Body fat did not change and only minimal changes in muscle inflammation were noted across the intervention. Serum and intramuscular ceramides (nuclear/myofibrillar fraction) were modestly increased at RA and REC. However, ceramides were not related to changes in inactivity-induced insulin sensitivity in healthy older adults. Short-term inactivity induced insulin resistance in older adults in the absence of significant changes in body composition (i.e. fat mass) are not related to changes in ceramides., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Our understanding of genetic influences on the response of lipids to specific interventions is limited. In this study, we sought to elucidate effects of rare genetic variants on lipid response to a high-fat meal challenge and fenofibrate (FFB) therapy in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) cohort using an exome-wide sequencing-based association study. Our results showed that the rare coding variants in ITGA7 , SIPA1L2 , and CEP72 are significantly associated with fasting LDL cholesterol response to FFB ( P = 1.24E-07), triglyceride postprandial area under the increase (AUI) ( P = 2.31E-06), and triglyceride postprandial AUI response to FFB ( P = 1.88E-06), respectively. We sought to replicate the association for SIPA1L2 in the Heredity and Phenotype Intervention (HAPI) Heart Study, which included a high-fat meal challenge but not FFB treatment. The associated rare variants in GOLDN were not observed in the HAPI Heart study, and thus the gene-based result was not replicated. For functional validation, we found that gene transcript level of SIPA1L2 is associated with triglyceride postprandial AUI ( P < 0.05) in GOLDN. Our study suggests unique genetic mechanisms contributing to the lipid response to the high-fat meal challenge and FFB therapy.

Background: Mutations in the genes for the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH)., Objective: The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab., Methods: Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR, apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations., Results: Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39-114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10-165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials., Conclusion: Clinically meaningful LDL-C-lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Sitosterolemia is associated with increases in intestinal sterol absorption, low-density lipoprotein cholesterol (LDL-C), and cardiovascular disease risk., Objective: We examined the relationship between hypercholesterolemia and sitosterolemia in a large population and report a new sitosterolemia case., Methods: Plasma sterol concentrations were measured by gas chromatography/mass spectrometry, and LDL-C by direct assay., Results: Of 207,926 subjects tested, 4.3% had LDL-C ≥190 mg/dL. Plasma β-sitosterol concentrations ≥8.0 mg/L (99th percentile) were found in 4.3% of these subjects vs 0.72% with LDL-C <130 mg/dL. Among all subjects, 0.050% had β-sitosterol levels ≥15.0 mg/L, consistent with sitosterolemia, while among those with LDL-C ≥190 mg/dL, 0.334% had this rare disorder. A 13-year-old boy with the highest LDL-C (679 mg/dL) of all subjects had planar xanthomas and a β-sitosterol level of 53.5 mg/L (normal <3.3 mg/L). He was a compound heterozygote for 2 ABCG8 mutations (p.N409D and an intron 11+2T>A splice site mutation). On a low-cholesterol and plant-sterol diet, his LDL-C decreased to 485 mg/dL (-29%) and β-sitosterol to 44.6 mg/L (-27%). On atorvastatin 20 mg/d, his LDL-C decreased to 299 mg/dL (-38%). With added ezetimibe 10 mg/d, his LDL-C normalized to 60 mg/dL (-80% further decrease); and his β-sitosterol decreased to 14.1 mg/L (-68% further decrease)., Conclusions: Our data indicate that about 4% of subjects with LDL-C concentrations ≥190 mg/dL have plasma β-sitosterol concentrations above the 99th percentile and about 0.3% have concentrations consistent with sitosterolemia. Therefore, this diagnosis should be considered in such patients., (Copyright © 2017. Published by Elsevier Inc.)

Background: Understanding the interactions between genetics, sodium (Na+) intake, and blood pressure (BP) will help overcome the lack of individual specificity in our current treatment of hypertension. This study had 3 goals: expand on the relationship between striatin gene (STRN) status and salt-sensitivity of BP (SSBP); evaluate the status of Na+ and volume regulating systems by striatin risk allele status; evaluate potential SSBP mechanisms., Methods: We assessed the relationship between STRN status in humans (HyperPATH cohort) and SSBP and on volume regulated systems in humans and a striatin knockout mouse (STRN+/-)., Results: The previously identified association between a striatin risk allele and systolic SSBP was demonstrated in a new cohort (P = 0.01). The STRN-SSBP association was significant for the combined cohort (P = 0.003; β = +5.35 mm Hg systolic BP/risk allele) and in the following subgroups: normotensives, hypertensives, men, and older subjects. Additionally, we observed a lower epinephrine level in risk allele carriers (P = 0.014) and decreased adrenal medulla phenylethanolamine N-methyltransferase (PNMT) in STRN+/- mice. No significant associations were observed with other volume regulated systems., Conclusions: These results support the association between a variant of striatin and SSBP and extend the findings to normotensive individuals and other subsets. In contrast to most salt-sensitive hypertensives, striatin-associated SSBP is associated with normal plasma renin activity and reduced epinephrine levels. These data provide clues to the underlying cause and a potential pathway to achieve, specific, personalized treatment, and prevention., (© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com)