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Background: We recently demonstrated how orthostatic hypotension might be used to identify out-of-office blood pressure phenotypes, including white coat effects and nocturnal non-dipping patterns. However, these findings have not been replicated in a population with chronic kidney disease (CKD). Objective: To examine the association between orthostatic hypotension (OH) or hypertension (OHTN) with ambulatory BP in adults with CKD. Methods: CRIC is a prospective multicenter observation cohort study of participants with CKD. Standing BP at 1 minute and ABPM were obtained on 1467 participants. OH was defined as a 20mmHg drop in systolic BP (SBP) or 10 mmHg drop in diastolic BP (DBP) when changing from seated to standing positions. OHTN was defined as a 20 mmHg or 10mmHg rise in SBP or DBP respectively when changing from seated to standing position. White coat effects, based on ABPM, was defined as the difference between seated clinic and ambulatory BP. Systolic and diastolic night to day ratio was also calculated. Results: Of the 1467 participants (age: 58 ± 10 yrs, 44% female, 39% black) 73 had OH and 165 had OHTN). OH was positively associated with systolic and diastolic white coat effect (β=5.9 [0.9, 10.9] and 4.2 [1.3, 7.1]). OHTN was negatively associated with diastolic white coat effect (-4.9 [-6.9, -3]). OH was positively associated with systolic and diastolic night-to-day ratio (0.03 [0.01, 0.05] and 0.03 [0.01, 0.06] respectively). Conclusions: Clinic-based assessments of OH and OHTN may be useful for identifying BP phenotypes often missed with seated office BP measurements in CKD patients.

A significant proportion of patients with non-dialysis chronic kidney disease (CKD) present with mild-to-moderate deficits in the cognitive domains of executive function and episodic memory. Excess blood flow pulsatility is damaging to the microvasculature of high-flow, low-resistance organs like the brain and may contribute to the cognitive deficits prevalent among CKD patients. We tested the hypothesis that patients with moderate-to-severe non-dialysis CKD have excess flow pulsatility along their carotid and cerebral vasculature that is associated with deficits in executive function and episodic memory. We recruited 10 non-dialysis CKD patients (age=68±8 yrs; estimated glomerular filtration rate, eGFR=36±18 mL/min/1.73 m 2 ) and 7 healthy age-matched adults (age=65±5 yrs; eGFR=81±17 mL/min/1.73 m 2 ). Global cognitive function was assessed with the Montreal Cognitive Assessment (MoCA). Executive function and episodic memory were assessed using the NIH Toolbox Flanker Inhibitory Control and Attention Test and California Verbal Learning Test III, respectively, and reported as standardized scores (mean=100, SD=15). Pulsatility index [(systolic blood velocity - diastolic blood velocity)/ mean blood velocity] was measured in the common carotid (CCA), internal carotid (ICA), and middle cerebral arteries (MCA) via Doppler and transcranial Doppler ultrasound. Compared to healthy adults, CKD patients did not differ in total brain blood flow (p=0.42) but had lower MoCA (CKD=26±3, Healthy=29±1; p=0.01) and memory recall scores (CKD=92±21, Healthy=110±9; p=0.05). CKD patients did not differ from our healthy control group in executive function (CKD=91±10, Healthy=90±11; p=0.80) but did produce a mean score that was 0.6 SD lower than the NIH Toolbox reference sample. CKD patients had a higher pulsatility index in the CCA (CKD=2.3±0.5, Healthy=1.9±0.3; p=0.05) but not in the ICA (p=0.68) or MCA (p=0.57). CCA pulsatility index was strongly and inversely associated with episodic memory recall scores (r=-0.64, p

High blood pressure (BP) is the leading cause of worldwide cardiovascular disease morbidity and mortality. Patients and clinicians dealing with hypertension have benefited from the evidence of event-based randomized controlled clinical trials. One result from those trials has been the development of evidence-based guidelines. The commitment to using evidence from these event-based randomized trials has been a cornerstone in the development of guideline treatment recommendations. However, in some situations, evidence from event-based trials is not available to guideline writers or clinicians for assistance in treatment decision making. Such is the case for the management of many patients with stage 1 hypertension. The purpose of this scientific statement is to provide information complementary to the 2017 Hypertension Clinical Practice Guidelines for the patient with untreated stage 1 hypertension (systolic BP/diastolic BP, 130–139/80–89 mm Hg) with a 10-year risk for atherosclerotic cardiovascular disease

Patients with chronic kidney diseases (CKDs) are at risk for further loss of kidney function and death, which occur despite reasonable blood pressure treatment. To determine whether arterial stiffness influences CKD progression and death, independent of blood pressure, we conducted a prospective cohort study of CKD patients enrolled in the CRIC study (Chronic Renal Insufficiency Cohort). Using carotid–femoral pulse wave velocity (PWV), we examined the relationship between PWV and end-stage kidney disease (ESRD), ESRD or halving of estimated glomerular filtration rate, or death from any cause. The 2795 participants we enrolled had a mean age of 60 years, 56.4% were men, 47.3% had diabetes mellitus, and the average estimated glomerular filtration rate at entry was 44.4 mL/min per 1.73 m 2 . During follow-up, there were 504 ESRD events, 628 ESRD or halving of estimated glomerular filtration rate events, and 394 deaths. Patients with the highest tertile of PWV (>10.3 m/s) were at higher risk for ESRD (hazard ratio [95% confidence interval], 1.37 [1.05–1.80]), ESRD or 50% decline in estimated glomerular filtration rate (hazard ratio [95% confidence interval], 1.25 [0.98–1.58]), or death (hazard ratio [95% confidence interval], 1.72 [1.24–2.38]). PWV is a significant predictor of CKD progression and death in people with impaired kidney function. Incorporation of PWV measurements may help define better the risks for these important health outcomes in patients with CKDs. Interventions that reduce aortic stiffness deserve study in people with CKD.

Obesity and obstructive sleep apnea tend to coexist. Little is known about the effects of obstructive sleep apnea, obesity, or their treatment on central aortic pressures and large artery stiffness. We randomized 139 adults with obesity (body mass index >30 kg/m 2 ) and moderate-to-severe obstructive sleep apnea to (1) continuous positive airway pressure (CPAP) therapy (n=45), (2) weight loss (WL) therapy (n=48), or (3) combined CPAP and WL (n=46) for 24 weeks. We assessed the effect of these interventions on central pressures and carotid–femoral pulse wave velocity (a measure of large artery stiffness), measured with arterial tonometry. Central systolic pressure was reduced significantly only in the combination arm (−7.4 mm Hg; 95% confidence interval, −12.5 to −2.4 mm Hg; P =0.004), without significant reductions detected in either the WL-only (−2.3 mm Hg; 95% confidence interval, −7.5 to 3.0; P =0.39) or the CPAP-only (−3.1 mm Hg; 95% confidence interval, −8.3 to 2.0; P =0.23) arms. However, none of these interventions significantly changed central pulse pressure, pulse pressure amplification, or the central augmentation index. The change in mean arterial pressure ( P =0.008) and heart rate ( P =0.027) induced by the interventions was significant predictors of the change in carotid–femoral pulse wave velocity. However, after adjustment for mean arterial pressure and heart rate, no significant changes in carotid–femoral pulse wave velocity were observed in any group. In obese subjects with obstructive sleep apnea, combination therapy with WL and CPAP is effective in reducing central systolic pressure. However, this effect is largely mediated by changes in mean, rather than central pulse pressure. WL and CPAP, alone or in combination, did not reduce large artery stiffness in this population. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00371293.

Studies of visit-to-visit office blood pressure (BP) variability (OBPV) as a predictor of cardiovascular events and death in high-risk patients treated to lower BP targets are lacking. We conducted a post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial), a well-characterized cohort of participants randomized to intensive (P =0.07). Our results suggest that clinicians should continue to focus on office BP control rather than on OBPV unless definitive benefits of reducing OBPV are shown in prospective trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01206062

We recently reported a linear association between higher systolic blood pressure (SBP) and risk of mortality in hemodialysis patients when SBP is measured outside of the dialysis unit (out-of-dialysis-unit-SBP), despite there being a U-shaped association between SBP measured at the dialysis unit (dialysis-unit-SBP) with risk of mortality. Here, we explored the relationship between SBP with cardiovascular events, which has important treatment implications but has not been well elucidated. Among 383 hemodialysis participants enrolled in the prospective CRIC study (Chronic Renal Insufficiency Cohort), multivariable splines and Cox models were used to study the association between SBP and adjudicated cardiovascular events (heart failure, myocardial infarction, ischemic stroke, and peripheral artery disease), controlling for differences in demographics, cardiovascular disease risk factors, and dialysis parameters. Dialysis-unit-SBP and out-of-dialysis-unit-SBP were modestly correlated ( r =0.34; P 2-fold increased risk of cardiovascular events compared with those with out-of-dialysis-unit-SBP ≤112 mm Hg (3rd SBP quartile: adjusted hazard ratio, 2.08 [95% confidence interval, 1.12–3.87] and fourth SBP quartile: adjusted hazard ratio, 2.76 [95% confidence interval, 1.42–5.33]). In conclusion, among hemodialysis patients, although there is a U-shaped (paradoxical) association of dialysis-unit-SBP and risk of cardiovascular disease, there is a linear association of out-of-dialysis-unit-SBP with risk of cardiovascular disease. Out-of-dialysis-unit blood pressure provides key information and may be an important therapeutic target.

Background: Regional measures of adipose distribution, such as visceral adiposity and waist circumference, are more strongly associated with metabolic activity of adipose tissue and longitudinal cardiovascular risk than broader metrics, such as body mass index (BMI) and total fat mass. Little is known about the differential relationship of BMI, waist circumference, visceral adiposity, and total fat mass with degree of blood pressure (BP) control on 24-hour ambulatory BP monitoring (ABPM) in adults with hypertension (HTN). Methods: We performed 24-hour ABPM in adults recruited from primary care clinics with a diagnosis of HTN on a stable dose of a single antihypertensive agent. Dual x-ray absorptiometry (DXA) was performed to determine visceral adiposity and total fat mass (indexed by height). Results: Of the 97 participants, mean age was 56 (+/- 13) years, with 56 (58%) women, 46 (47%) black, 28 (29%) with diabetes, and 13 (13%) smokers. Mean BMI was 31.7 (+/- 7.2) kg/m 2 and mean waist circumference was 104 (+/- 17) cm. Mean 24-hour systolic BP (SBP) was 135 (+/- 13) mmHg, mean 24-hour SBP average real variability (ARV) was 13 (+/- 3), 47 (48%) were non-dippers, 26 (27%) had masked HTN, and 21 (22%) had uncontrolled HTN. After adjusting for age, sex, race, and antihypertensive class, the highest quartiles of waist circumference and visceral adiposity were associated with higher 24-hour mean SBP (waist circumference β = 9.5, 95% CI 1.9-17.2; visceral adiposity β = 8.6, 95% CI 0.5-16.8) and SBP ARV (waist circumference β = 2.8, 95% CI 1.0 to 4.6; visceral adiposity β = 2.9, 95% CI 1.1 to 4.7) compared to the lowest quartiles; BMI and total fat mass were not associated with these ABPM parameters. Individuals in the highest quartile of visceral adiposity had a 6.3-fold greater odds (95% CI 1.2-33.1) of masked HTN compared to the lowest quartile; no other adiposity measures were associated with masked HTN. Conclusions: Elevated visceral adiposity is associated with high 24-hour SBP and SBP variability in individuals with HTN. Unlike other measures of adiposity, higher visceral adiposity is strongly linked with masked hypertension. Measurement of visceral adiposity may help to identify those individuals who would benefit most from 24-hour ABPM to screen for masked hypertension.

Recent prospective randomized clinical trials have demonstrated blood pressure lowering following renal denervation (RDN) with radiofrequency (RF) ablation systems and minimal adverse events in relatively small populations with short follow up duration. The current analysis estimates the rate of renal artery adverse events based on a comprehensive review of published reports. An online database search was performed to identify trials, registries and case reports that employed either the SYMPLICITY Flex or Spyral RF denervation systems (Medtronic, Santa Rosa, CA). Updated reviews of the SYMPLICITY HTN-3 trial and the Global SYMPLICITY Registry were also included. Renal artery stenoses classified as “significant”, greater than 50%, resulted in stent implant or if not specified were counted. The pooled incidence rate of stent implantation was determined by fixed-effects meta-analysis of the study-level incidence rates. Review of 45 published RDN trials reporting on procedural safety with 10,130 patient-years of follow up identified 0.44% of patients (25 of 5,657) with reported renal artery stenosis or dissection and 0.39% of patients (22 of 5,657) with required renal artery stenting. Meta-analysis of all reports indicated an 0.20% pooled annual incidence rate of stent implantation (95% CI: 0.11 to 0.29 % per patient-year). This result was consistent with a fixed effects Poisson regression model (0.22%; 95% CI: 0.14 to 0.32%). An additional 10 case reports including 11 patients with renal artery stenosis resulting in at least one stent implant were identified, with most cases diagnosed after recurrent hypertension, occasionally with concomitant symptoms. Median time from RDN procedure to all renal artery interventions, including both case reports and clinical trials, was 5.5 months (range: 0 to 33 months). A separate review of 14 clinical trials reporting on prospective follow up high resolution imaging of main renal arteries or branches using either MRI, CT or angiography following RDN found a new significant stenosis rate of 0.20% (one event out of 511 patients). Renal artery stenosis and re-intervention following renal denervation with the most commonly applied RF renal denervation system are rare.

Results from recent sham-controlled clinical trials demonstrate the efficacy of renal denervation (RDN) in blood pressure reduction, however the effects of RDN on the renin-angiotensin system are not clear. We sought to evaluate changes in plasma renin activity (PRA) and serum sodium levels after RDN in the absence of anti-hypertensive medications in the SPYRAL HTN-OFF MED trial. SPYRAL HTN-OFF MED is a randomized, sham-controlled trial to evaluate the impact of RDN in the absence of anti-hypertensive medications. Patients were enrolled with an office systolic BP (SBP) ≥150 and Figure ). Comparison of 3-month changes in PRA using a Wilcoxon test stratified by 3 equal groups of baseline PRA also found a significant difference between groups (p=0.033). Changes in sodium levels were similar between groups: 0 mmol/L [-2, 2] (RDN, N=37) vs. 0 mmol/L [-1, 1] (control, N=41), p=0.920). In this sham-controlled feasibility trial, renal denervation was associated with a reduction in PRA but no difference in serum sodium levels was observed. The impact on sodium excretion will need to be assessed in future studies.

The effect of clinic-based intensive hypertension treatment on ambulatory blood pressure (BP) is unknown. The goal of the SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP ancillary study was to evaluate the effect of intensive versus standard clinic-based BP targets on ambulatory BP. Ambulatory BP was obtained within 3 weeks of the 27-month study visit in 897 SPRINT participants. Intensive treatment resulted in lower clinic systolic BP (mean difference between groups=16.0 mm Hg; 95% confidence interval, 14.1–17.8 mm Hg), nighttime systolic BP (mean difference=9.6 mm Hg; 95% confidence interval, 7.7–11.5 mm Hg), daytime systolic BP (mean difference=12.3 mm Hg; 95% confidence interval, 10.6–13.9 mm Hg), and 24-hour systolic BP (mean difference=11.2 mm Hg; 95% confidence interval, 9.7–12.8 mm Hg). The night/day systolic BP ratio was similar between the intensive (0.92±0.09) and standard-treatment groups (0.91±0.09). There was considerable lack of agreement within participants between clinic systolic BP and daytime ambulatory systolic BP with wide limits of agreement on Bland–Altman plots. In conclusion, targeting a systolic BP of Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01835249.

The association between apparent treatment resistant hypertension (ATRH) and clinical outcomes is not well studied in chronic kidney disease. We analyzed data on 3367 hypertensive participants in the Chronic Renal Insufficiency Cohort (CRIC) to determine prevalence, associations, and clinical outcomes of ATRH in nondialysis chronic kidney disease patients. ATRH was defined as blood pressure ≥140/90 mm Hg on ≥3 antihypertensives, or use of ≥4 antihypertensives with blood pressure at goal at baseline visit. Prevalence of ATRH was 40.4%. Older age, male sex, black race, diabetes mellitus, and higher body mass index were independently associated with higher odds of having ATRH. Participants with ATRH had a higher risk of clinical events than participants without ATRH—composite of myocardial infarction, stroke, peripheral arterial disease, congestive heart failure (CHF), and all-cause mortality (hazard ratio [95% confidence interval], 1.38 [1.22–1.56]); renal events (1.28 [1.11–1.46]); CHF (1.66 [1.38–2.00]); and all-cause mortality (1.24 [1.06–1.45]). The subset of participants with ATRH and blood pressure at goal on ≥4 medications also had higher risk for composite of myocardial infarction, stroke, peripheral arterial disease, CHF, and all-cause mortality (hazard ratio [95% confidence interval], (1.30 [1.12–1.51]) and CHF (1.59 [1.28–1.99]) than those without ATRH. ATRH was associated with significantly higher risk for CHF and renal events only among those with estimated glomerular filtration rate ≥30 mL/min per 1.73 m 2 . Our findings show that ATRH is common and associated with high risk of adverse outcomes in a cohort of patients with chronic kidney disease. This underscores the need for early identification and management of patients with ATRH and chronic kidney disease.

Background: Variable adherence to prescribed antihypertensive drugs may have confounded prior renal denervation trials. Adherence to prescribed drugs was measured in the SPYRAL HTN-OFF MED and ON MED trials of renal denervation for uncontrolled hypertension when no drugs, and when up to 3 anti-hypertensive drug classes were prescribed, respectively. Methods: Patients were enrolled with uncontrolled hypertension defined as office systolic blood pressure (SBP) ≥150 and 90 mmHg and 24-hour mean SBP ≥140 and Results: In OFF MED, antihypertensive drug or drug metabolites were detected in 10% of patients just prior to randomization, 11.2% at 3 months following randomization, and in 15% of patients at either time point, despite protocol-required absence of all antihypertensive medications following enrollment. In ON MED, 62.5% were fully adherent to prescribed medications (i.e., all prescribed medications identified) at baseline, 55% at 3 months and 62.5% at 6 months. Drug adherence was not consistent: 24% of baseline adherent patients were non-adherent at 3 months, and 16% of patients adherent at 3 months were no longer adherent at 6 months. Conclusions: Despite being aware that drug adherence testing was being conducted, almost half did not take all medication when they were prescribed and a minority took anti-hypertensive medications when instructed to abstain. Furthermore, non-adherence was inconsistent, with individual behavior at one time point not predictive of drug adherence at other time points. Attention to protocol adherence in device-based clinical hypertension trials is critical to determine non-drug treatment effects.

Background: Short sleep duration has been widely linked to increased cardiovascular morbidity and mortality, although the underlying mechanisms for this relationship remain unclear. Maladaptive circadian variations in blood pressure (BP) may be an important mediator of adverse outcomes in people with short sleep duration. Our goal was to evaluate the association between sleep duration and 24-hour BP control. Methods: We performed a post-hoc analyses of 24-hour ambulatory BP monitoring in 219 non-hypertensive and pre-hypertensive adults in the Lifestyle Modification in BP Lowering Study (LIMBS) and Penn Icelandic Sleep Apnea (PISA) Study. Results: The 24-hour mean systolic BP was 12.7 mmHg higher in LIMBS (see Figure; p Conclusions: Shorter sleep duration is strongly associated with higher systolic BP on 24-hour ambulatory BP monitoring; the association seems to be independent of nocturnal and in-office BP. Adults with shorter sleep duration may benefit from screening with 24-hour ambulatory BP monitoring to promote earlier detection of hypertension and potentially mitigate their increased risk for future cardiovascular disease.

Studies of hemodialysis patients have shown a U-shaped association between systolic blood pressure (SBP) and mortality. These studies have largely relied on dialysis-unit SBP measures and have not evaluated whether this U-shape also exists in advanced chronic kidney disease, before starting hemodialysis. We determined the association between SBP and mortality at advanced chronic kidney disease and again after initiation of hemodialysis. This was a prospective study of Chronic Renal Insufficiency Cohort participants with advanced chronic kidney disease followed through initiation of hemodialysis. We studied the association between SBP and mortality when participants (1) had an estimated glomerular filtration rate 2 (n=1705), (2) initiated hemodialysis and had dialysis-unit SBP measures (n=403), and (3) initiated hemodialysis and had out-of-dialysis-unit SBP measured at a Chronic Renal Insufficiency Cohort study visit (n=326). Cox models were adjusted for demographics, cardiovascular risk factors, and dialysis parameters. A quadratic term for SBP was included to test for a U-shaped association. At advanced chronic kidney disease, there was no association between SBP and mortality (hazard ratio, 1.02 [95% confidence interval, 0.98–1.07] per every 10 mm Hg increase). Among participants who started hemodialysis, a U-shaped association between dialysis-unit SBP and mortality was observed. In contrast, there was a linear association between out-of-dialysis-unit SBP and mortality (hazard ratio, 1.26 [95% confidence interval, 1.14–1.40] per every 10 mm Hg increase). In conclusion, more efforts should be made to obtain out-of-dialysis-unit SBP, which may merit more consideration as a target for clinical management and in interventional trials.

Background: Measurements obtained by 24-hour ambulatory blood pressure monitoring (ABPM), such as nocturnal dipping and 24-hour blood pressure variability, are strongly associated with long-term renal and cardiovascular outcomes. Sparse data exist about how these parameters change after resection of catecholamine-secreting neuroendocrine tumors (NETs). Methods: We performed a prospective observational study of patients who underwent resection of catecholamine-secreting NETs at Penn between January 2014 and December 2016. Patients underwent 24-hour ABPM 1-3 weeks prior to and 6-8 weeks following resection. Results: Of the 32 patients who underwent resection, median age was 56 years, with 44% males (14 of 32), 78% Caucasians (25 of 32), and 84% (27 of 32) on at least one antihypertensive medication pre-operatively. Following resection, 50% (16 of 32) were on no antihypertensive medications and 74% (20 of 27) were on less medications than at baseline. There was a significant decline in clinic systolic blood pressure ([SBP] 134.6 vs. 122.5 mmHg, p Conclusion: Following resection of catecholamine-secreting NETs, patients had a significant decline in 24-hour blood pressure variability and many experienced resolution of white coat, masked, and sustained hypertension, on less antihypertensive medications compared to baseline. There was no significant decline in non-dipping. NET resection may have greater prognostic significance than appreciated by changes in in-office blood pressure measurements and related parameters.

Many antihypertensive medications and lifestyle changes are proven to reduce blood pressure. Over the past few decades, numerous additional modalities have been evaluated in regard to their potential blood pressure–lowering abilities. However, these nondietary, nondrug treatments, collectively called alternative approaches, have generally undergone fewer and less rigorous trials. This American Heart Association scientific statement aims to summarize the blood pressure–lowering efficacy of several alternative approaches and to provide a class of recommendation for their implementation in clinical practice based on the available level of evidence from the published literature. Among behavioral therapies, Transcendental Meditation ( Class IIB, Level of Evidence B ), other meditation techniques ( Class III, Level of Evidence C ), yoga ( Class III, Level of Evidence C ), other relaxation therapies ( Class III, Level of Evidence B ), and biofeedback approaches ( Class IIB, Level of Evidence B ) generally had modest, mixed, or no consistent evidence demonstrating their efficacy. Between the noninvasive procedures and devices evaluated, device-guided breathing ( Class IIA, Level of Evidence B ) had greater support than acupuncture ( Class III, Level of Evidence B ). Exercise-based regimens, including aerobic ( Class I, Level of Evidence A ), dynamic resistance ( Class IIA, Level of Evidence B ), and isometric handgrip ( Class IIB, Level of Evidence C ) modalities, had relatively stronger supporting evidence. It is the consensus of the writing group that it is reasonable for all individuals with blood pressure levels >120/80 mm Hg to consider trials of alternative approaches as adjuvant methods to help lower blood pressure when clinically appropriate. A suggested management algorithm is provided, along with recommendations for prioritizing the use of the individual approaches in clinical practice based on their level of evidence for blood pressure lowering, risk-to-benefit ratio, potential ancillary health benefits, and practicality in a real-world setting. Finally, recommendations for future research priorities are outlined.

Microvascular rarefaction (reduced capillary density) is associated with hypertension. Little is known about capillary rarefaction in young individuals, in whom brachial and central blood pressure (BP) may be quite divergent. Thus, we compared capillary density in young subjects with their office and central BP profiles. We measured central BP using the SphygmoCor XCEL device, and office BP in 102 healthy young participants ( Table 1 ). Capillary density was measured progressively in the nailbed at baseline rest, following ischemic stimulus, and using passive venous congestion. All capillary densities were significantly associated with central DBP and MAP ( Table 2 ). Only post-ischemic capillary density was significantly associated with office brachial SBP and MAP (rest and venous densities were marginally associated). In conclusion, capillary density is consistently and significantly associated with central MAP in young, non-hypertensive individuals. Since MAP is a key determinant of systemic vascular resistance, capillary rarefaction may lead to the future development of hypertension.

Arterial stiffness and enhanced wave reflections independently predict cardiovascular risk. Wave reflections augment central (aortic) pulse pressure (PP), an index of arterial stiffness, and systolic pressure. Increased wave reflections and PP have previously been associated with endothelial dysfunction in hypertensive and healthy middle-aged adults. The study objective was to determine whether endothelial dysfunction is associated with PP and other measures of vascular stiffness in young normotensive and prehypertensive subjects. We measured office, central, and 24-hour measurements in 102 (64 female, 38 male) non-hypertensive, non-diabetic participants. Endothelial function was assessed non-invasively using post-ischemic reactive hyperemia with strain-gauge plethysmography. The racially diverse subject pool was comprised of 60% Caucasians, 18% African Americans, and 24% Asians, with mean age 30, mean BMI 25.6, mean office SBP/DBP = 110 ± 13 mm Hg/70 ± 9 mm Hg. Endothelial function was highly associated with office (β= - 4.2 mm Hg, p In conclusion, endothelial dysfunction is significantly and consistently associated with arterial stiffness and increased wave reflections in young non-hypertensive adults. Identification of endothelial dysfunction in otherwise healthy young individuals may provide an opportunity to reduce vascular stiffness and associated cardiovascular risk.

A previous genetic analysis comparing the Dahl salt-sensitive (S) rat with the spontaneously hypertensive rat identified a major locus on chromosome 2 that influences proteinuria in the S rat. In the present study, blood pressure, proteinuria, and renal hemodynamics were evaluated in congenic strains with small segments of the protective spontaneously hypertensive rat genome on the S background. Proteinuria and renal function were significantly improved in the congenic strains compared with the S. The causative locus interval was narrowed to Arhgef11 , Pear1 , and Sh2d2 were identified as important candidate genes that may be linked to kidney injury in the S rat. In particular, Arhgef11 plays an important role in the activation of the Rho-ROCK signaling pathway. Inhibition of this pathway using fasudil resulted in a significant reduction of proteinuria in treated S rats (compared with untreated S). However, no difference was observed between treated or untreated spontaneously hypertensive rat or congenic strains. The homologous region in humans was found to be associated with estimated glomerular filtration rate in the Candidate Gene Association Resource population. In summary, these findings demonstrate that allelic variants in Arhgef11 , acting through the Rho-ROCK pathway, could influence kidney injury in the S as well as provide insight into human kidney disease.

Central pulse pressure can be non-invasively derived using the radial artery tonometric methods. Knowledge of central pressure profiles has predicted cardiovascular morbidity and mortality in several populations of patients, particularly those with known coronary artery disease and those receiving dialysis. Few data exist characterizing central pressure profiles in patients with mild-moderate chronic kidney disease who are not on dialysis. We measured central pulse pressure cross-sectionally in 2531 participants in the Chronic Renal Insufficiency Cohort study to determine correlates of the magnitude of central pulse pressure in the setting of chronic kidney disease. Tertiles of central pulse pressure (CPP) were < 36 mmHg, 36–51 mmHg and > 51 mmHg with an overall mean (± S.D.) of 46 ± 19 mmHg. Multivariable regression identified the following independent correlates of central pulse pressure: age, gender, diabetes mellitus, heart rate (negatively correlated), glycosylated hemoglobin, hemoglobin, glucose and PTH concentrations. Additional adjustment for brachial mean arterial pressure and brachial pulse pressure showed associations for age, gender, diabetes, weight and heart rate. Discrete intervals of brachial pulse pressure stratification showed substantial overlap within the associated central pulse pressure values. The large size of this unique chronic kidney disease cohort provides an ideal situation to study the role of brachial and central pressure measurements in kidney disease progression and cardiovascular disease incidence.

The relationship between blood pressure (BP) and sodium intake is well documented. Large observational studies have shown that sodium chloride (NaCl) intake is directly related to BP, whereas various interventional studies demonstrated a relationship between the reduction in NaCl intake and magnitude of BP reduction. Similarly, a low-potassium diet is associated with high BP and increased cardiovascular risk. In the Intersalt Study, urinary potassium excretion (a surrogate for intake) was associated with a lower BP after adjustment for various confounders, including urinary sodium excretion. The effects of dietary sodium and potassium on BP are closely related. The first strain of rats bred by Dahl for the trait of “salt sensitivity” demonstrated less NaCl-induced hypertension when potassium intake was high. Well-controlled human studies subsequently showed that the BP-rising effect of extremely high NaCl intake can be blunted by potassium supplementation. Clinical trials showed that potassium supplementation modestly reduces BP, an effect that is, however, enhanced in blacks and in the presence of a high-sodium diet. Conversely, hypertension in potassium deficiency is associated with increased renal sodium reabsorption, whereas sodium restriction may prevent the development of hypertension induced by potassium restriction. Recent literature has identified regulatory pathways of tubular sodium and potassium handling (eg, those mediated by with-no-lysine-kinase 1)1 that may, at least partially, mediate interactions between dietary sodium and potassium on extracellular volume and BP. Importantly, whereas high-sodium/low-potassium intake are associated with hypertension, both have been shown to predict an increased cardiovascular risk even after adjustment for brachial BP and other observed factors, indicating that unmeasured factors played a role. Accumulating evidence indicates that central arterial pulsatile hemodynamic abnormalities predict cardiovascular risk independent of brachial BP in various populations.2 It should be noted that there is a highly variable relationship between brachial pulse pressure (PP) and aortic pulsatile hemodynamics. …

Blood pressure variability (BPV) is associated with adverse cardiovascular outcomes. Factors determining BPV are unclear. Arterial stiffness manifested by pulse pressure (PP) may be related to BPV, and is reflected in the pulse wave velocity (PWV), as well as the regression of diastolic on systolic pressure determined by the Ambulatory Arterial Stiffness Index (AASI). We hypothesized that arterial stiffness was associated with PP variability (PPVAR) and determined arterial stiffness using AASI and PWV. Ambulatory blood pressure (BP) data from untreated subjects (n=56, 28 men) with SBP >130 to AASI correlated positively with day PPVAR (r=0.57, p The relationship between AASI and PPVAR was only evident when the blood pressure periods were broken down into day and night. The 24 hour regression relationship of diastolic on systolic blood pressure with PPVAR appears different between day or night compared with the 24 hour aggregate, suggesting circadian differences in factors which modify PPVAR. Poor PWV correlation with PPVAR is likely due to relatively young age of our subjects.

Endothelial dysfunction occurs in chronic kidney disease (CKD) and cardiovascular disease is the most common cause of death in these patients. Oxidative stress has been shown to be a mechanism of vascular dysfunction in CKD. We utilized the cutaneous circulation to test the hypothesis that superoxide derived from NAD(P)H oxidase and xanthine oxidase impair nitric oxide (NO)-dependent cutaneous vasodilation patients with CKD. Twenty subjects, 10 stage 3 and 4 CKD patients (61±4 years; 5 male/5 female; eGFR: 39 ± 4 ml·min -1 ·1.73m -2 ) and 10 healthy controls (HC) (55±2 years; 4 male/6 female; eGFR: >60 ml·min -1 ·1.73m -2 ) were instrumented with 4 intradermal microdialysis fibers in the forearm for the local delivery of 1) Ringers solution (Control), 2) 10 μM Tempol to scavenge superoxide, 3) 100 μM apocynin to inhibit NAD(P)H oxidase, and 4) 10 μM allopurinol to inhibit xanthine oxidase. Red blood cell (RBC) flux was measured via laser Doppler flowmetry during standardized local heating (42°C). After the local heating response was established, 10 mM L-NAME was infused into all four sites to quantify the NO-dependent portion of the response. Cutaneous vascular conductance (CVC) was calculated as RBC flux/mean arterial pressure and all data are presented as a percentage of maximum CVC achieved during 28mM sodium nitroprusside infusion at 43°C. The plateau in cutaneous vasodilation was attenuated in CKD at the control site (CKD: 77±3 vs. HC: 88±3 %, p0.05). These data suggest that NAD(P)H oxidase is a source of superoxide and contributes to microvascular dysfunction in CKD.

Introduction Ambulatory blood pressure monitoring (ABPM) has been proposed as the most effective way to characterize a person’s BP profile. However, there are very limited data in the literature comparing two simultaneously worn ABPM devices. Therefore, we compared an eight hour daytime simultaneous ABPM using two monitors (Mobil-O-Graph [I.E.M., Stolberg, Germany] and Spacelabs 90207 [Spacelabs Medical, Issequah, WA]). Methods Simultaneous BP and heart rate data were measured on 13 adult volunteers at the University of Pennsylvania using the two monitors over an 8 hour period. Other demographic data were also collected. Standard seated BPs were obtained in triplicate at the beginning and end of the 8 hour monitoring period using an Accutor (Datascope, Mahwah, NJ) device. Three blood pressures were obtained at 1 minute intervals, recorded and averaged for each arm using the Accutor device. Results The data show high concordance of measured mean arterial pressures (Mobil-O-Graph 101.4 [SEM-2.0] mmHg, Spacelabs 100.6 [SEM-2.4] mmHg) and heart rates (Mobil-O-Graph measuring 82.4 [ SEM- 4.1] beats/minute, Spacelabs 81.7 [4.0] beats/minute) between the monitors. Spacelabs measured a 10 mmHg higher systolic pressure (p=0.0016) and a non-statistically significant, but numerically higher (2.8 mmHg) diastolic pressure (Figure 1). Conclusion The systolic BP difference between the two devices has public health importance. These differences if confirmed in larger cohorts, ABPM manufacturers should consider developing a normative database to help practitioners interpret ABPM data obtained with their device.

Vascular rigidity predicts cardiovascular disease (CVD). Pulse wave velocity (PWV), reflecting vascular rigidity, though determined largely by mean arterial pressure; is also sensitive to insulin and glucose. Capacitance in small (C2) and large vessels (C1), reflecting vascular responsiveness to hemodynamic challenges, may also be influenced by insulin and glucose. The purpose of this study was to test the effects of insulin and glucose on arterial function in healthy people. METHODS: Excluding people with BMI > 27.5 kg/m2, diabetes, impaired glucose tolerance, hypotension or hypertension, 14 adults were enrolled. Subjects underwent randomly either a 2 hour euglycemic clamping, or a 2-hr OGTT first, and the other a month later. Pulse wave velocity (PWV; carotid->dorsalis) and vascular compliance were measured by tonometry. Repeated measures ANOVA was used to compare parameter means over different time points. Results: The sample (n=14) included 10 Caucasians, 8males, mean age=28.14+7.6 years, BMI=23.46+1.7kg/m2, SBP=112.79+8.6mmHg, DBP=69.57+6.1mmHg, and glucose=73+10.5mg/dl. There was a significant increase in mean PWV between 30 and 120 minutes (p=0.049), by euglycemic clamp (PWV change in OGTT was n.s.). Conclusion: Insulin increased the PWV in clamp condition with minimal changes in C1 or C2. Oral glucose had less effect on PWV and again changes in C1 and C2 were minimal. These data support mechanisms that interweave insulin and arterial stiffness in vascular physiology and suggest that part of the mechanism of CVD in insulin resistance may relate to insulin’s effects on arterial rigidity.

Blood pressure (BP) predicts kidney function decline in CKD. It’’s unclear if systolic (SBP), diastolic (DBP), or pulse pressure (PP) is the strongest predictor, or if BP variability is a determinant. In a prospective study of CKD we examined the association of 3 brachial BP measures on a composite kidney function outcome: end-stage kidney disease (ESKD) or a halving in the estimated GFR compared to baseline. We also examined whether the amount of variability within the 3 BP measurements at baseline predicted the outcome. CRIC participants (∼half DM; ∼half M; eGFR 44.8(16.8) mL/min/1.73 m 2 ) had 3 seated brachial BP at study baseline. Mean BP [mmHg(SD)] and PP were 128(22)/72(13) and 57(19). Mean BP variability, as the SD of SBP (SBPSD) at baseline was 3.3(2.5). After 3.7 years, 766 participants had a halving in eGFR from baseline or ESKD. We modeled the time to the event with Cox proportional hazards regression. For comparability across different BP measures, results were expressed per 1 SD difference in SBP, DBP, and PP; adjusting for eGFR, proteinuria, age, gender, race, clinical site and diabetes(Y/N) in the 3379 participants with complete data. Death was a censoring event. Akaike Information Criterion (AIC; lower values better) evaluated overall model fit characteristics. The same regression parameters were used to model CKD associated with SBPSD, including the mean of the SBP at baseline as a covariate in this analysis. SBP was the strongest BP predictor of loss of kidney function. Variability of baseline SBP also predicted loss of kidney function, independent of level of SBP at baseline, but this association was considerably weaker than those observed for other BP measures.

Refractory hypertension is an extreme phenotype of antihypertensive treatment failure. Participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, a large (n=30,239), population-based cohort were evaluated to determine the prevalence of refractory hypertension and associated cardiovascular risk factors and comorbidities. Refractory hypertension was defined as uncontrolled blood pressure (systolic/diastolic ≥ 140/90 mm Hg) on ≥ 5 antihypertensive drug classes. Participants with resistant hypertension (systolic/diastolic ≥140/90 mm Hg on ≥ 3 or

We previously used the Doppler transmitral flow velocity ratio A/E (A = late ventricular filling peak velocity; E = early ventricular filling peak velocity) and the age-adjusted ratio A/E/Age to detect left ventricular filling abnormalities in untreated mild hypertension. This study is a double-blind assessment of the effect of combined alpha- and beta-blockade (labetalol) and beta-blockade alone (atenolol) on left ventricular filling in mild hypertension. Twenty-seven patients blindly randomized to labetalol (12 patients) and atenolol (15 patients) treatment completed the echocardiographic and Doppler studies. Clinical and echo-Doppler data obtained at baseline and 6 weeks after initiation of therapy showed no difference between the two groups for age (49 +/- 10 vs 46 +/- 10 years), mean blood pressure (before therapy, 118 +/- 9 vs 117 +/- 8 mm Hg; after therapy, 108 +/- 12 mm Hg), left ventricular dimensions, wall thickness, systolic function, and mean late filling velocity A. There was no significant change in left ventricular mass and mass index with labetalol (left ventricular mass, 211 +/- 36 vs 216 +/- 38; mass index, 110 +/- 17 vs 112 +/- 16) or atenolol (245 +/- 41 vs 271 +/- 65; 120 +/- 18 vs 130 +/- 35). The mean velocity E, A/E, and A/E/Age ratios significantly improved with labetalol (p less than 0.05) but did not change significantly with atenolol. The improvement in A/E and A/E/Age ratios was primarily due to an increase in early filling velocity E.(ABSTRACT TRUNCATED AT 250 WORDS)