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Postmenopausal women (PMW) display exaggerated increases in blood pressure (BP) during exercise, yet the mechanism(s) involved remain unclear. Moreover, research on the impact of menopausal changes in estradiol on cardiovascular control during exercise are limited. Herein, we tested the hypothesis that sympathetic responses during exercise are augmented in PMWcompared with young women (YW), and estradiol administration attenuates these responses.Muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP) were measured in 13 PMW (58 ± 1 yr) and 17 YW (22 ± 1 yr) during 2 min of isometric handgrip. Separately, MSNA and BP responses were measured during isometric handgrip in six PMW (53 ± 1 yr) before and after 1 month of transdermal estradiol (100 μg·d-1). A period of postexercise ischemia (PEI) to isolate muscle metaboreflex activation followed all handgrip bouts.Resting MAP was similar between PMW and YW, whereas MSNA was greater in PMW (23 ± 3 vs 8 ± 1 bursts per minute; P0.05). During handgrip, the increases in MSNA (PMW Δ16 ± 2 vs YW Δ6 ± 1 bursts per minute; P0.05) and MAP (PMW Δ18 ± 2 vs YW Δ12 ± 2 mm Hg; P0.05) were greater in PMW and remained augmented during PEI. Estradiol administration decreased resting MAP but not MSNA in PMW. Moreover, MSNA (PMW (-E2) Δ27 ± 8 bursts per minute versus PMW (+E2) Δ12 ± 5 bursts per minute; P0.05) and MAP (Δ31 ± 8 mm Hg vs Δ20 ± 6 mm Hg; P0.05) responses during handgrip were attenuated in PMW after estradiol administration. Likewise, MAP responses during PEI were lower after estradiol.These data suggest that PMW exhibit an exaggerated MSNA and BP response to isometric exercise, due in part to heightened metaboreflex activation. Furthermore, estradiol administration attenuated BP and MSNA responses to exercise in PMW.

The blood pressure response to exercise is exaggerated in type 2 diabetes mellitus (T2DM). However, the underlying mechanisms remain unclear. It is hypothesized that one mechanism mediating the potentiated cardiovascular response in T2DM is the sensitization of chemically sensitive afferent neurons by activation of metaboreceptors. To test this hypothesis, we examined transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced cardiovascular responses in vivo and muscle afferent discharge ex vivo in T2DM rats. Additionally, TRPV1 and protein kinase C (PKC) protein levels in dorsal root ganglia (DRG) subserving skeletal muscle were assessed. For 14-16 weeks, Sprague-Dawley rats were given either a normal diet (control) or high fat diet in combination with a low dose (35 and 25 mg/kg) of streptozotocin (T2DM). Administration of capsaicin, TRPV1 agonist, in hindlimb evoked significantly greater increases in mean arterial pressure and renal sympathetic neve activity in decerebrated T2DM than control. In a muscle-nerve preparation, the discharge to capsaicin exposure in group IV afferents isolated from T2DM was likewise significantly augmented at a magnitude that was proportional to glucose concentration. Moreover, the discharge to capsaicin was potentiated by acute exposure of group IV afferents to a high glucose environment. T2DM showed significantly increased phospholyrated-TRPV1 and −PKCα levels in DRG neurons as compared with control. These findings suggest that group IV muscle afferents are sensitized by PKC-induced TRPV1 overactivity in early-stage T2DM with hyperglycemia and, thereby, may contribute to the potentiated circulatory response to TRPV1 activation in the disease.

BACKGROUND Renal denervation (RDN) is effective at lowering blood pressure. However, it is unknown if ablative procedures elicit sympathetic denervation of the kidneys in humans. The aim of this investigation was to assess sympathetic innervation of the renal cortex following perivascular chemical RDN, which may be particularly effective at ablating perivascular efferent and afferent nerves. METHODS Seven hypertensive patients (4F:3M; 50–65 years) completed PET–CT sympathetic neuroimaging of the renal cortex using 11C-methylreboxetine (11C-MRB, norepinephrine transporter ligand) and 6-[18F]-fluorodopamine (18F-FDA; substrate for the cell membrane norepinephrine transporter) before and 8 weeks after chemical RDN (Peregrine System Infusion Catheter, Ablative Solutions; n = 4; 2F:2M) or control renal angiography (n = 3; 2F:1M). Patients completed physiological phenotyping including 24-hour ambulatory blood pressure, hemodynamics, muscle sympathetic nerve activity, and 24-hour urine collection. RESULTS RDN decreased 11C-MRB-derived radioactivity by ~30% (Δ 11C-MRB/chamber: −0.95 a.u. confidence interval (CI): −1.36 to −0.54, P = 0.0002), indicative of efferent RDN. In contrast, 18F-FDA-derived radioactivity increased (Δ 18F-FDA/chamber: 2.72 a.u. CI: 0.73–4.71, P = 0.009), consistent with reduced vesicular turnover. Controls showed no change in either marker. Ambulatory systolic pressure decreased in 3 of 4 patients (−9 mm Hg CI: −27 to 9, P = 0.058), and central systolic pressure decreased in all patients (−23 mm Hg CI: −51 to 5, P = 0.095). CONCLUSIONS These results are the first to show efferent sympathetic denervation of the renal cortex following RDN in humans. Further studies of mechanisms underlying variable blood pressure lowering in the setting of documented RDN may provide insights into inconsistencies in clinical trial outcomes. CLINICAL TRIALS REGISTRATION Trial Number NCT03465917.

Background: Little is known about the prevalence of polypharmacy, the taking of five or more medications a day, in older adults with specific dementia risk factors. Objective: To examine the prevalence of polypharmacy in participants at baseline in a vascular risk reduction focused Alzheimer’s disease (rrAD) trial targeting older patients with hypertension and elevated dementia risk. Methods: We conducted a detailed review of medications in a cross-sectional study of community-dwelling older adults with hypertension and elevated dementia risk. Medications were identified in a structured interview process with an onsite pharmacist or qualified designee. Polypharmacy was defined as use of five or more medications on a regular basis. Descriptive analyses were conducted on the sample as well as direct comparisons of subgroups of individuals with hypertension, diabetes, and hyperlipidemia. Results: The 514 rrAD participants, mean age 68.8 (standard deviation [sd] 6), reported taking different combinations of 472 unique medications at their baseline visit. The median number of medications taken by participants was eight [Range 0–21], with 79.2% exhibiting polypharmacy (n = 407). Sites differed in their prevalence of polypharmacy, χ2(3) = 56.0, p

Patients with type 2 diabetes display an exaggerated pressor response to exercise. However, evidence supporting the association between the magnitude of the pressor response to exercise and insulin resistance-related factors including hemoglobin A1c (HbA1c) or homeostatic model assessment of insulin resistance (HOMA-IR) in nondiabetic subjects has remained sparse and inconclusive. Thus we investigated the relationship between cardiovascular responses to exercise and insulin resistance-related factors in nondiabetic healthy men (n = 23) and women (n = 22) above 60 yr old. We measured heart rate (HR) and blood pressure (BP) responses during: isometric handgrip (IHG) exercise of 30% maximal voluntary contraction, a period of skeletal muscle ischemia (SMI) induced by tourniqueting the arm after IHG, and rhythmic dynamic handgrip (DHG) exercise during SMI. Greater diastolic BP (DBP) responses to DHG with SMI was associated with male sex (r = 0.44, P = 0.02) and higher HbA1c (r = 0.33, P = 0.03), heart-ankle pulse wave velocity (haPWV) (r = 0.45, P < 0.01), and resting systolic BP (SBP) (r = 0.36, P = 0.02). HbA1c persisted as a significant determinant explaining the variance in the DBP response to DHG with SMI in multivariate models despite adjustment for sex, haPWV, and resting SBP. It was also determined that the DBP response to DHG with SMI in a group in which HOMA-IR was abnormal (Δ33 ± 3 mmHg) was significantly higher than that of groups in which HOMA-IR was at intermediate (Δ20 ± 4 mmHg) and normal (Δ23 ± 2 mmHg) levels. These data suggest that even in nondiabetic older adults, insulin resistance is related to an exaggerated pressor response to exercise especially when performed under ischemic conditions. NEW & NOTEWORTHY The diastolic blood pressure response to rhythmic dynamic handgrip exercise under ischemic conditions was demonstrated to be correlated with insulin resistance-related factors in nondiabetic older adults. This finding provides important insight to the prescription of exercise in this particular patient population as the blood pressure response to exercise, especially under ischemic conditions, could be exaggerated to nonsafe levels.

The updated scientific statement by the American Heart Association has defined resistant hypertension (HTN;RH) as uncontrolled blood pressure (BP) ≥ 130/80 mmHg, despite concurrent use of 3 anti-HTN drug classes comprising a calcium channel blocker, a blocker of renin-angiotensin system, and a thiazide diuretic, preferably chlorthalidone. Using the updated BP criteria, the prevalence of RH in the United States is found to be modestly increased by approximately 3–4% among treated population. Meta-analysis of observational studies have demonstrated that pseudo-RH from white coat HTN or medication nonadherence is as much common as the truly RH. Thus, screening for pseudo-resistance in the evaluation of all apparent RH is of utmost importance as diagnosis of white-coat HTN requires no treatment, while medication nonadherence would benefit from identifying and targeting barriers to adherence.

The widespread treatment of hypertension and resultant improvement in blood pressure have been major contributors to the dramatic age-specific decline in heart disease and stroke. Despite this progress, a persistent gap remains between stated public health targets and achieved blood pressure control rates. Many factors may be important contributors to the gap between population hypertension control goals and currently observed control levels. Among them is the extent to which patients adhere to prescribed treatment. The goal of this scientific statement is to summarize the current state of knowledge of the contribution of medication nonadherence to the national prevalence of poor blood pressure control, methods for measuring medication adherence and their associated challenges, risk factors for antihypertensive medication nonadherence, and strategies for improving adherence to antihypertensive medications at both the individual and health system levels.

Importance National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned. Objective To examine AVF usability, longer-term functional patency, and remedial procedures to facilitate maturation, manage complications, or maintain patency in the Hemodialysis Fistula Maturation (HFM) Study. Design, setting, and participants The HFM Study was a multicenter (n = 7) prospective National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases cohort study performed to identify factors associated with AVF maturation. A total of 602 participants were enrolled (dialysis, kidney failure: 380; predialysis, chronic kidney disease [CKD]: 222) with AVF maturation ascertained for 535 (kidney failure, 353; CKD, 182) participants. Interventions All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation. Main outcomes and measures In this case series analysis, the primary outcome was unassisted maturation. Functional patency, freedom from intervention, and participant survival were summarized using Kaplan-Meier analysis. Results Most participants evaluated (n = 535) were men (372 [69.5%]) and had diabetes (311 [58.1%]); mean (SD) age was 54.6 (13.6) years. Almost two-thirds of the AVFs created (342 of 535 [64%]) were in the upper arm. The AVF maturation rates for the kidney failure vs CKD participants were 29% vs 10% at 3 months, 67% vs 38% at 6 months, and 76% vs 58% at 12 months. Several participants with kidney failure (133 [37.7%]) and CKD (63 [34.6%]) underwent interventions to facilitate maturation or manage complications before maturation. The median time from access creation to maturation was 115 days (interquartile range [IQR], 86-171 days) but differed by initial indication (CKD, 170 days; IQR, 113-269 days; kidney failure, 105 days; IQR, 81-137 days). The functional patency for the AVFs that matured at 1 year was 87% (95% CI, 83.2%-90.2%) and at 2 years, 75% (95% CI, 69.7%-79.7%), and there was no significant difference for those receiving interventions before maturation. Almost half (188 [47.5%]) of the AVFs that matured had further intervention to maintain patency or treat complications. Conclusions and relevance The findings of this study suggest that AVF remains an accepted hemodialysis access option, although both its maturation and continued use require a moderate number of interventions to maintain patency and treat the associated complications.

Background: Medication nonadherence presents one of the greatest challenges to hypertension management. Previous studies from our group have shown therapeutic drug monitoring (TDM), biochemical monitoring of drug levels, is more accurate than self-report, detailed questionnaires, or prescription fill rate in detecting nonadherence. Prior studies have also shown a prevalence of nonadherence from 45% to 80% among insured patients with uncontrolled hypertension despite having been prescribed a multi-drug regimen. Previous studies have not assessed adherence to antihypertensive drugs in a safety net population by TDM. Methods: We performed a cross-sectional study in patients with uncontrolled hypertension in the primary care Internal Medicine and Cardiology Clinics at Parkland Health& Hospital System (PHHS). Patients with BP of 130/80 mmHg, prescribed ≥2 antihypertensive medications, and self-reporting medication adherence were enrolled after informed consent. Plasma samples were obtained for measurement of 44 cardiovascular drugs using liquid chromatography mass spectrometry. Results: Among 77 patients with uncontrolled hypertension (57% female, 65% Black, 12% Hispanic), 13 (17%) were nonadherent to at least one anti-hypertensive drug by TDM. There was no difference in baseline characteristics between the two groups. The adherent and nonadherent groups had similar systolic (146±13 vs 148±18, p=0.67) and diastolic (83±9 vs 88±10 mmHg, p=0.13) BP. All patients had either medical insurance or some form of prescription financial assistance. 15 patients had prescription financial assistance, while 62 patients had medical insurance. Nonadherence rates for patients on financial assistance programs did not significantly differ from patients with medical insurance (13% vs 18%, p>0.999). Conclusions: We found a surprisingly low prevalence of anti-hypertensive medication nonadherence in this uncontrolled hypertension population despite many barriers to treatment. Our study suggests a lesser role of medication nonadherence in uncontrolled hypertension in the safety net population.

Hypertension affects nearly half of the US population but only 43% achieved blood pressure control with medication alone. Medical devices for hypertension include implantable lead electrodes that stimulate the carotid baroreceptors with promising results, albeit with significant adverse complications. To address these limitations, we have proposed the use of deep peroneal nerve stimulation (DPNS), which elicited a depressor response in anesthetized, breathing supported, spontaneously hypertensive rats (SHR). In this study, we further define the electrical stimulation parameters that optimize the DPNS depressor response, and demonstrated that increasing the pulse duration from 0.15 ms to 1ms, of 1.0 mA pulses at 2 Hz for 10 sec, significantly reduced the mean arterial pressure (MAP) by 8±4 mmHg (p

Patients with diabetes display heightened blood pressure response to exercise but the underlying mechanism are remains to be elucidated. There is no direct evidence that insulin resistance (hyperinsulinemia or hyperglycemia) impact neural cardiovascular control during exercise. We propose a novel paradigm in which hyperinsulinemia or hyperglycemia significantly influence neural regulatory pathways controlling the circulation during exercise in diabetes.

Background: Risk for atherosclerotic cardiovascular disease was a novel consideration for antihypertensive medication initiation in the 2017 American College of Cardiology/American Heart Association Blood Pressure (BP) guideline. Whether biomarkers of chronic myocardial injury (high-sensitivity cardiac troponin T ≥6 ng/L] and stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥100 pg/mL) can inform cardiovascular (CV) risk stratification and treatment decisions among adults with elevated BP and hypertension is unclear. Methods: Participant-level data from 3 cohort studies (Atherosclerosis Risk in Communities Study, Dallas Heart Study, and Multiethnic Study of Atherosclerosis) were pooled, excluding individuals with prevalent CV disease and those taking antihypertensive medication at baseline. Participants were analyzed according to BP treatment group from the 2017 American College of Cardiology/American Heart Association BP guideline and those with high BP (120 to 159/ Results: The study included 12 987 participants (mean age, 55 years; 55% women; 21.5% with elevated high-sensitivity cardiac troponin T; 17.7% with elevated NT-proBNP) with 825 incident CV events over 10-year follow-up. Participants with elevated BP or hypertension not recommended for antihypertensive medication with versus without either elevated high-sensitivity cardiac troponin T or NT-proBNP had a 10-year CV incidence rate of 11.0% and 4.6%, with a 10-year number needed to treat to prevent 1 event for intensive BP lowering of 36 and 85, respectively. Among participants with stage 1 or stage 2 hypertension recommended for antihypertensive medication with BP Conclusions: Elevations in high-sensitivity cardiac troponin T or NT-proBNP identify individuals with elevated BP or hypertension not currently recommended for antihypertensive medication who are at high risk for CV events. The presence of nonelevated biomarkers, even in the setting of stage 1 or stage 2 hypertension, was associated with lower risk. Incorporation of biomarkers into risk assessment algorithms may lead to more appropriate matching of intensive BP control with patient risk.

The cardiovascular responses to exercise are potentiated in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanisms causing this abnormality remain unknown. Central command (CC) and the exercise pressor reflex (EPR) are known to contribute significantly to cardiovascular control during exercise. Thus these neural signals are viable candidates for the generation of the abnormal circulatory regulation in this disease. We hypothesized that augmentations in CC as well as EPR function contribute to the heightened cardiovascular responses during exercise in T2DM. To test this hypothesis, changes in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in response to electrical stimulation of mesencephalic locomotor region (MLR), a putative component of the central command pathway, and activation of the EPR, evoked by electrically induced hindlimb muscle contraction, were examined in decerebrate animals. Sprague-Dawley rats were given either a normal diet (control) or a high-fat diet (14–16 wk) in combination with two low doses (35 mg/kg week 1, 25 mg/kg week 2) of streptozotocin (T2DM). The changes in MAP and RSNA responses to MLR stimulation were significantly greater in T2DM compared with control (2,739 ± 123 vs. 1,298 ± 371 mmHg/s, 6,326 ± 1,621 vs. 1,390 ± 277%/s, respectively, P < 0.05). Similarly, pressor and sympathetic responses to activation of the EPR in diabetic animals were significantly augmented compared with control animals (436 ± 74 vs. 134 ± 44 mmHg/s, 645 ± 135 vs. 139 ± 65%/s, respectively, P < 0.05). These findings provide the first evidence that CC and the EPR may generate the exaggerated rise in sympathetic activity and blood pressure during exercise in T2DM.

Alzheimer's Disease (AD) is an age-related disease with modifiable risk factors such as hypertension, hypercholesterolemia, obesity, and physical inactivity influencing the onset and progression. There is however, no direct evidence that reducing these risk factors prevents or slows AD. The Risk Reduction for Alzheimer's Disease (rrAD) trial is designed to study the independent and combined effects of intensive pharmacological control of blood pressure and cholesterol and exercise training on neurocognitive function. Six hundred and forty cognitively normal older adults age 60 to 85 years with hypertension and increased risk for dementia will be enrolled. Participants are randomized into one of four intervention group for two years: usual care, Intensive Reduction of Vascular Risk factors (IRVR) with blood pressure and cholesterol reduction, exercise training (EX), and IRVR+EX. Neurocognitive function is measured at baseline, 6, 12, 18, and 24 months; brain MRIs are obtained at baseline and 24 months. We hypothesize that both IRVR and EX will improve global cognitive function, while IRVR+EX will provide a greater benefit than either IRVR or EX alone. We also hypothesize that IRVR and EX will slow brain atrophy, improve brain structural and functional connectivity, and improve brain perfusion. Finally, we will explore the mechanisms by which study interventions impact neurocognition and brain. If rrAD interventions are shown to be safe, practical, and successful, our study will have a significant impact on reducing the risks of AD in older adults. NCT Registration: NCT02913664

Background: Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. Physical inactivity, a common feature of Western societies, is associated with increased cardiovascular morbidity and mortality. It is unknown whether dietary Pi excess contributes to exercise intolerance and physical inactivity. Methods: To determine an association between Pi excess and physical activity in humans, we assessed the relationship between serum Pi and actigraphy-determined physical activity level, as well as left ventricular function by cardiac magnetic resonance imaging, in DHS-2 (Dallas Heart Study phase 2) participants after adjusting for relevant variables. To determine direct effects of dietary Pi on exercise capacity, oxygen uptake, serum nonesterified fatty acid, and glucose were measured during exercise treadmill test in C57/BL6 mice fed either a high-Pi (2%) or normal-Pi (0.6%) diet for 12 weeks. To determine the direct effect of Pi on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in differentiated C2C12 myotubes were conducted after subjecting to media containing 1 to 3 mmol/L Pi (pH 7.0) to simulate in vivo phosphate conditions. Results: In participants of the DHS-2 (n=1603), higher serum Pi was independently associated with reduced time spent in moderate to vigorous physical activity ( P =0.01) and increased sedentary time ( P =0.004). There was no association between serum Pi and left ventricular ejection fraction or volumes. In animal studies, compared with the control diet, consumption of high-Pi diet for 12 weeks did not alter body weight or left ventricular function but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, and fatty acid levels and led to downregulation of genes involved in fatty acid synthesis, release, and oxidation, including Fabp4 , Hsl , Fasn , and Pparγ , in muscle. Similar results were recapitulated in vitro by incubating C2C12 myotubes with high-Pi media. Conclusions: Our data demonstrate a detrimental effect of dietary Pi excess on skeletal muscle fatty acid metabolism and exercise capacity that is independent of obesity and cardiac contractile function. Dietary Pi may represent a novel and modifiable target to reduce physical inactivity associated with the Western diet.

Numerous studies have demonstrated that sympathetic nervous system overactivation during exercise in hypertensive rodents and humans is due, in part, to an exaggerated reflex response known as the exercise pressor reflex. Our prior studies have implicated a key role of mineralocorticoid receptor activation in mediating an augmented exercise pressor reflex in spontaneously hypertensive rats, which is mitigated by blockade with eplerenone. However, the effect of eplerenone on exercise pressor reflex has not been assessed in human hypertension. Accordingly, the authors performed a randomized crossover study to compare the effects of eplerenone to another antihypertensive drug from a different class amlodipine on sympathetic nerve activity (SNA) in 14 patients with uncomplicated hypertension. The authors found that amlodipine unexpectedly augmented the increase in SNA during the second minute of isometric handgrip, which persisted into the post‐exercise circulatory arrest period (∆ SNA, from rest of 15 ± 2 vs. 9 ± 2 vs. 10 ± 2 bursts/min, amlodipine vs. baseline vs. eplerenone, respectively, p

Introduction: The proximal aorta has been shown to enlarge with aging in humans, but the long-term impact of hormonal and hemodynamic changes associated with pregnancy on aortic size and function are unknown. We examined if number of live births was independently associated with aortic dimensions and stiffness in a healthy multi-ethnic population-based cohort, the Dallas Heart Study (DHS). We hypothesized that multiparity (>/=4 live births) is independently associated with aortic dilation and aortic stiffness after adjustment for CV risk factors. Methods: Women with available thoracic aortic MRI measurements (n=1468, mean 44.5 years old) from DHS were stratified based on self-reported number of live births (0,1,2,3,>/=4). Sequential multivariable logistic regression models were used to assess independent associations of the number of live births with ascending aortic cross-sectional area/height, aortic pulse wave velocity (PWV) and aortic compliance. Models were adjusted for major CV risk factors. Results: Women with >/=4 live births were older, more likely to be Black, and had higher blood pressure, triglycerides and body mass index. Compared with nulliparous women, women with >/=4 had larger ascending aortic areas indexed to height [5.19 vs 4.74 cm2/m; p/=4 live births also had higher aortic PWV (5.54 vs 4.54 m/s; p Conclusions: Multiparity was associated with thoracic aortic enlargement, independent of age and relevant risk factors. Parity is an emerging sex-specific risk factor in cardiovascular disease that may have an impact on aortic remodeling in women.

A 39-year-old man with hypertension presented for an elective knee surgery. Within 15 minutes of induction of anesthesia, he developed malignant hypertension and acute hypoxia. Surgery wasaborted and he was subsequently transferred to our facility. High-sensitivity troponin was elevated. Chest X-ray demonstrated bilateral hilar opacities, consistent with pulmonary edema.Transthoracic echocardiography demonstrated mildly depressed left ventricular function with hypokinesis of the septum and inferolateral wall. Cardiac catheterization showed normal filling pressures and no coronary artery disease. Initial work up for secondary hypertension, including Duplex Doppler ultrasonography of renal artery and serum aldosterone level were unrevealing. Because of high index of suspicion, additional workup was pursued for adrenal hypertension. Hewas found to have severely elevated plasma normetanephrine level (36 nmol/L) and 24-hrurinary normetanephrine of 8,990 mcg while plasma metanephrine and epinephrine levels were within normal limits. Computed tomography of abdomen showed no adrenal mass but revealed contrast-enhancing mass in the bladder wall with surrounding lymphadenopathy, suggestive of metastatic paraganglioma. He underwent genetic evaluation which identified a heterozy gouspathogenic variant in the succinate dehydrogenase subunit B (SDHB) gene. He was treated withalpha- and beta-blockade and underwent partial cystectomy with lymph node dissection. Follow-up Gallium-68 DOTATATE scan was positive for uptake in several lymph nodes withsubsequent successful lymph node dissection. He is now asymptomatic. Discussion: This case illustrates the importance of a complete history in the evaluation of hypertension inyoung people. The presence of labile hypertension and acute cardiomyopathy which isprecipitated by stress or noncardiac surgery should prompt an evaluation of pheochromocytoma.The isolated elevation in plasma and urinary normetanephrine with normal plasma/urinarymetanephrine level is consistent with extra-adrenal production of catecholamines, which iscommon in the presence of SDHB mutation.

An increasing number of studies have reported a deleterious role of inorganic phosphate (Pi) in promoting hypertension. Previously, we have shown high Pi diet-induced excessive pressor and sympathetic responses to muscle contraction in otherwise normal rats, which were primarily mediated by an overactive exercise pressor reflex (EPR), a reflex arising from contracting muscle. However, the mechanism underlying these abnormalities generated by excess Pi intake remains unclear. Dietary Pi is known to increase release of bone-derived fibroblast growth factor (FGF) 23 to regulate Pi homeostasis. Evidence suggests that FGF23 and FGF receptors (FGFRs) are also present in the central nervous system. The aim of this study was to determine the role of brain FGFRs in mediating augmented EPR activity induced by dietary Pi excess. Accordingly, we assessed cerebrospinal fluid FGF23 levels in Sprague-Dawley rats fed either a normal 0.6% Pi diet (NP) or a high 1.2% Pi diet (HP) for 12 weeks. To determine the role of central FGFRs in mediating the EPR, we measured mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to hindlimb muscle contraction before and after intracerebroventricular (ICV) administration of either a selective FGFR4 inhibitor BLU9931 or a FGFR1/2/3 inhibitor AZD4547 in decerebrate NP and HP animals. Cerebrospinal fluid FGF23 levels were significantly higher in HP rats compared to NP rats (8.3±0.9 vs. 7.2±0.8 pM, P

Importance Self-identified Black race is associated with higher hypertension prevalence and worse blood pressure (BP) control compared with other race/ethnic groups. The contribution of genetic West African ancestry to these racial disparities appears not to have been completely determined. Objective To determine the association between the proportion of West African ancestry with the response to antihypertensive medication, BP control, kidney function, and risk of adverse cardiovascular (CV) events among self-identified Black individuals in the Systolic Blood Pressure Intervention Trial (SPRINT). Design, Setting, and Participants This post hoc analysis of the SPRINT trial incorporated data from a multicenter study of self-identified Black participants with available West African ancestry proportion, estimated using 106 biallelic autosomal ancestry informative genetic markers. Recruitment started on October 20, 2010, and ended on August 20, 2015. Data were analyzed from May 2020 to September 2020. Main Outcomes and Measures Trajectories of BP and kidney function parameters on follow-up of the trial were assessed across tertiles of the proportion of West African ancestry using linear mixed-effect modeling after adjustment for potential confounders. Multivariable adjusted Cox models evaluated the association of West African ancestry with the risk of composite CV events (nonfatal myocardial infarction, CV death, and heart failure event). Results Among 2466 participants in the current analysis (1122 women [45.5%]; median West African ancestry, 81% [interquartile range, 73%-87%]), there were 120 composite CV events (4.9%) over a mean (SD) of 3.2 (0.9) years of follow-up. At baseline, mean (SD) high-density lipoprotein cholesterol levels were higher (tertile 3: 56.5 [15.0] mg/dL vs tertile 1: 54.2 [14.9] mg/dL;P = .006), smoking prevalence (never smoking: tertile 3: 367 [47.9%] vs tertile 1: 372 [42.2%];P = .009) and mean (SD) Framingham Risk scores (tertile 3: 16.7 [9.7] vs tertile 1: 18.1 [10.2];P = .01) were lower, and baseline BP was not different across increasing tertiles of West African ancestry. On follow-up, there was no evidence of differences in longitudinal trajectories of BP, kidney function parameters, or left ventricular mass (Cornell voltage by electrocardiogram) across tertiles of West African ancestry in either intensive or standard treatment arms. In adjusted Cox models, higher West African ancestry was associated with a lower risk of a composite CV event after adjustment for potential confounders (adjusted hazard ratio per 5% higher West African ancestry, 0.92 [95% CI, 0.85-0.99]). Conclusions and Relevance Among self-reported Black individuals enrolled in SPRINT, the trajectories of BP, kidney function, and left ventricular mass over time were not different across tertiles of the proportion of West African ancestry. A higher proportion of West African ancestry was associated with a modestly lower risk for CV events. These findings suggest that extrinsic and structural societal factors, more than genetic ancestry, may be the major drivers of the well-established racial disparity in cardiovascular health associated with hypertension.

Colorectal cancer kills nearly 700,000 people each year worldwide. The use of chemotherapeutic agents in the treatment of colorectal cancer has broadened considerably over the past few decades. The cardiovascular care of patients being treated with these agents has received increasing attention over recent years due to the known cardiovascular toxicities associated with certain treatment regimens, but there may still be unidentified cardiovascular toxicities. Here we present a case of a patient with colorectal cancer without any modifiable cardiovascular risk factors who experienced coronary vasospasm shortly after initiation of therapy with 5-flourouracil, leucovorin, and oxaliplatin with bevacizumab, despite having previously tolerated boluses of 5-flourouracil alone without incident. Coronary vasospasm attributed to this combination of chemotherapy has never before been reported. Additionally, our case and other available literature demonstrate the efficacy of dihydropyridine calcium channel blocker therapy in treatment of vasospasm induced by chemotherapeutic agents.

Key points In this study, we focused on muscle sympathetic nerve activity (MSNA) burst size and occurrence separately as subcomponents of the sympathetic baroreflex in older adults, and we found that the distribution (variation) of burst size against burst occurrence was greater in women than men. Older women had greater carotid artery stiffness compared with older men, while blood pressure (BP) distribution (variation) was comparable between sexes. Sympathetic baroreflex sensitivity assessed with burst incidence was less sensitive as the carotid artery became stiffer in older men and women, while that assessed with burst area was more sensitive as the carotid artery became stiffer in older women but not in older men. These results help us understand the mechanisms underlying the compensation for the impaired response of MSNA burst occurrence in older women with greater carotid artery stiffness to regulate BP similar to that in older men. Abstract There are sex differences in arterial stiffness and neural control of blood pressure (BP) among older adults. We examined whether the sympathetic response to BP is greater in older women than men in burst size but not burst occurrence. Burst occurrence and size were assessed with burst interval and area of muscle sympathetic nerve activity, respectively, and the distributions of these indices were evaluated by range during supine rest in 61 healthy older subjects (30 men (69 ± 6 years) and 31 women (68 ± 6 years); means ± SD). Also, we analysed sympathetic baroreflex sensitivity (BRS) with burst occurrence and area simultaneously. Carotid β-stiffness was measured with B-mode ultrasonic image and carotid BP. The range of burst interval was smaller in older women than men (P = 0.002), while there was no difference in the range of burst area. Carotid β-stiffness was greater in older women than men (6.7 ± 2.7 vs. 5.1 ± 2.7, P = 0.027). Sympathetic BRS assessed with burst incidence was lower in older women than men (-2.3 ± 1.4 vs. -3.3 ± 1.4 bursts·100 beats-1 mmHg-1 , P = 0.007), while this sex difference was observed when assessed with burst area after adjusting for carotid β-stiffness (-116.1 ± 135.0 vs. -185.9 ± 148.2 a.u. burst-1 mmHg-1 , P = 0.040), but not before. Sympathetic BRS assessed with burst area was negatively (more sensitive) correlated with carotid β-stiffness in older women (r = -0.53, P = 0.002) but not men. These data suggest that the response of burst size within each burst is augmented for the baroreflex BP control despite the impaired response of burst occurrence in older women with greater carotid stiffness.

The blood pressure response to exercise is exaggerated in the type 1 diabetes mellitus (T1DM). An overactive exercise pressor reflex (EPR) contributes to the potentiated pressor response. However, the mechanism(s) underlying this abnormal EPR activity remains unclear. This study tested the hypothesis that the heightened blood pressure response to exercise in T1DM is mediated by EPR-induced sympathetic overactivity. Additionally, the study examined whether the single muscle afferents are sensitized by PKC (protein kinase C) activation in this disease. Sprague-Dawley rats were intraperitoneally administered either 50 mg/kg streptozotocin (T1DM) or saline (control). At 1 to 3 weeks after administration, renal sympathetic nerve activity and mean arterial pressure responses to activation of the EPR, mechanoreflex, and metaboreflex were measured in decerebrate animals. Action potential responses to mechanical and chemical stimulation were determined in group IV afferents with pPKCα (phosphorylated-PKCα) levels assessed in dorsal root ganglia. Compared with control, EPR (58±18 versus 96±33%; P P P P P

This study tested the hypothesis that older hypertensive women display augmented pressor responses and aberrant sympathetic neural discharge patterning in response to orthostatic stress versus older hypertensive men. We evaluated, in older hypertensive and normotensive men and women (n=12 each group), blood pressure, heart rate, cardiac index (acetylene rebreathing), total peripheral resistance, and muscle sympathetic nerve activity (microneurography) at baseline (supine; 3 minutes) and during graded head-up tilt (30° for 5 minutes and 60° for 20 minutes). Sympathetic action potential discharge patterns were studied using wavelet-based methodology. In the upright posture, systolic and diastolic blood pressure responses were greater in hypertensive women versus hypertensive men and normotensive women ( P P P P

The prognostic relevance of masked uncontrolled hypertension (MUCH) is incompletely clear and its global impact on cardiovascular outcomes and mortality has not been assessed. The aim of this study was to perform a meta-analysis on the prognostic value of MUCH. We searched for articles assessing outcome in patients with MUCH compared to those with controlled hypertension and reporting adjusted hazard ratio and 95% confidence interval. We identified six studies using ambulatory blood pressure monitoring (12610 patients with 933 events) and five using home blood pressure measurement (17742 patients with 394 events). The global population included 30352 patients who experienced 1327 events. Selected studies had cardiovascular outcomes and all-cause mortality as primary outcome and the main result is a composite of these events. The overall adjusted hazard ratio was 1.80 (95% confidence interval 1.57–2.06) for MUCH versus controlled hypertension. Subgroup meta-analysis showed that adjusted hazard ratio was 1.83 (95% confidence interval 1.52–2.21) in studies using ambulatory blood pressure monitoring and 1.75 (95% confidence interval 1.38–2.20) in those using home blood pressure measurement. Risk was significantly higher in MUCH than in controlled hypertension independently of follow-up length and types of studied events. MUCH was at significantly higher risk than controlled hypertension in all ethnic groups, but the highest hazard ratio was found in studies including Black patients. Risk of cardiovascular events and all-cause mortality is significantly higher in patients with MUCH than in those with controlled hypertension. MUCH detected by ambulatory or home blood pressure measurement appear to convey similar prognostic information.

NEW FINDINGS What is the central question of this study? The venoarteriolar response (VAR) contributes substantially to the maintenance of orthostatic tolerance in humans. Despite its importance in haemodynamic homeostasis, the impact of ageing on the VAR remains understudied. What is the main finding and its importance? Older adults exhibit an augmented VAR in response to leg dependency. The age-related augmentation of the VAR might be linked with progressive increases of peripheral vascular resistance with ageing. We found a modest but significant correlation between the leg VAR and the morning blood pressure surge in older adults. Augmented leg VAR might contribute to the blood pressure elevation in the early morning. ABSTRACT The venoarteriolar response (VAR) is a non-adrenergic, non-baroreflex-mediated mechanism of vasoconstriction, which has been proposed to contribute ∼45% of the increase in total peripheral resistance during orthostasis. Despite its importance in human cardiovascular control during orthostatic stress, there is no information available regarding the impact of age and sex on the VAR or its role in diurnal blood pressure (BP) variation. We studied 33 (15 women) young (mean ± SD; 28 ± 4 years old) and 26 (12 women) older (71 ± 3 years old) healthy individuals. Brachial and femoral blood flow were measured using Doppler ultrasound. The percentage reduction in vascular conductance (blood flow/mean BP) during 4 min of limb dependency (35-40 cm below the heart level) was used to assess the VAR. The morning surge in BP was assessed using 24 h ambulatory BP monitoring. Peak VAR in the lower limb, but not in the upper limb, was significantly higher in the older than the younger adults (33 ± 4 versus 26 ± 6%, older versus young; P < 0.05). There was no sex difference in the VAR in either the young or the older group. A greater leg VAR was related to a greater morning surge in BP in older adults (r = -0.4, P = 0.02) but not in the young adults (r = -0.26, P = 0.1). Thus, advancing age enhances the VAR in the lower limb and is associated with the morning blood pressure surge in older adults. Sex does not affect this local axonal reflex in healthy humans.

The aim of this study was to assess characteristic impedance (Z c ) of the proximal aorta in young and middle-aged individuals with isolated systolic hypertension (ISH). Z c is an index of aortic stiffness relative to aortic size. In the Dallas Heart Study, 2001 untreated participants 18 to 64 years of age (mean age: 42.3 years; 44% black race) were divided into the following groups based on office blood pressure (BP) measurements: (1) optimal BP (systolic BP [SBP] c , aortic arch pulse wave velocity, and minimum ascending aortic size were quantified using cardiovascular magnetic resonance. In multivariable-adjusted linear models, Z c was highest in the ISH group compared with the optimal BP, isolated diastolic hypertension, or systolic–diastolic hypertension groups (103.2±4.0 versus 68.3±2.1, 75.4±6.0, and 88.9±4.8 dyne*seconds/cm 5 , respectively; all P c –ISH association did not differ by race. Aortic pulse wave velocity was highest in the ISH group compared with the optimal BP, isolated diastolic hypertension, or systolic–diastolic hypertension groups (6.3±0.3 versus 4.3±0.1, 4.4±0.4 and 5.5±0.3 m/s, respectively; all P P >0.2). Results were similar in a subgroup of 1551 participants 18 to 49 years of age. In a multiracial population-based sample, we found evidence of a mismatch between proximal aortic stiffness and diameter in young and middle-aged adults with ISH.

Objectives This study aims to compare ethnic difference in proximal aortic pulse wave velocity (PWV) and characteristic impedance (Zc). Background Increased aortic stiffness is an independent predictor of target organ damage, incident hypertension, and all-cause mortality. However, previous studies have not directly assessed proximal aortic function in Blacks, the ethnic population with disproportionately high risk for incident hypertension and target organ complications. Methods We evaluated the multiethnic, population-based DHS (Dallas Heart Study) participants (N = 2,544, 54.2% women, 49.7% Black) who underwent cardiac magnetic resonance at 1.5-T. Aortic stiffness and Zc were determined from aortic arch PWV and lumen area measurements. Linear regression was used to evaluate ethnic differences in proximal aortic wall stiffness using aortic arch PWV and Zc as dependent variables with and without adjustment for traditional cardiovascular risk factors. Because cardiac output was significantly higher in Blacks compared to Whites and Hispanics, additional comparisons of PWV and Zc were performed after adjustment for cardiac output and peripheral vascular resistance. Results Compared with Whites, both Blacks and Hispanics had higher levels of aortic arch PWV (4.25, 95% confidence interval [CI]: 4.15 to 4.35 m/s, vs. 4.72, 95% CI: 4.64 to 4.81 m/s, vs. 4.48, 95% CI: 4.33 to 4.63 m/s, respectively, both p 5 , vs. 75.6, 95% CI: 74.0 to 77.2 dyne·s/cm 5 , vs. 70.1, 95% CI: 67.6 to 72.8 dyne·s/cm 5 , respectively, both p Conclusions In a multiethnic population-based-sample, Blacks and Hispanics had higher proximal aortic stiffness compared with Whites independent of blood pressure and relevant risk factors.

Black Americans suffer disproportionately from hypertension and hypertensive heart disease. Out-of-office blood pressure (BP) is more predictive for cardiovascular complications than clinic BP; however, the relative abilities of clinic and out-of-office BP to predict left ventricular hypertrophy in black and white adults have not been established. Thus, we aimed to compare associations of out-of-office and clinic BP measurement with left ventricular hypertrophy by cardiac magnetic resonance imaging among non-Hispanic black and white adults. In this cross-sectional study, 1262 black and 927 white participants of the Dallas Heart Study ages 30 to 64 years underwent assessment of standardized clinic and out-of-office (research staff-obtained) BP and left ventricular mass index. In multivariable-adjusted analyses of treated and untreated participants, out-of-office BP was a stronger determinant of left ventricular hypertrophy than clinic BP (odds ratio per 10 mm Hg, 1.48; 95% CI, 1.34–1.64 for out-of-office systolic BP and 1.15 [1.04–1.28] for clinic systolic BP; 1.71 [1.43–2.05] for out-of-office diastolic BP, and 1.03 [0.86–1.24] for clinic diastolic BP). Non-Hispanic black race/ethnicity, treatment status, and lower left ventricular ejection fraction were also independent determinants of hypertrophy. Among treated Blacks, the differential association between out-of-office and clinic BP with hypertrophy was more pronounced than in treated white or untreated participants. In conclusion, protocol-driven supervised out-of-office BP monitoring provides important information that cannot be gleaned from clinic BP assessment alone. Our results underscore the importance of hypertension management programs outside the medical office to prevent hypertensive heart disease, especially in high-risk black adults. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00344903.

ispartof: HYPERTENSION vol:74 issue:2 pages:229-236 ispartof: location:United States status: published

Background: Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension. Methods: Involvement of IgG was studied using IgG μ heavy chain–null mice deficient in mature B cells and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell–specific deletion of the receptor. Obesity was induced by high-fat diet (HFD), and blood pressure (BP) was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by Sambucus nigra lectin blotting. Effects of IgG on endothelial NO synthase were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human participants by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc). Results: Mice deficient in B cells were protected from obesity-induced hypertension. Compared with IgG from control chow–fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor activation of endothelial NO synthase by altering endothelial NO synthase phosphorylation. In humans, obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension. Conclusions: Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesity-induced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension.

Objective: Therapeutic drug monitoring (TDM) is the assessment of medication adherence by detection of a drug or its metabolites in blood or urine samples. TDM-guided feedback has been shown to improve medication adherence and subsequent blood pressure (BP) control in patients with resistant hypertension. Herein, we sought to evaluate the attitudes of patients with uncontrolled hypertension as well as their providers towards incorporating TDM in clinical practice. Methods: We conducted a qualitative study consisting of in-depth, cognitive interviews in 10 patients seen in Parkland General Cardiology and Internal Medicine Clinics with uncontrolled hypertension. The patients were asked a series of 9 standardized questions to elicit their attitudes towards TDM use in the management of hypertension after informed consent. In addition, 10 providers, including faculty, trainees, and pharmacists, were also interviewed, using the same questionnaire to evaluate their attitudes of incorporating TDM in hypertension management. Results: Of the patients interviewed, 90% (9 of 10) were supportive of TDM use in clinical practice. Similarly, 100% (10 of 10) of providers thought TDM was a good idea and should be used regularly. On subsequent questioning, 78% (7 of 9) of patients who felt TDM was a good idea expressed reservation that TDM could negatively impact the physician-patient relationship. Nonetheless, 86% (6 of 7) of these patients felt TDM could be a useful tool to identifying and solving non-adherence of antihypertensive drugs, if providers are mindful of patients’ unique circumstances. Amongst providers, 90% (9 of 10) felt TDM may negatively impact the physician-patient relationship, yet felt TDM could still be useful in addressing non-adherence. Conclusion: TDM was found to be well accepted amongst patients and providers, though between 80-90% of patients and providers still had concerns that TDM could negatively impact the physician-patient relationship. However, the majority of patients and providers believed that TDM could be an effective tool in identifying and solving barriers to adherence, if the providers are sensitive to the patients’ specific needs. Our survey suggested feasibility of adopting TDM in improving medication adherence.

Pharmacy refill data are frequently used to screen for medication non-adherence in clinical practice but its accuracy has not been validated against therapeutic drug monitoring (TDM) in patients with uncontrolled hypertension. Accordingly, we evaluated the accuracy of proportions of days covered (PDC) and medication possession ratio (MPR) in assessing non-adherence to cardiovascular medications against therapeutic drug monitoring (TDM) in patients with uncontrolled hypertension at outpatient clinics of Parkland Memorial Hospital. Patients who had blood pressure of >130/80 mmHg, were on ≥2 antihypertensive medications, and verbally reported full medication compliance were enrolled in the study after an informed consent. Plasma samples were obtained for measurement of 36 cardiovascular drugs including statins, using liquid chromatography mass spectrometry assay. Among 38 patients enrolled in our study, 21% (8/38 patients) were non-adherent to at least 1 antihypertensive medication, while 39% (12/31 patients) were non-adherent to statin drugs. The non-adherent patients were younger than the adherent patients (57.2±12.0 vs. 62.9±7.8, p=0.08), and were less likely to be African Americans (7/17 vs. 16/21, p2 =0.15, p=0.11 for PDC; r 2 =0.15, p=0.16 for MPR). Using a threshold of < 80%, low PDC has a sensitivity of 100% and a specificity of 63% in detecting medication non-adherence when compared to TDM. Similar results were obtained for MPR: sensitivity of 100% and specificity of 65%. While medication refill data may be a sensitive screening tool for medication non-adherence, it has limited specificity and availability when compared to TDM. Thus, TDM constitutes a more efficient and reliable way to assess medication non-adherence, which is crucial in optimizing cardiovascular risk factors in this indigent population.

Background Increased blood pressure ( BP ) variability and nondipping status seen on 24‐hour ambulatory BP monitoring are often observed in autonomic failure ( ATF ). Methods and Results We assessed BP variability and nocturnal BP dipping in 273 patients undergoing ambulatory BP monitoring at Southwestern Medical Center between 2010 and 2017. SD , average real variability, and variation independent of mean were calculated from ambulatory BP monitoring. Patients were divided into a discovery cohort (n=201) and a validation cohort (n=72). ATF was confirmed by formal autonomic function test. In the discovery cohort, 24‐hour and nighttime average real variability, SD , and variation independent of mean did not differ significantly between ATF (n=25) and controls (n=176, all P >0.05). However, daytime SD, daytime coefficient of variation, and daytime variation independent of mean of systolic BP ( SBP ) were all significantly higher in patients with ATF than in controls in both discovery and validation cohorts. Nocturnal BP dipping was more blunted in ATF patients than controls in both cohorts (both P SBP yielded a sensitivity of 77% and specificity of 82% in detecting ATF in the validation cohort, whereas nondipping status had a sensitivity of 80% and specificity of 44%. The area under the receiver operator characteristic of daytime SD SBP was greater than the area under the receiver operator characteristic of nocturnal SBP dipping (0.79 [0.66‐0.91] versus 0.73 [0.58‐0.87], respectively). Conclusions Daytime SD of SBP is a better screening tool than nondipping status in detecting autonomic dysfunction.

Background/Aims: Intradialytic hypertension (IH) occurs frequently in some hemodialysis patients and increases mortality risk. We simultaneously compared pre-dialysis, post-dialysis and changes in extracellular volume and hemodynamics in recurrent IH patients and controls. Methods: We performed a case-control study among prevalent hemodialysis patients with recurrent IH and hypertensive hemodialysis controls. We used bioimpedance spectroscopy and impedance cardiography to compare pre-dialysis, post-dialysis, and intradialytic change in total body water (TBW) and extracellular water (ECW), as well as cardiac index (CI) and total peripheral resistance index (TPRI). Results: The ECW/TBW was 0.453 (0.05) pre-dialysis and 0.427 (0.04) post-dialysis in controls vs. 0.478 (0.03) and 0.461 (0.03) in IH patients (p=0.01 post-dialysis). The ECW/TBW change was -0.027 (0.03) in controls and -0.013 (0.02) in IH patients (p=0.1). In controls, pre- and post-dialysis TPRI were 3254 (994) and 2469 (529) dynes/sec/cm2/m2 vs. 2983 (747) and 3408 (980) dynes/sec/cm2/m2 in IH patients (p=0.002 post-dialysis). There were between-group differences in TPRI change (0=0.0001), but not CI (p=0.09). Conclusions: Recurrent intradialytic hypertension is associated with higher post-dialysis extracellular volume and TPRI. Intradialytic TPRI surges account for the vasoconstrictive state post-dialysis, but intradialytic fluid shifts may contribute to post-hemodialysis volume expansion.

Diet rich in fruits, vegetables, and dairy products, known as the Dietary Approaches to Stop Hypertension (DASH) diet, is known to reduce blood pressure (BP) in hypertensive patients. More recently, the DASH diet was shown to reduce oxidative stress in hypertensive and nonhypertensive humans. However, the main nutritional components responsible for these beneficial effects of the DASH diet remain unknown. Because the DASH diet is rich in potassium (K), magnesium (Mg), and alkali, we performed a randomized, double-blinded, placebo-controlled study to compare effects of potassium magnesium citrate (KMgCit), potassium chloride (KCl), and potassium citrate (KCit) to allow dissociation of the three components of K, Mg, and citrate on 24-hour ambulatory BP and urinary 8-isoprostane in hypertensive and prehypertensive subjects, using a randomized crossover design. We found that KCl supplementation for 4 weeks induced a significant reduction in nighttime SBP compared with placebo (116 ± 12 vs 121 ± 15 mm Hg, respectively, p0.01 vs placebo), whereas KMgCit and KCit had no significant effect in the same subjects (118 ± 11 and 119 ± 13 mm Hg, respectively, p0.1 vs placebo). In contrast, urinary 8-isoprostane was significantly reduced with KMgCit powder compared with placebo (13.5 ± 5.7 vs 21.1 ± 10.5 ng/mgCr, respectively, p0.001), whereas KCl and KCit had no effect (21.4 ± 9.1 and 18.3 ± 8.4, respectively, p0.1 vs placebo). In conclusion, our study demonstrated differential effects of KCl and KMgCit supplementation on BP and the oxidative stress marker in prehypertensive and hypertensive subjects. Clinical significance of the antioxidative effect of KMgCit remains to be determined in future studies.

Use of β-adrenergic receptor (AR) blocker is associated with increased risk of fatigue and exercise intolerance. Nebivolol is a newer generation β-blocker, which is thought to avoid this side effect via its vasodilating property. However, the effects of nebivolol on skeletal muscle perfusion during exercise have not been determined in hypertensive patients. Accordingly, we performed contrast-enhanced ultrasound perfusion imaging of the forearm muscles in 25 untreated stage I hypertensive patients at rest and during handgrip exercise at baseline or after 12 wk of treatment with nebivolol (5–20 mg/day) or metoprolol succinate (100–300 mg/day), with a subsequent double crossover for 12 wk. Metoprolol and nebivolol each induced a reduction in the resting blood pressure and heart rate (130.9 ± 2.6/81.7 ± 1.8 vs. 131.6 ± 2.7/80.8 ± 1.5 mmHg and 63 ± 2 vs. 64 ± 2 beats/min) compared with baseline (142.1 ± 2.0/88.7 ± 1.4 mmHg and 75 ± 2 beats/min, respectively, both P < 0.01). Metoprolol significantly attenuated the increase in microvascular blood volume (MBV) during handgrip at 12 and 20 repetitions/min by 50% compared with baseline (mixed-model P < 0.05), which was not observed with nebivolol. Neither metoprolol nor nebivolol affected microvascular flow velocity (MFV). Similarly, metoprolol and nebivolol had no effect on the increase in the conduit brachial artery flow as determined by duplex Doppler ultrasound. Thus our study demonstrated a first direct evidence for metoprolol-induced impairment in the recruitment of microvascular units during exercise in hypertensive humans, which was avoided by nebivolol. This selective reduction in MBV without alteration in MFV by metoprolol suggested impaired vasodilation at the precapillary arteriolar level.

The sympathetic response during the cold pressor test (CPT) has been reported to be greater in young blacks than whites, especially in those with a family history of hypertension. Because blood pressure (BP) increases with age, we evaluated whether elderly blacks have greater sympathetic activation during CPT than age-matched whites. BP, heart rate, cardiac output, and muscle sympathetic nerve activity were measured during supine baseline, 2-minute CPT, and 3-minute recovery in 47 elderly (68±7 [SD] years) volunteers (12 blacks and 35 whites). Baseline BP, heart rate, cardiac output, or muscle sympathetic nerve activity did not differ between races. Systolic and diastolic BP and heart rate increased during CPT (all P P >0.05). Cardiac output increased during CPT and ≤30 s of recovery in both groups, but was lower in blacks than whites. Muscle sympathetic nerve activity increased during CPT in both groups (both P P =0.030 for interaction). Peak change (Δ) in diastolic BP was correlated with Δ total activity at 1 minute into CPT in both blacks ( r =0.78, P =0.003) and whites ( r =0.43, P =0.009), whereas the slope was significantly greater in blacks ( P =0.007). Thus, elderly blacks have smaller sympathetic and central hemodynamic (eg, cardiac output) responses, but a greater pressor response for a given sympathetic activation during CPT than elderly whites. This response may stem from augmented sympathetic vascular transduction, greater sympathetic activation to other vascular bed(s), or enhanced nonadrenergically mediated vasoconstriction in elderly blacks.

Premature clopidogrel discontinuation is an important cause of stent thrombosis, myocardial infarction, and death after drug-eluting stent (DES) placement. Previous studies of clopidogrel nonadherence after DES placement have had short follow-up and have relied on self-reported adherence. All patients who underwent DES placement from January 2008 to December 2011 at a single safety-net hospital and received medications through the county-subsidized health plan were considered for inclusion; those with1-year follow-up were excluded. We retrospectively collected 1-year refill data from a large, closed pharmacy system. Our primary outcome was time to failure to obtain a clopidogrel refill, allowing a 5-day grace period. Our study cohort (n = 369) was 34% female, 39% Hispanic, 26% white, and 26% African-American; 26% identified Spanish as their primary language. The time to failure to obtain a clopidogrel refill was 153 days. Cumulative failure to obtain at least 1 refill was 23% for the first refill, increasing to 52% at 6 months and 68% at 1 year. Examining the proportion of days covered (PDC), 21% of patients had 100% coverage, whereas 34% had PDC80%. There were no independent predictors of nonadherence (PDC80%). In conclusion, we identified a high rate of clopidogrel nonadherence in a multiethnic urban poor patient population where clopidogrel was provided at discharge and at nominal cost thereafter. In this cohort, prediction models of nonadherence performed poorly. Novel strategies are needed to address this important problem.

The sympathetic nervous system (SNS) plays a major role in the pathogenesis of hypertension and contributes to hypertensive target organ complications. Advances in technology over the last three decades have improved the ability to measure sympathetic nerve activity (SNA), thus enabling investigators to probe the role of SNS in the development of cardiovascular diseases. The most direct method of measuring SNA employs the technique of microneurography, which involves recording of postganglionic sympathetic action potential using a subcutaneous electrode inserted into the candidate nerve. This method allows assessment of sympathetic vasoconstrictor discharge to the peripheral circulation in hypertension and provides prognostic information in patients with cardiovascular diseases. However, application of microneurography and other methods of assessment of SNS activity, including norepinephrine spillover and imaging of SNS innervation, in routine clinical practice is limited by availability of the technique and lack of normal reference range established from large population-based data. Nevertheless, these measurements provide further insight into mechanisms of hypertension and effectiveness of various interventions in modifying sympathetic regulation of blood pressure.

ObjectivesPrevious studies have implicated therapeutic drug monitoring (TDM), by measuring serum or urine drug levels, as a highly reliable technique for detecting medication non-adherence but the attitudes of patients and physicians toward TDM have not been evaluated previously. Accordingly, we solicited input from patients with uncontrolled hypertension and their physicians about their views on TDM.DesignProspective analysis of responses to a set of questions during semistructured interviews.SettingOutpatient clinics in an integrated health system which provides care for a low-income, uninsured population.ParticipantsPatients with uncontrolled hypertension with either systolic blood pressure of at least 130 mm Hg or diastolic blood pressure of at least 80 mm Hg despite antihypertensive drugs and providers in the general cardiology and internal medicine clinics.Primary and secondary outcome measuresAttitudes towards TDM and the potential impact on physician–patient relationship.ResultsWe interviewed 11 patients and 10 providers and discussed the findings with 13 community advisory panel (CAP) members. Of the patients interviewed, 91% (10 of 11) and all 10 providers thought TDM was a good idea and should be used regularly to better understand the reasons for poorly controlled hypertension. However, 63% (7 of 11) of patients and 20% of providers expressed reservations that TDM could negatively impact the physician–patient relationship. Despite some concerns, the majority of patients, providers and CAP members believed that if test results are communicated without blaming patients, the potential benefits of TDM in identifying suboptimal adherence and eliciting barriers to adherence outweighed the risks.ConclusionThe idea of TDM is well accepted by patients and their providers. TDM information if delivered in a non-judgmental manner, to encourage an honest conversation between patients and physicians, has the potential to reduce patient–physician communication obstacles and to identify barriers to adherence which, when overcome, can improve health outcomes.

Previous studies have demonstrated a relationship between subclinical cardiac dysfunction and cognitive impairment in older adults. However, association between hemodynamic variables and cognitive function has not been determined in an ethnically diverse middle-aged population. Furthermore, previous