24-hour Mean Arterial Pressure Research Articles

4D.08

Objective: Although the pro-fibrotic inflammatory substance galectin-3 predicts outcomes in the general population, the mechanisms responsible for this effect are uncertain. As galectin-3 expression contributes to aortic stiffness in preclinical studies, we aimed to determine whether circulating galectin-3 concentrations are associated with carotid femoral (aortic) pulse wave velocity (PWV) and aortic reflective wave index (RI) in a community sample. Design and method: Aortic PWV and RI were determined using applanation tonometry and SphygmoCor software in 966 randomly selected participants older than 16 years of age from a community sample of the South West Township (SOWETO) of Johannesburg. 661 participants had 24-hour ambulatory blood pressure (BP) monitoring that met with pre-specified quality control criteria. Results: Galectin-3 concentrations were not independently associated with office or 24-hour systolic (SBP) (p = 0.88–0.92), or diastolic (p = 0.65–0.94) BP. In contrast, with adjustments for age, sex, office or 24-hour mean arterial pressure (or SBP and pulse pressure), pulse rate, body mass index, regular smoking, regular alcohol intake, total cholesterol concentrations, diabetes mellitus or an HbA1c > 6.1%, treatment for hypertension and estimated glomerular filtration rate, galectin-3 was independently associated with aortic PWV (partial r = 0.15, p < 0.0001) and RI (partial r = 0.10, p < 0.005). In 745 participants that had never received antihypertensive therapy, galectin-3 concentrations were similarly independently associated with PWV (partial = 0.16, p < 0.0001), and RI (partial r = 0.11, p < 0.005). With adjustments for all confounders, markedly higher PWV and RI values were noted in the highest 3–4 octiles as compared to the lowest 3 octiles of galectin-3 concentrations. The BP-independent relations between galectin-3 concentrations and aortic haemodynamics persisted with further adjustments for C-reactive protein concentrations (PWV: partial r = 0.14, p < 0.0001, RI: partial r = 0.10, p = 0.002). Conclusions: Despite a lack of independent association with brachial BP, the pro-fibrotic inflammatory substance galectin-3 may contribute toward adverse outcomes through an impact on aortic stiffness and the magnitude of aortic reflected waves, effects that cannot be attributed to general inflammatory changes.

Assessment of Arterial Stiffness by 24-Hour Ambulatory Blood Pressure Monitoring in Nocturnal Hypertensive or Normotensive Subjects

Background: Nocturnal hypertension, male gender, age and arterial stiffness are important risk factors for cardiovascular morbidity and mortality. The objective of this study was to assess arterial stiffness in nocturnal hypertensive or normotensive men and women >40 years of age. Methods: Twenty-four-hour ambulatory blood pressure monitoring was performed in 144 men and 137 women. Eighty-eight subjects were between 40 and 49 years old (53% men), 98 were between 50 and 59 years old (55% men) and 95 were >60 years old (45% men). They were classified as nocturnal hypertensive if their average night systolic blood pressure and/or diastolic blood pressure was >120/70 mm/Hg. Arterial stiffness was assessed by the Ambulatory Arterial Stiffness Index (AASI), which is calculated as 1 minus the slope of diastolic on systolic blood pressure during the 24-hour recording period. Results were analyzed by analysis of covariance and were adjusted for 24-hour mean arterial pressure, the presence of antihypertensive treatment, height and heart rate. Results: Women showed a higher AASI compared to men, independently of age. In men, the AASI increased with age, being higher in nocturnal hypertensive than in nocturnal normotensive subjects, independently of age. Nocturnal hypertensive women showed higher AASI values than their respective nocturnal normotensive controls in the 50- to 59-year and >60-year age groups only. Conclusion: The results show that arterial stiffness is higher among nocturnal hypertensive subjects, especially in women >50 years old.

Abstract 100: Interference with Smooth Muscle Peroxisome Proliferator-Activated Receptor-gamma (PPARG) Exacerbates Hypertension and Vascular Dysfunction: Role of TIMP-4

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that interference of smooth muscle cell (SMC) PPARG exacerbates hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p&lt;0.05 vs NT). Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p&lt;0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p&lt;0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p&lt;0.05 vs NT) in S-P467L MA after DOCA-salt. Gene expression profiling in MA revealed a loss of the tissue inhibitor of metalloproteinases (TIMP)-4 in S-P467L compared to NT at baseline (fold change compared to NT; 0.39±0.2, p&lt;0.05). Interestingly, expression of TIMP-4 was significantly increased in MA of NT treated with DOCA-salt compared to NT baseline (1.5±0.1 fold). However, the induction of TIMP-4 was lost in S-P467L with DOCA-salt. There was no difference in mRNA expression of other TIMPs between NT and S-P467L after DOCA-salt. Inhibition of PPARG in primary SMC cultures either by pharmacological inhibitor, GW9662 or mutant PPARG resulted in down-regulation of TIMP-4 expression. Moreover, GW9662 treatment led to an increased total matrix metalloproteinases activity in SMC. We conclude that loss of PPARG function sensitizes the mice to the effects of DOCA-salt induced HT and vascular dysfunction, in part, by preventing the normal protective up-regulation of TIMP-4.

CPAP versus Oxygen in Obstructive Sleep Apnea

BackgroundObstructive sleep apnea is associated with hypertension, inflammation, and increased cardiovascular risk. Continuous positive airway pressure (CPAP) reduces blood pressure, but adherence is often suboptimal, and the benefit beyond management of conventional risk factors is uncertain. Since intermittent hypoxemia may underlie cardiovascular sequelae of sleep apnea, we evaluated the effects of nocturnal supplemental oxygen and CPAP on markers of cardiovascular risk.MethodsWe conducted a randomized, controlled trial in which patients with cardiovascular disease or multiple cardiovascular risk factors were recruited from cardiology practices. Patients were screened for obstructive sleep apnea with the use of the Berlin questionnaire, and home sleep testing was used to establish the diagnosis. Participants with an apnea–hypopnea index of 15 to 50 events per hour were randomly assigned to receive education on sleep hygiene and healthy lifestyle alone (the control group) or, in addition to education, either CPAP or nocturnal supplemental oxygen. Cardiovascular risk was assessed at baseline and after 12 weeks of the study treatment. The primary outcome was 24-hour mean arterial pressure.ResultsOf 318 patients who underwent randomization, 281 (88%) could be evaluated for ambulatory blood pressure at both baseline and follow-up. On average, the 24-hour mean arterial pressure at 12 weeks was lower in the group receiving CPAP than in the control group (−2.4 mm Hg; 95% confidence interval [CI], −4.7 to −0.1; P=0.04) or the group receiving supplemental oxygen (−2.8 mm Hg; 95% CI, −5.1 to −0.5; P=0.02). There was no significant difference in the 24-hour mean arterial pressure between the control group and the group receiving oxygen. A sensitivity analysis performed with the use of multiple imputation approaches to assess the effect of missing data did not change the results of the primary analysis.ConclusionsIn patients with cardiovascular disease or multiple cardiovascular risk factors, the treatment of obstructive sleep apnea with CPAP, but not nocturnal supplemental oxygen, resulted in a significant reduction in blood pressure. (Funded by the National Heart, Lung, and Blood Institute and others; HeartBEAT ClinicalTrials.gov number, NCT01086800.)

Normotensive Blood Pressure in Pregnancy

A successful pregnancy requires an accommodating environment. Salt and water availability are critical for plasma volume expansion. Any changes in sodium intake would alter aldosterone, a hormone previously described beneficial in pregnancy. To date, it remains ambiguous whether high aldosterone or high salt intake is preferable. We hypothesized that increased aldosterone is a rescue mechanism and appropriate salt availability is equally effective in maintaining a normotensive blood pressure (BP) phenotype in pregnancy. We compared normotensive pregnant women (n=31) throughout pregnancy with young healthy female individuals (n=31–62) and performed salt sensitivity testing within the first trimester. Suppression of urinary tetrahydro-aldosterone levels by salt intake as measured by gas chromatography–mass spectrometry and urinary sodium excretion corrected for creatinine, respectively, was shifted toward a higher salt intake in pregnancy ( P &lt;0.0001). In pregnancy, neither high urinary tetrahydro-aldosterone nor sodium excretion was correlated with higher BP. In contrast, in nonpregnant women, systolic BP rose with aldosterone ( P &lt;0.05). Testing the impact of salt on BP, we performed salt sensitivity testing in a final cohort of 19 pregnant and 24 nonpregnant women. On salt loading, 24-hour mean arterial pressure rose by 3.6±1.5 and dropped by –2.8±1.5 mm Hg favoring pregnant women ( P &lt;0.01; χ 2 =6.04; P &lt;0.02). Our data suggest first that salt responsiveness of aldosterone is alleviated in conditions of pregnancy without causing aldosterone-induced hypertension. Second, salt seems to aid in BP lowering in pregnancy for reasons incompletely elucidated, yet involving renin suppression and potentially placental sensing mechanisms. Further research should identify susceptible individuals and clarify effector mechanisms.

A randomized controlled trial comparing the effects of yoga with an active control on ambulatory blood pressure in individuals with prehypertension and stage 1 hypertension.

The purpose of this study was to compare the effects of yoga with an active control (nonaerobic exercise) in individuals with prehypertension and stage 1 hypertension. A randomized clinical trial was performed using two arms: (1) yoga and (2) active control. Primary outcomes were 24-hour day and night ambulatory systolic and diastolic blood pressures. Within-group and between-group analyses were performed using paired t tests and repeated-measures analysis of variance (time × group), respectively. Eighty-four participants enrolled, with 68 participants completing the trial. Within-group analyses found 24-hour diastolic, night diastolic, and mean arterial pressure all significantly reduced in the yoga group (-3.93, -4.7, -4.23 mm Hg, respectively) but no significant within-group changes in the active control group. Direct comparisons of the yoga intervention with the control group found a single blood pressure variable (diastolic night) to be significantly different (P=.038). This study has demonstrated that a yoga intervention can lower blood pressure in patients with mild hypertension. Although this study was not adequately powered to show between-group differences, the size of the yoga-induced blood pressure reduction appears to justify performing a definitive trial of this intervention to test whether it can provide meaningful therapeutic value for the management of hypertension.

Ambulatory Blood Pressure Monitoring in Children With Vesicoureteral Reflux

To assess the value of ambulatory blood pressure monitoring (ABPM) for identifying the risk of hypertension (HT) in children with vesicoureteral reflux (VUR). Seventy-six children with primary VUR were enrolled. Patients were divided into 2 groups according to renal scarring (RS). Serum creatinine, urine protein, and urine creatinine were measured. All patients underwent ABPM and casual blood pressure (BP) examination. ABPM measurements were standardized to age, gender, and height by Lambda-Mu-Sigma method. Urine protein and creatinine concentrations were statistically higher in RS (+) group than RS (-) group (P = .05). Casual systolic and diastolic BP standard deviation score (SDS) values were not statistically different between RS (+) and RS (-) groups. Day, night and 24-hour systolic BP SDS, day and 24-hour mean arterial blood pressure SDS values were significantly higher in RS (+) group than that of RS (-) group (P = .015, P = .031, P = .013, P = .07, and P = .021, respectively). All ABPM values significantly increased in patients with severe RS compared with ones with mild and moderate RS (P <.05). Casual and ambulatory BP SDS values did not significantly differ by grade of VUR (P >.05). ABPM is more sensitive than casual BP measurements and might be used for early identification of HT in VUR patients. The severity of RS increases the risk of HT in children with VUR. Controlling HT with proteinuria would decrease the progression of renal damage in VUR.

Mandibular Advancement Device vs CPAP in the Treatment of Obstructive Sleep Apnea: Are they Equally Effective in Short Term Health Outcomes?

Is the treatment of obstructive sleep apnea (OSA) with mandibular advancement device (MAD) similar in health outcomes to continuous positive airway pressure (CPAP) in the short term (one month health outcomes)? Randomized, open labeled, cross over, non-inferiority trial; Clinical trial registered with https://www.anzctr.org.au (ACTRN 12607000289415). Patients randomized to both the treatment acclimatization and treatment arm orders, resulting in 4 randomized sequences for MAD (M) and CPAP (C): MCMC, MCCM, CMMC and CMCM. Each sequence was generated by a computer program using random permuted blocks. The acclimatization periods for each treatment were generally between 4-6 weeks. Treatment periods were for 1 month each. The investigators and participants were not blinded to study arm assignment. 1 month. The study was conducted at three sleep centers in Sydney, Australia. 126 adults, mean age 49.5 years, 81% male, mean AHI 25.6 events/h, were randomized. patients with newly diagnosed OSA, AHI > 10 events/h, age ≥ 20 years, ≥ 2 symptoms of OSA (snoring, fragmented sleep, witnessed apneas, or daytime sleepiness), and a willingness to use both treatments. previous OSA treatment or a need for immediate treatment, central sleep apnea, a coexisting sleep disorder, regular use of sedatives or narcotics, preexisting lung or psychiatric disease, and any contraindication for oral appliance therapy (e.g., periodontal disease or insufficient dentition). Patients meeting eligibility criteria were randomized to a 4-6 week each, acclimatization to CPAP and MAD. A 2 week wash out period was then followed by initial assignment to CPAP or MAD treatment and subsequent cross over. During each of the 4-6 weeks of acclimatization with each device, all patients were asked to use their device for as long as they could tolerate it on a nightly basis. The primary outcome was the difference in 24-hour mean arterial pressure (24MAP) between CPAP and MAD determined by 24-hour ambulatory blood pressure (BP) monitoring. Secondary outcome measures were central BP and arterial stiffness measurements, neurobehavioral function, and quality of life (QOL) using the Functional Outcomes of Sleep Questionnaire (FOSQ), the Short Form-36 (SF-36), the Epworth Sleepiness Score (ESS), and the AusEd driving simulator. Daily diaries were also used to monitor treatment side effects and determine subjective compliance. The sample size was calculated to show the non-inferiority of MAD relative to CPAP in the 24MAP after 1 month of therapy, using an a priori determined non-inferiority margin of 1.6 mmHg, assuming 90% power and a true difference between treatment means of zero. The primary hypothesis was tested by comparing the upper limit of the 95% confidence interval for the MAD-CPAP difference in 24MAP with the a priori non-inferiority margin using the paired t-test. 18 patients (14%) withdrew after randomization, leaving 108 (86%) who completed the study. Two patients withdrew because of treatment intolerance (one CPAP and one both CPAP and MAD). Analyses were limited to the 108 subjects who completed the trial, regardless of compliance with their assigned treatment. There was no statistically significant difference between the groups in the primary outcome. MAD was non-inferior to CPAP with a CPAP-MAD 24MAP difference, 0.2 mmHg (95% confidence interval, -0.7 to 1.1 mmHg). However, ultimately neither treatment lowered BP from baseline in the entire group, after 1 month of therapy. In the subgroup of patients with baseline hypertension (n = 45), there were consistent treatment-related 24MAP improvements (p < 0.05) of 2.5 mmHg (CPAP) and 2.2 mmHg (MAD), with neither treatment having a superior effect. There were no differences in secondary outcome measures between groups, except MAD performed better than CPAP in improving four of eight SF-36 general QOL domains, and the overall mental component score (p < 0.05). Subjective reports of nightly compliance were less for CPAP compared with MAD (mean compliance 5.2 ± 2.0 vs. 6.5 ± 1.3 h/night, p < 0.0001).Treatment preference results showed that 55 patients (51%) preferred MAD, 25 (23%) preferred CPAP, 23 (21%) preferred either, and 5 (4.6%) preferred neither. In adults with predominately moderate to severe OSA, the short term (one month) use of an adjustable MAD was not inferior to CPAP in its impact on 24 hour mean ambulatory blood pressure, daytime sleepiness, disease specific and general quality of life. The study was supported by Project Grant 457557, Practitioner Fellowship 202916 (R.R.G.), Health Professional Fellowship 571179, and CIRUS Postdoctoral Fellowship (C.L.P.) from the Australian National Health and Medical Research Council. ResMed Inc. donated all continuous positive airway pressure equipment for the trial. SomnoMed Ltd. donated all oral appliances for the trial and an unrestricted grant of A$60,000 to support the study.

Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p&lt;0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p&lt;0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p&lt;0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p&lt;0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p&lt;0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

Blood Pressure Rhythmicity and Visceral Fat in Children With Hypertension

Primary hypertension is associated with disturbed activity of the sympathetic nervous system and altered blood pressure rhythmicity. We analyzed changes in cardiovascular rhythmicity and its relation with target organ damage during 12 months of antihypertensive treatment in 50 boys with hypertension (median, 15.0 years). The following parameters were obtained before and after 12 months of antihypertensive treatment: 24-hour ambulatory blood pressure, left ventricular mass, carotid intima-media thickness, and MRI for visceral and subcutaneous adipose tissue. Amplitudes and acrophases of mean arterial pressure and heart rate rhythms were obtained for 24-, 12-, and 8-hour periods. After 1 year of treatment, 68% of patients were normotensive, and left ventricular mass and carotid intima-media thickness decreased in 60% and 62% of patients, respectively. Blood pressure and heart rate rhythmicity patterns did not change. Changes in blood pressure amplitude correlated with the decrease of waist circumference (P=0.035). Moreover, the decrease of visceral fat correlated with the decrease of 24-hour mean arterial pressure and heart rate acrophases (both P<0.05). There were no differences in changes of blood pressure and heart rate rhythms between patients who achieved or did not achieve normotension and regression of left ventricular mass and carotid intima-media thickness. It was concluded that abnormal cardiovascular rhythmicity persists in children with primary hypertension despite effective antihypertensive treatment, which suggests that it may be the primary abnormality. The correlation between changes in cardiovascular rhythmicity and visceral obesity may indicate that the visceral fat plays an important role in the sympathetic activity of adolescents with hypertension.

Health Outcomes of Continuous Positive Airway Pressure versus Oral Appliance Treatment for Obstructive Sleep Apnea

Continuous positive airway pressure (CPAP) and mandibular advancement device (MAD) therapy are commonly used to treat obstructive sleep apnea (OSA). Differences in efficacy and compliance of these treatments are likely to influence improvements in health outcomes. To compare health effects after 1 month of optimal CPAP and MAD therapy in OSA. In this randomized crossover trial, we compared the effects of 1 month each of CPAP and MAD treatment on cardiovascular and neurobehavioral outcomes. Cardiovascular (24-h blood pressure, arterial stiffness), neurobehavioral (subjective sleepiness, driving simulator performance), and quality of life (Functional Outcomes of Sleep Questionnaire, Short Form-36) were compared between treatments. Our primary outcome was 24-hour mean arterial pressure. A total of 126 patients with moderate-severe OSA (apnea hypopnea index [AHI], 25.6 [SD 12.3]) were randomly assigned to a treatment order and 108 completed the trial with both devices. CPAP was more efficacious than MAD in reducing AHI (CPAP AHI, 4.5 ± 6.6/h; MAD AHI, 11.1 ± 12.1/h; P < 0.01) but reported compliance was higher on MAD (MAD, 6.50 ± 1.3 h per night vs. CPAP, 5.20 ± 2 h per night; P < 0.00001). The 24-hour mean arterial pressure was not inferior on treatment with MAD compared with CPAP (CPAP-MAD difference, 0.2 mm Hg [95% confidence interval, -0.7 to 1.1]); however, overall, neither treatment improved blood pressure. In contrast, sleepiness, driving simulator performance, and disease-specific quality of life improved on both treatments by similar amounts, although MAD was superior to CPAP for improving four general quality-of-life domains. Important health outcomes were similar after 1 month of optimal MAD and CPAP treatment in patients with moderate-severe OSA. The results may be explained by greater efficacy of CPAP being offset by inferior compliance relative to MAD, resulting in similar effectiveness. Clinical trial registered with https://www.anzctr.org.au (ACTRN 12607000289415).

Deoxycorticosterone acetate (DOCA)‐salt exacerbates hypertension and vascular dysfunction in mice expressing dominant negative Peroxisome Proliferator‐Activated Receptor‐gamma (PPARG) in smooth muscle

PPARG, a ligand‐activated transcription factor plays a critical role in regulation of blood pressure and vascular function. We hypothesized that smooth muscle PPARG protects against hypertension and resistance vessel dysfunction. Mice expressing dominant negative PPARG (S‐P467L) in smooth muscle or non‐transgenic control (NT) were implanted with DOCA‐salt and allowed ad lib. 0.15 M NaCl for 21 days in addition to chow and tap water. Blood pressure was monitored by telemetry and mesenteric arterial function was assessed by pressurized myograph. At baseline, 24‐hour mean arterial pressure (MAP) was similar between NT and S‐P467L mice, while the transgenic mice were tachycardic. DOCA‐salt increased MAP in all animals, but S‐P467L mice exhibited increased sensitivity (Δ mmHg; S‐P467L n=5, +34.2±7.3 p=0.003 vs baseline; NT n=3, +15.0±8.5 p=0.152 vs baseline). Heart rate was similarly decreased in both groups after DOCA‐salt. Vasorelaxation to acetylcholine was impaired in S‐P467L mesenteric arteries compared to NT at baseline and this effect was further exaggerated after DOCA salt. Vasopressin‐induced constriction was significantly reduced in S‐P467L compared to NT arteries after DOCA‐salt, but the response to KCl and endothelin‐1 did not differ between groups. We conclude that impaired smooth muscle PPARG sensitizes the effects of DOCA‐salt induced hypertension and vascular dysfunction.

Altered Genes Profile of Renin–Angiotensin System, Immune System, and Adipokines Receptors in Leukocytes of Children With Primary Hypertension

Renin-angiotensin system, metabolic abnormalities, and immune activity have a role in the pathogenesis of primary hypertension. We assessed the leukocyte mRNA expression of angiotensinogen, angiotensin converting enzyme, renin, angiotensin 2 type 1 receptor, CD14 molecule, adiponectin type 1 receptor, and leptin receptor in hypertensive children before and after nonpharmacological treatment. Leukocyte mRNA expression was measured by means of quantitative real-time reverse transcriptase-polymerase chain reaction in 23 hypertensive children before and after 6 months of nonpharmacological treatment based on dietary advice and physical activities. Twenty-three normotensive children matched for age, sex, and body mass index served as a control group. Before treatment patients had elevated expression of angiotensin converting enzyme and CD14 mRNA, decreased expression of angiotensinogen and angiotensin type 1 receptor mRNA, and unchanged expression of renin, adiponectin, and leptin receptors mRNA as compared with controls. Renin mRNA negatively correlated with 24-hour mean arterial pressure and carotid intima-media thickness. Six months of nonpharmacological treatment caused decrease of blood pressure and normalization of metabolic abnormalities. Renin, adiponectin, and leptin receptors mRNA expression decreased and were lower than in control group. Changes in blood pressure, left ventricular mass, carotid intima-media thickness, body mass index, and waist circumference did not correlate with changes in the expression of renin-angiotensin system genes, CD14, leptin, and adiponectin receptors mRNA. We conclude that leukocytes of hypertensive children displayed alterations in the expression of renin-angiotensin system genes as well as those of CD14. Nonpharmacological treatment resulted in downregulation of genes involved in renin-angiotensin activation and those engaged in leukocyte responses to adipokines.

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Introduction: To determine the BP values associated with worse outcomes in hypertensive (HTN) and non-hypertensive (N) critically-ill patients. Hypothesis: The threshold at which low blood pressure becomes associated with worse clinical outcomes will be higher for those with pre-existing hypertension than those without. Methods: We conducted a retrospective observational study of all adult patients admitted through the emergency department to the intensive care unit (ICU) between July 2003 and March 2010 entered in the project IMPACT Database. We analyzed the associations between lowest systolic blood pressure (SBP) and mean arterial pressure (MAP) in the first 24 hours and the combined outcome of in-hospital death or need for vasopressors (DOV). We used Chi-squared and multivariate regression analysis. Results: 3446 subjects were included. Mean age was 58 (± 17.7) years old. There were 47.8% female, 41% of Caucasian race, 17.3% CHF, 13.4% CKD, 14.8 % COPD, 33.1% DM, and 55.9% HTN. 604 (17.5%) died in the hospital, 786 (22.8%) needed vasopressors, and 1034 (30%) DOV. Mean low SBP was 95[83-109] and MAP 68[60-78]. We divided those variables into the following quartiles: SBP (I-IV): <84; 84-95; 96-109; >110 and MAP (I-IV): <61;61-68; 69-78; >78 quartiles. In the population as a whole, DOV was 62 %, 28.7%, 15.2% and 10.5% in the SBP I-IV quartiles and 61%, 27.7%, 16%, and 11.2% in the MAP I-IV quartiles, respectively. After performing univariate and multivariate analysis we found that SBP I –II, and MAP I and II were significantly associated with DOV in both hypertensive and non hypertensive subjects (all P<0.001). SBP III and MAP III, however, were significantly associated with DOV only in hypertensive subjects. Conclusions: We found that a 24-hour low SBP between 96-109 mm Hg and 24-hour low MAP between 69-78 mm Hg were significantly associated with worse outcomes in hypertensive subjects, but not in non-hypertensive subjects. These findings should be examined by prospective trials and if confirmed trigger a new definition for shock in critically ill subjects depending on HTN history.

Air-Pollution and Cardiometabolic Diseases (AIRCMD): A prospective study investigating the impact of air pollution exposure and propensity for type II diabetes

There is a paucity of prospective cohort studies investigating the impact of environmental factors on the development of cardiometabolic (CM) disorders like type II diabetes (T2DM). The objective of the Air-Pollution and Cardiometabolic Diseases (AIRCMD) study is to investigate the impact of personal level air pollution measures [personal black carbon (BC)/sulfate measures] and ambient fine particulate matter [(PM2.5)/NO2] levels on propensity to type II diabetes in Beijing, China. Subjects with metabolic syndrome will undergo four repeated study visits within each season over a one year period following an initial screening visit. At each study visit, subjects will be monitored for sub-acute exposure to personal and ambient measures of air-pollution exposure and will undergo a series of functional CM outcomes. The primary endpoints include independent associations between integrated 5-day mean exposure to PM2.5 and BC and homeostasis model assessment of insulin resistance (HOMA-IR) measures, 24-hour mean diastolic and mean arterial pressure and endothelial-dependent vasodilatation. The secondary endpoints will explore the mechanistic explanation for a causal relationship between exposures and propensity for type II diabetes and will include additional functional outcomes such as arterial compliance, heart rate variability and plasma adipokines. The novel aspects of the study include the launch of infrastructure for future translational investigations in highly polluted urbanized environments and the creation of novel methodologies for linking personalized exposure measurements with functional CM outcomes. We believe that AIRCMD will allow for unprecedented new investigations into the association between environmental risk factors and CM disorders.

Sex Differences in the Pressor and Tubuloglomerular Feedback Response to Angiotensin II

Awareness of sex differences in the pathology of cardiovascular disease is increasing. Previously, we have shown a role for the angiotensin type 2 receptor (AT(2)R) in the sex differences in the arterial pressure response to Ang II. Tubuloglomerular feedback (TGF) contributes in setting pressure-natriuresis properties, and its responsiveness is closely coupled to renal Ang II levels. We hypothesize that, in females, the attenuated pressor response to Ang II is mediated via an enhanced AT(2)R mechanism that, in part, offsets Ang II-induced sensitization of the TGF mechanism. Mean arterial pressure was measured via telemetry in male and female wild-type (WT) and AT(2)R knockout (AT(2)R-KO) mice receiving Ang II (600 ng/kg per minute SC). Basal 24-hour mean arterial pressure did not differ among the 4 groups. After 10 days of Ang II infusion, mean arterial pressure increased in the male WT (28±6 mm Hg), male AT(2)R-KO (26±2 mm Hg), and female AT(2)R-KO (26±4 mm Hg) mice, however, the response was attenuated in female WT mice (12±4 mm Hg; P between sex and genotype=0.016). TGF characteristics were determined before and during acute subpressor Ang II infusion (100 ng/kg per minute IV). Basal TGF responses did not differ between groups. The expected increase in maximal change in stop-flow pressure and enhancement of TGF sensitivity in response to Ang II was observed in the male WT, male AT(2)R-KO, and female AT(2)R-KO but not in the female WT mice (P between sex and genotype <0.05; both). In conclusion, these data indicate that an enhanced AT(2)R-mediated pathway counterbalances the hypertensive effects of Ang II and attenuates the Ang II-dependent resetting of TGF activity in females. Thus, the enhancement of the AT(2)R may, in part, underlie the protection that premenopausal women demonstrate against cardiovascular disease.

Haptoglobin Phenotype Correlates with the Extent of Cerebral Deep White Matter Lesions in Hypertensive Patients

Cerebral white matter lesions (WMLs), due to small vessel disease, can be regarded as an early "silent" sign of hypertensive cerebral end-organ damage. As haptoglobin (Hp) phenotype has earlier been associated with symptomatic vascular disease, we now examined the relationship between Hp phenotype and asymptomatic cerebral small vessel disease, manifested by deep and periventricular WMLs, in hypertensive patients. We determined Hp phenotype using starch gel electrophoresis in 152 hypertensive patients without symptomatic vascular disease. We found 26 (17.1%) Hp1-1, 89 (58.6%) Hp2-1 and 37 (24.3%) Hp2-2. Volumes of deep and periventricular WMLs were quantitatively measured on brain MR images. Patients were ranked in 5 categories according to ascending WMLs volumes. Compared to Hp2-2, Hp1-1 was associated with larger deep WMLs volumes when adjusted for age, gender, brain volume, 24-hour mean arterial pressure, duration of hypertension and previous antihypertensive treatment (ordinal regression analysis, OR 2.77, 95%CI 1.08-7.11, p=0.034). No association was found between Hp phenotype and periventricular WMLs. Hp1-1 phenotype correlates with the extent of hypertensive deep white matter damage. One of the possibilities is that this is related to lower regenerating power against endothelial injury in Hp1-1 individuals.

Comparison of Candesartan Versus Metoprolol for Treatment of Systemic Hypertension After Repaired Aortic Coarctation

Even after successful repair, hypertension is one of the main determinants of cardiovascular morbidity and mortality in patients with aortic coarctation (CoA). We compared the effect of candesartan (angiotensin II receptor blockade) and metoprolol (beta-adrenergic receptor blockade) on blood pressure, large artery stiffness, and neurohormonal status in hypertensive patients after repair of CoA. In the present open-label, crossover study, hypertensive patients after CoA repair were first randomly assigned to treatment with candesartan 8 mg or metoprolol 100 mg once per day. After 8 weeks of treatment with one of the drugs, the other treatment was given for 8 weeks. The treatment effects were assessed with 24-hour ambulatory blood pressure monitoring, measurement of large artery stiffness, and neurohormonal plasma levels at baseline and after 8 weeks of either treatment. Sixteen patients (mean age 37 +/- 12 years, 26 +/- 15 years after repair, 63% men) completed the study. The 24-hour mean arterial pressure at baseline was 97.7 +/- 6.2 mm Hg. Metoprolol (mean dose 163 +/- 50 mg/day) decreased the mean arterial pressure (7.0 +/- 4.2 and 4.1 +/- 3.6 mm Hg, respectively) more than did candesartan (mean dose 13 +/- 4 mg/day; p = 0.018, 95% confidence interval 0.6 to 5.5). Large artery stiffness did not change with either treatment. With metoprolol, plasma B-type natriuretic peptide increased and plasma renin decreased. With candesartan, the plasma renin and noradrenaline levels increased and aldosterone levels decreased. In conclusion, in adult hypertensive patients after CoA repair, metoprolol had more of an antihypertensive effect than did candesartan. Moreover, the neurohormonal outcome did not support a significant role for the renin-angiotensin system in the causative mechanism of hypertension after CoA.

A Diet and Exercise Program to Improve Clinical Outcomes in Patients with Obstructive Sleep Apnea – A Feasibility Study

To assess the feasibility and efficacy of a novel 16-week exercise and diet program for important clinical outcomes in obstructive sleep apnea (OSA). Cohort study assessing sleep disordered breathing, cardiovascular risk factors, and neurobehavioral function prior to and following completion of the 16-week program. The program used a proprietary very low energy diet (Optifast, Novartis), and subjects participated in a supervised exercise schedule, which included both aerobic and resistance training. Follow-up contact was made at 12 months after program exit. Consecutive patients with newly diagnosed sleep apnea were approached who had an apnea-hypopnea index (AHI) of 10 to 50, a body mass index (BMI) of greater than 30 kg/m2, no significant comorbidities, and able to exercise. All data are presented as mean [SD]. Of 21 patients with OSA who were approached, 12 middle-aged (42.3 [10.4] years old), obese (BMI 36.1 [4.3] kg/m2), and predominantly female (75%) subjects with mild to moderate OSA were enrolled (AHI 24.6 [12.0]). Weight loss was significant (12.3 [9.6] kg, p <0.001), and 5 of the 10 who completed the program were able to independently maintain good weight loss at 12 months. At the 16-week assessment, there was a small nonsignificant fall in the AHI. Six of the 10 subjects had a reduction in sleep disordered breathing, and the AHI was less than 10 in 3 patients. There were significant improvements in neurobehavioral and cardiometabolic outcomes. Snoring improved in most subjects, but the improvement was clinically important (a score of < 2) in only 7. A supportive diet and exercise program may be of benefit to obese patients with mild to moderate sleep apnea. The results of this feasibility study showed significant weight loss and improvement in clinically important neurobehavioral and cardiometabolic outcomes but no significant change in sleep disordered breathing. These promising preliminary results need confirmation with a larger randomized trial.

Twenty-four Hour Ocular Perfusion Pressure Fluctuation and Risk of Normal-Tension Glaucoma Progression

To investigate the relationship between clinical factors including 24-hour mean ocular perfusion pressure (MOPP, (2/3) x mean arterial pressure [MAP] - intraocular pressure [IOP]) and visual field (VF) progression in eyes with medically treated normal-tension glaucoma (NTG). One hundred one eyes of 101 NTG patients followed up for more than 4 years (mean follow-up, 6.2 years +/- 12.1 months) were included after retrospective chart review. Several clinical factors including demographic, systemic, ocular risk factors, and 24-hour MOPP were explored for associations with decreasing VF. Kaplan-Meier analyses were performed to compare outcomes with reference to four risk factors (age, myopia, and elevated MAP and MOPP fluctuation) for VF deterioration. Hazard ratios (HRs) for the association between potential risk factors and glaucoma progression were obtained using Cox proportional hazards models. Overall VF progression was detected in 29 (28.7%) eyes. There were significant differences between progressors and nonprogressors in nocturnal MAP and MOPP fluctuations (both P < 0.0001), 24-hour MAP, and MOPP fluctuations (both P < 0.0001), initial mean deviation (P = 0.0034), and pattern standard deviation (PSD) score (P < 0.0001). Both elevated 24-hour MAP and MOPP fluctuations were associated with greater VF progression probabilities based on Kaplan-Meier analyses. Among all risk factors investigated, the Cox proportional hazards model indicated that VF progression was significantly associated with 24-hour MOPP fluctuation and initial PSD score. Clinical factors other than IOP were associated with VF progression in our series of medically treated NTG eyes. Twenty-four-hour MOPP fluctuation was the most consistent prognostic factor for glaucoma progression.