Increased Blood Pressure Variability Research Articles

Increased Blood Pressure Variability Is Associated with Worse Neurologic Outcome in Acute Anterior Circulation Ischemic Stroke.

Background. Although research suggests that blood pressure variability (BPV) is detrimental in the weeks to months after acute ischemic stroke, it has not been adequately studied in the acute setting. Methods. We reviewed acute ischemic stroke patients from 2007 to 2014 with anterior circulation stroke. Mean blood pressure and three BPV indices (standard deviation, coefficient of variation, and successive variation) for the intervals 0–24, 0–72, and 0–120 hours after admission were correlated with follow-up modified Rankin Scale (mRS) in ordinal logistic regression models. The correlation between BPV and mRS was further analyzed by terciles of clinically informative stratifications. Results. Two hundred and fifteen patients met inclusion criteria. At all time intervals, increased systolic BPV was associated with higher mRS, but the relationship was not significant for diastolic BPV or mean blood pressure. This association was strongest in patients with proximal stroke parent artery vessel occlusion and lower mean blood pressure. Conclusion. Increased early systolic BPV is associated with worse neurologic outcome after ischemic stroke. This association is strongest in patients with lower mean blood pressure and proximal vessel occlusion, often despite endovascular or thrombolytic therapy. This hypothesis-generating dataset suggests potential benefit for interventions aimed at reducing BPV in this patient population.

Impact of Renal Denervation on Patients With Obstructive Sleep Apnea and Resistant Hypertension - Insights From the SYMPLICITY HTN-3 Trial.

Obstructive sleep apnea (OSA) is associated with activation of the sympathetic nervous system, and patients with this condition often experience elevated blood pressure (BP), increased BP variability, and nocturnal BP surges. The SYMPLICITY HTN-3 trial was a large prospective, randomized, blinded, sham-controlled trial of renal denervation for treatment of uncontrolled, apparently treatment-resistant hypertension. In a post hoc analysis, we examined the effect of renal denervation vs. sham control on office and ambulatory (including nocturnal) systolic BP in patients with and without OSA. 26% (94/364) of renal denervation subjects and 32% (54/171) of sham control subjects had OSA. Baseline office and nighttime systolic BP values were similar in both arms, including in subjects with and without OSA. Compared with sham control, renal denervation reduced the 6-month office systolic BP in subjects with (-17.0±22.4 vs. -6.3±26.1 mmHg, P=0.01) but not in subjects without OSA (-14.7±24.5 vs. -13.4±26.4 mmHg, P=0.64), P=0.07 for the interaction between treatment arm and OSA status. In those with sleep apnea, renal denervation was also associated with a reduction in maximum (-4.8±21.8 vs. 4.5±24.6 mmHg, P=0.03) and average peak (-5.6±20.4 vs. 3.2±22.4 mmHg, P=0.02) nighttime systolic BP. OSA subjects appeared to be responsive to renal denervation therapy. However, this hypothesis requires prospective testing. (Circ J 2016; 80: 1404-1412).

Bilateral Renal Denervation Ameliorates Isoproterenol-Induced Heart Failure through Downregulation of the Brain Renin-Angiotensin System and Inflammation in Rat.

Heart failure (HF) is characterized by cardiac dysfunction along with autonomic unbalance that is associated with increased renin-angiotensin system (RAS) activity and elevated levels of proinflammatory cytokines (PICs). Renal denervation (RD) has been shown to improve cardiac function in HF, but the protective mechanisms remain unclear. The present study tested the hypothesis that RD ameliorates isoproterenol- (ISO-) induced HF through regulation of brain RAS and PICs. Chronic ISO infusion resulted in remarked decrease in blood pressure (BP) and increase in heart rate and cardiac dysfunction, which was accompanied by increased BP variability and decreased baroreflex sensitivity and HR variability. Most of these adverse effects of ISO on cardiac and autonomic function were reversed by RD. Furthermore, ISO upregulated mRNA and protein expressions of several components of the RAS and PICs in the lamina terminalis and hypothalamic paraventricular nucleus, two forebrain nuclei involved in cardiovascular regulations. RD significantly inhibited the upregulation of these genes. Either intracerebroventricular AT1-R antagonist, irbesartan, or TNF-α inhibitor, etanercept, mimicked the beneficial actions of RD in the ISO-induced HF. The results suggest that the RD restores autonomic balance and ameliorates ISO-induced HF and that the downregulated RAS and PICs in the brain contribute to these beneficial effects of RD.

THE RELATIONSHIP BETWEEN BLOOD PRESSURE VARIABILITY AND CARDIOVASCULAR REMODELING IN HYPERTENSION DEVELOPED IN THE ELDERLY

Background. The prevalence of arterial hypertension (HTN) increases with age, but the causes of HTN in elderly and young age are different. The contribution of the specific parameters of high blood pressure (BP) in the pathogenesis of organ damage in the elderly has not been studied enough. Objective. We assessed the effect of BP variability (BPV) on left ventricular (LV) remodeling and vascular stiffness in patients with HTN developed at age before and over 65 years. design and methods. Altogether 122 elderly patients were enrolled and divided into 3 groups: group 1–45 patients with newly diagnosed HTN 1–2 degree at the age over 65 years (21 males, 24 females, the average age — 71,7 ± 2,6 years), group 2–39 subjects with newly diagnosed HTN 1–2 degree under 65 years old (18 males, 21 females, the average age — 68,4 ± 2,4 years). The 3rd control group, comprised 38 elderly subjects without HTN (20 males, 18 females, the average age — 67,5 ± 2,0 years). At baseline, none of the patients achieved target BP. At admission to the hospital, two-component antihypertensive therapy was prescribed to all patients, it included a blocker of the renin-angiotensine-aldosterone system (RAAS) — an angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist) and calcium channel blocker (amlodipine in all cases). Short-term BPV was assessed by ambulatory BP monitoring (ABPM), medium-term BPV — based on the BP monitoring for 7 days, and long-term BPV — based on the 3-month self-monitoring of BP. Central aortic pressure was also measured. LV myocardial mass index and LV relative wall thickness (2T/DD) were assessed by 2D-echocardiography, and early diastolic flow velocities E, A and the ratio E/A were evaluated by spectral Doppler. Pulse wave velocity, cardio-ankle vascular index (R-CAVI and L–CAVI), ankle-brachial index (ABI) and the biological arterial age were assessed by sphygmomanometry. Results. Increased BPV seems to be an indicator in elderly, as elderly patients without HTN show increased SBP and DBP short-term variability. However, the maximum rate of BPV increase was found in patients with the HTN development in the age over 65 years. In the same group, the correlation between BPV and LV and vascular remodeling was the most severe. The increase in visit-to-visit DBP variability had the greatest impact on the arterial wall stiffness, while visit-tovisit SBP variability affected LV remodeling. The increase in the mediumand long-term BPV was found to be a more powerful predictor of cardiovascular remodeling compared to the increase in short-term BPV assessed by ABPM. Thus, arterial stiffness may be an important factor leading to the increase in both short-term and longterm BPV. Conclusions. BPV measurement should be widely implemented for the assessment of cardiovascular risk and the overall effectiveness of antihypertensive therapy.

Orthostatic stress causes immediately increased blood pressure variability in women with vasovagal syncope

The cardiovascular and respiratory autonomic nervous regulation has been studied mainly by hemodynamic responses during different physical stressors. In this study, dynamics of autonomic response to an orthostatic challenge was investigated by hemodynamic variables and by diverse linear and nonlinear indices calculated from time series of beat-to-beat intervals (BBI), respiratory cycle duration (RESP), systolic (SYS) and diastolic (DIA) blood pressure. This study included 16 young female patients (SYN) with vasovagal syncope and 12 age-matched female controls (CON). The subjects were enrolled in a head-up tilt (HUT) test, breathing normally, including 5min of baseline (BL, supine position) and 18min of 70° orthostatic phase (OP). To increase the time resolution of the analysis the time series were segmented in five-minute overlapping windows with a shift of 1min. Hemodynamic parameters did not show any statistical differences between SYN and CON. Time domain linear analysis revealed increased respiratory frequency and increased blood pressure variability (BPV) in patients during OP meaning increased sympathetic activity and vagal withdrawal. Frequency domain analysis confirmed a predominance of sympathetic tone by steadily increased values of low over high frequency power in BBI and of low frequency power in SYS and DIA in patients during OP. The nonlinear analysis by symbolic dynamics seemed to be highly suitable for differentiation of SYN and CON in the early beginning of OP, i.e., 5min after tilt-up. In particular the index SYS_plvar3 showed less patterns of low variability in patients reflecting a steadily increase in both BPV and sympathetic activity. The proposed dynamical analysis could lead to a better understanding of the temporal underlying mechanisms in healthy subjects and patients under orthostatic stress.

Abstract 16967: Increased Blood Pressure Variability is Associated With Worse Outcome in Acute Ischemic Stroke

Background: Increased blood pressure variability (BPV) is detrimental in the weeks to months after ischemic stroke, but it has not been adequately studied in the acute phase. We hypothesized that increased BPV in acute ischemic stroke (AIS) patients would be associated with worse outcome. Methods: We retrospectively reviewed inpatients at our hospital between 2010-2014 with an ICD-9 code of AIS; 213 were confirmed to have AIS by a vascular neurologist. A modified Rankin Score (mRS) after discharge was available in 148/213, at a mean of 86 ± 60 days. In 45/213 the discharge mRS was either 0 or 6, in which case they were included in the final analysis. BPV was measured as the standard deviation (SD) of each patient’s systolic blood pressure readings during the first 24 hours and 5 days of hospitalization (9,844 total readings), or until discharge if discharged in <5 days (Figure 1). The SBP SD was further divided in quartiles. A multivariate ordinal logistic regression with the outcome of mRS, the primary predictor of quartiles of SBP SD, and baseline NIH stroke scale (NIHSS) to control for initial stroke severity. Results: Mean±SD age was 64.2 ± 16.3 years, NIHSS was 12.6 ± 7.9, and mRS was 2.7 ± 2.1. The mean SBP SDs for the first 24 hours and 5 days were 12.1 ± 6.2 mm Hg and 14.1 ± 4.9 mm Hg. In the ordinal logistic regression model, the quartiles of SBP SD for the first 24 hours and 5 days were positively associated with higher mRS (OR = 1.37, 95% CI 1.01 - 1.74, p = 0.009; OR = 1.30, 95% CI 1.03 - 1.63, p = 0.028). This effect became even more pronounced in patients with the highest quartile of variability (OR = 2.76, 95% CI 1.29 - 5.88, p = 0.009; OR = 2.10, 95% CI 1.01 - 4.36, p = 0.046). Conclusion: In our cohort of 193 patients with AIS, there was a significant association between increased systolic BPV and worse functional outcome, after controlling for initial stroke severity. This data suggests that increased BPV may have a harmful effect for AIS patients, which warrants a prospective observational study.

Abstract 15410: ACE Gene Dosage Influences the Magnitude of Blood Pressure Increase After Chronic High Fructose Intake: Role of Resistance Arteries

We investigated the mechanisms involved in blood pressure (BP) increase induced by chronic high fructose (F) intake and its association with angiotensin converting enzyme (ACE) dosage. Male mice harbouring 1, 2 or 3 copies of the ACE gene received F (100g/l) or tap water (C) for 8 weeks. Glucose tolerance and BP were evaluated. BP variability was analyzed in frequency domain. Mesenteric resistance artery reactivity to noradrenaline (Nor; 0.1nM - 1μM), and acetylcholine (Ach; 1nM - 10μM, after or not L-NAME incubation, 100 μM) were studied in an isometric myograph (DMT, 620M). Glucose intolerance was seen in all F groups vs. C (1 copy: 100+3 vs. F=198+5; 2 copies: 121+4 vs. F=201+8; 3 copies: 86+4 vs. F=212+5 mg/dl at the 120thmin after 1.5 g/Kg ip glucose overload). Systolic BP increased in all F-fed mice (mean C=112+2; F:1 copy=119+3, 2 copies=123+2, 3 copies=129+2 mmHg), with a significant augment in 3-copy group vs. 1 and 2-copy mice. Not only BP variability (1 copy: 39+3 vs. F=57+2; 2 copies: 38+2 vs. F=59+3; 3 copies: 40+3 vs. F=73+7 mmHg 2 ) but also its sympathetic component (LF; 1 copy: 5+1 vs. F=12+3; 2 copies: 6+2 vs. F=19+3; 3 copies: 7+2 vs. F=31+5 %) increased in all F groups, with a more pronounced augment in 3-copy mice vs. 1 and 2. Moreover, F-fed 3-copy mice reactivity to Nor was superior than the other groups (1 copy: 170+5; 2 copies: 190+7; 3 copies: 214+10 %) while Ach-induced relaxation was more reduced in 3-copy mice than 1 and 2 (mean C: 76+5%; F: 1 copy=58+8, 2 copies=47+6, 3 copies=36+5 %). L-NAME in F-fed groups significantly blocked ~95% of Ach relaxation in 3-copy mice vs. 75 and 82% in 1 and 2-copy mice, respectively. Additionally, BP variability was negatively correlated to Ach maximal relaxation (r 2 =0.75) and positively correlated to Nor maximal constriction (r 2 =0.78) while glucose levels in the tolerance test were also negatively correlated to Ach maximal relaxation (r 2 =0.72) and positively correlated to Nor maximal constriction (r 2 =0.9). In conclusion, F-induced BP increase is influenced by ACE levels in mice. Increased BP variability and glucose intolerance are highly associated with microvascular dysfunction.

Plasma copeptin levels and ambulatory blood pressure characteristics in healthy adults.

We investigated whether copeptin - a well characterized vasopressin-related stress hormone - is associated with circadian ambulatory blood pressure (BP) variability and/or mean BP levels in young adults. We studied a population-based sample of healthy adults aged 25-41 years. Individuals with diabetes, treated hypertension, and cardiovascular disease were excluded. Ambulatory 24-h BP monitoring was performed using validated devices. To evaluate the relationships of copeptin with mean ambulatory BP levels and BP variability during daytime and night-time, multivariable adjusted regression models were constructed. BP variability was defined as SD of all intraindividual BP values. Of the 2012 individuals included in this study, 53% were women and the median age was 37 years. Median plasma copeptin levels were 3.9 (interquartile range 2.7, 5.8) in men and 2.3 pmol/l (interquartile range 1.6, 3.6) in women (P < 0.0001). In multivariable linear regression models, log-transformed copeptin was significantly associated with systolic and diastolic night-time BP levels among men [β = 1.9, 95% confidence interval (CI) 0.6, 3.1, P = 0.003; and β = 1.4, 95% CI 0.6, 2.3, P = 0.001, respectively], but not among women. In addition, copeptin was strongly associated with an increased systolic and diastolic daytime (β = 0.5, 95% CI 0.2, 0.7, P = 0.001; β = 0.5, 95% CI 0.3, 0.8, P < 0.0001, respectively) and night-time BP variability (β = 0.6, 95% CI 0.3, 0.9, P = 0.0002; β = 0.4, 95% CI 0.2, 0.7, P = 0.002, respectively). In this large population-based study of young and healthy adults, plasma levels of copeptin were significantly associated with an increased BP variability in both sexes and an elevated night-time BP among men.

Effects of Chronic Carvedilol Administration on Blood Pressure Variability and Target Organ Injury in Rats with Sinoaortic Denervation

Background: Increased blood pressure variability is a novel risk factor for the development of target organ injury both inhypertensive and normotensive subjects, so its reduction should be considered as a new therapeutic goal.Objective: The aim of this study was to evaluate the effect of long-term oral carvedilol treatment on blood pressure, bloodpressure variability and target organ injury in the left ventricle and thoracic aorta in a model of blood pressure liability.Methods: Twelve male Wistar rats submitted to sinoaortic denervation were treated during 8 weeks with a single dose ofcarvedilol 30 mg/kg or vehicle. At the end of treatment, echocardiographic evaluation and blood pressure and short-term variabilitymeasurements were performed. Left ventricular and thoracic aortic weights were determined and histological sampleswere prepared from both tissues. Metalloproteinase MMP-2 and transforming growth factor b (TGF-b) were quantified in theleft ventricle and thoracic aorta.Results: Carvedilol reduced systolic blood pressure and its variability in sinoaortic-denervated rats compared with the controlgroup (126±5 vs. 142±11 mmHg, p<0.05; SD: 2.9±0.5 vs. 6.0±0.5 mmHg; p<0.05). A lower amount of connective tissue wasfound in carvedilol-treated animals. The expression of TGF-b decreased in both organs after carvedilol treatment.Conclusions: Chronic carvedilol treatment significantly reduces systolic blood pressure and its short-term variability insinoaortic-denervated rats, decreasing the degree of left ventricular fibrosis.

Effect of Renal Disease on Ambulatory Blood Pressure Monitoring

Background: Chronic renal disease is a growing public health problem, not only for its progression to end-stage renal failurebut for its close association with cardiovascular disease, especially hypertension. Currently, there is scarce information onambulatory blood pressure monitoring (ABPM) in hypertensive patients with renal failure.Objective: The aim of this study was to assess ABPM pulse pressure, circadian rhythm and blood pressure variability in apopulation of hypertensive patients with renal failure.Methods: A cross-sectional study evaluated 123 consecutive ABPM performed in a Hypertension Service. The glomerularfiltration rate was estimated using the abridged formula from the “Modification of diet in renal disease” (MDRD) study.Results: A total of 123 hypertensive patients were evaluated (age 66±7.5 years, 56% men), whose glomerular filtration ratewas 64.5±19.4 ml/min/1.73m2. Thirty-seven percent of patients presented with renal failure with a glomerular filtrationrate of 45±12.5 ml/min/1.73m2 vs. 76±11.9 ml/min/1.73m2 in patients without renal failure. Fifty-five hypertensive patients(44%) had elevated pulse pressure: 28 (60.9%) with renal failure vs. 27 (35%) without renal failure (p<0.005). After adjustingfor different variables, this difference remained significant. No differences were found in blood pressure variability or in thepresence of non-dipper pattern.Conclusions: The main ABPM characteristic in hypertensive patients with renal failure was a significant increase of pulsepressure. There was no greater prevalence of non-dipper pattern or increased blood pressure variability, as classically describedfor the general population of renal disease patients.

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Background: Increased blood pressure variability is a novel risk factor for the development of target organ injury both in hypertensive and normotensive su...

PP.17.31

Objective: The effect of mean blood pressure levels on arterial stiffness development is well known; however, the role of dynamic factors as autonomic dysfunction (AD) over the pulse wave velocity (PWV) in the mid-term is still under evaluation. Objectives: a) To evaluate the contribution of home blood pressure (BP) and heart rate (HR) variability to assess arterial stiffness in essential hypertension (EH). b) To determinate if autonomic dysfunction (increased BP variability and decreased HR variability) is associated to higher PWV. Design and method: We evaluated 202 consecutive hypertensive patients who assist to be evaluated in a primary cardiovascular prevention program. All patients underwent anthropometric measurements. BP and HR were recorded through home BP monitoring/ 7 consecutive days (MicroLife®). Measurements of PWV were carried out using an automatic oscillometric device (Mobil-O-Graph®) at rest. We defined an autonomic dysfunction index (ADI) as follows: -ADI: standard deviation of systolic BP (SBP_SD)/standard deviation of HR (HR_SD) Correlations between mean systolic BP, SBP_SD, HR_SD and ADI with PWV were performed. Results: After applying exclusion criteria 120 patients with EH (135 ± 14/90 ± 10 mm Hg, 55 +/-10 years, 74% male, 107 treated) were included. Mean SBP was associated with PWV (r=0.23, p: 0.01) while SBP_SD showed a higher direct association with PWV (r = 0.32, P < 0.0003), unlike HR_SD (r = -0.20, P = 0.03). The index of autonomic dysfunction –ADI- presented the more significant association with PWV (r = 0.43, p < 0.0001).Conclusions: Home SBP variability showed a higher and direct association than mean SBP values with PWV in EH. The AD phenomenon (expressed as higher BP variability/ lesser BP variability) presented a close positive relationship with PWV, which could indicate some role of mid-term AD in the increment of PWV in essential hypertension.

PP.34.03

Objective: Several features of ambulatory (ABPM) blood pressure (BP) have been explored as potential predictors of stroke. Some studies, limited among other factors by relying on a single, low reproducible 24 h ABPM per participant, use of arbitrarily fixed clock hours to defined awake and asleep spans, and/or analysis of the prognostic value of a single unadjusted ABPM-derived parameter, have concluded that elevated morning BP surge or increased BP variability might be significant markers of stroke. We evaluated the comparative prognostic value for stroke of clinic BP and multiple ABPM-derived characteristics among the participants in the Hygia Project, designed to evaluate prospectively CVD risk by ABPM in primary care centers of Northwest Spain. Design and method: This study involved 11255 subjects, 6028 men/5227 women, 58.9 ± 14.5 years of age, with baseline BP ranging from normotension to hypertension according to ABPM criteria, prospectively evaluated throughout a 4.0-year median follow-up. BP was measured at 20-min intervals from 07:00 to 23:00 h and every 30-min at night for 48 h. During monitoring, subjects maintained a diary listing the times of going to bed and awakening. Results: We documented 147 ischemic and 29 hemorrhagic strokes. When each ABPM-derived parameter was analyzed separately, the asleep systolic BP mean was the most significant predictor of stroke (adjusted hazard ratio 1.35; 95%CI [1.20–1.52] for each 1-SD increase; P < 0.001). A greater morning BP surge was significantly associated with lower, not higher, stroke risk (0.87 [0.76–0.99], P = 0.042). After adjustment by asleep BP, neither clinic BP nor any other ABPM-derived parameter, including awake and 48 h means, sleep-time relative BP decline, morning surge, and indices of awake, asleep and 24 h BP variability, was significantly associated with increased/decreased risk of stroke. Conclusions: Progressively elevated sleep-time systolic BP was the only significant and independent prognostic marker of stroke. Contrary to current believe, neither a greater morning BP surge, morning hypertension, or extreme-dipper BP patterning increased the risk of stroke after adjusting by asleep BP level. On the basis of the null prognostic value of clinic BP here corroborated, ABPM should be considered a clinical requirement for proper stroke risk stratification.

Chronic Central Infusion of Hypertonic NaCl Increase Blood Pressure Variability and Exaggerates Sympathetic Reflexes

Recent studies indicate that dietary salt loading increases blood pressure variability (BPV) and exaggerates sympathetic reflexes in salt‐resistant animals. This effect was attributed to a central action of sodium as high salt diet increased plasma sodium concentration and lesion of the forebrain hypothalamus prevented these responses. Since dietary salt loading also affects neurohumoral systems, the present study tested whether central hypernatremia can increase BPV and exaggerate sympathetic reflexes. Sprague‐Dawley rats were implanted with telemetry units and infused with artificial cerebrospinal fluid (aCSF, n=6) or 1M NaCl (n=6, 6uL/h) for 10 days. Baseline blood pressure (BP) did not differ animals infused with 1M NaCl vs aCSF (99±3 vs 99±1 mmHg). Although mean BP did not change after 10 day infusion of 1M NaCl vs aCSF (3±1 vs ‐3±1 mmHg), the SD of 24‐h systolic BP was significantly greater in animals infused with 1M NaCl versus aCSF (9.8±1.2 vs 6.4±1.0, P&lt;0.05). Under Inactin anesthesia, stimulation of sciatic afferents (1ms, 500µA, 1‐20Hz) produced frequency‐dependent increases in renal SNA, splanchnic SNA, and mean BP in both groups. However, animals infused with 1M NaCl vs aCSF displayed significantly larger increases in renal SNA (5Hz: 91±17% vs 43±15%, P&lt;0.05), splanchnic SNA (5Hz: 111±25% vs 31±3%, P&lt;0.05), and mean BP (5Hz: 25±3 vs 15±3mmHg, P&lt;0.05). Plasma renin activity at rest was not different between groups (1M: 3.1±1.0 vs aCSF: 3.7±1.2 ng AngI/mL/min). Collectively, these findings suggest that central hypernatremia increases BPV and exaggerates sympathetic reflexes in salt‐resistant, normotensive rats.

Blood pressure variability: assessment, predictive value, and potential as a therapeutic target.

A large body of evidence has consistently supported the relationship between blood pressure (BP) levels and the risk of cardiovascular complications. In recent years, several independent studies have also indicated that this risk may not only depend on the magnitude of the blood pressure elevation per se but also on the presence of other associated conditions such as increased blood pressure variability. This concept has been supported by a series of reports, most of which post hoc analyses of clinical trials in hypertension, showing that increasing values of BP variability (BPV) (either in the short term, in the midterm, or in the long term) may predict development, progression, and severity of cardiac, vascular, and renal organ damage, as well as cardiovascular events and mortality. Remarkably, studies conducted in populations at high cardiovascular risk have shown increasing values of BPV in the individual subjects (so-called intra- or within-individual BPV) to be strong predictors of cardiovascular morbidity and mortality, even to a larger extent than average BP values. However, in subjects at low to moderate cardiovascular risk, the contribution of BPV to cardiovascular risk prediction over and beyond average BP values has been shown to be only moderate. The aim of this paper is to critically review the evidence addressing the prognostic relevance of different components of BPV addressing a yet open question, i.e., whether routine assessment of BPV in clinical practice should be regarded as an additional target of antihypertensive treatment to improve cardiovascular protection.

Indirect measures of arterial stiffness and cognitive performance in individuals without traditional vascular risk factors or disease.

Whether cognition is influenced by arterial stiffness in the absence of vascular disease remains uncertain. To test the hypotheses that indirect measures of arterial stiffness are important predictors of cognitive performance and that this relationship varies depending on the presence of vascular disease. Participants included 2573 noninstitutionalized US adults randomly selected from 2 cycles of the National Health and Nutrition Examination Survey (1999-2002). The sample was stratified by groups based on the presence (VASC+) vs the absence (VASC-) of vascular variables negatively associated with cognition to assess the effects of indirect measures of arterial stiffness on cognitive performance. We used logistic regression to obtain odds ratios (ORs) and their 95% CIs. P < .05 was considered statistically significant. The Digit Symbol Substitution Test score was used as a continuous variable, and the lowest quintile was designated as an indicator of poorer cognitive performance. In the VASC+ group, poorer cognitive performance was more likely with increasing age (OR, 1.12 [95% CI, 1.08-1.17]; P < .001), a sedentary lifestyle (OR, 2.99 [95% CI, 1.62-5.55]; P = .002), and the use of dihydropyridine calcium channel blockers (OR, 9.24 [95% CI, 1.35-63.23]; P = .02). Poorer cognitive performance in the VASC+ group was less likely in women (OR, 0.37 [95% CI, 0.18-0.72]; P = .02), non-Hispanic white individuals (OR, 0.16 [95% CI, 0.09-0.26]; P < .001), those with higher educational attainment (OR, 0.23 [95% CI, 0.14-0.38]; P < .001), those with higher income levels (OR, 0.56 [95% CI, 0.72-0.76]; P < .001), and those who used renin-angiotensin system blockers (OR, 0.24 [95% CI, 0.07-0.79]; P = .02). In the VASC- group, the most important significant predictors of poorer cognitive performance were an ankle brachial index greater than 1.30 (OR, 18.56 [95% CI, 2.94-117.05]; P = .002) and increased blood pressure variability (OR, 3.49 [95% CI, 1.07-11.35]; P = .04). Among participants in the VASC- group who had both of these variables, the prevalence of poorer cognitive performance was greater (β = 16.65; P < .001). Two indirect measures of arterial stiffness, an ankle brachial index greater than 1.30 and increased blood pressure variability, are associated with poorer cognitive performance among adults 60 years or older without clinical atherosclerotic disease. Among those with vascular disease, factors capable of influencing arterial stiffness, such as exercise and the use of renin-angiotensin system blockers, may be protective against poorer cognitive performance.

Molecular mechanism of aggravation of hypertensive organ damages by short-term blood pressure variability.

There is increasing evidence that not only the elevation of systolic and diastolic blood pressure (BP) but also the increase in BP variability (or fluctuation) are associated with hypertensive organ damages and the morbidity and mortality of cerebrovascular and cardiovascular events. However, the molecular mechanism whereby the increase in BP variability aggravates hypertensive organ damages remains unknown. Thus, we created a rat chronic model of a combination of hypertension and large BP variability by performing bilateral sino-aortic denervation in spontaneously hypertensive rat. A series of our studies using this model revealed that large BP variability induces chronic myocardial inflammation by activating local angiotensin II and mineralocorticoid receptor systems and thereby aggravates cardiac hypertrophy and myocardial fibrosis, leading to systolic dysfunction, in hypertensive hearts. In addition, large BP variability induces the aggravation of arteriolosclerotic changes and ischemic cortical fibrosis in hypertensive kidney via local angiotensin II system.

Relationship between cerebral blood flow and blood pressure in long-term heart transplant recipients.

Heart transplant recipients are at an increased risk for cerebral hemorrhage and ischemic stroke; yet, the exact mechanism for this derangement remains unclear. We hypothesized that alterations in cerebrovascular regulation is principally involved. To test this hypothesis, we studied cerebral pressure-flow dynamics in 8 clinically stable male heart transplant recipients (62±8 years of age and 9±7 years post transplant, mean±SD), 9 male age-matched controls (63±8 years), and 10 male donor controls (27±5 years). To increase blood pressure variability and improve assessment of the pressure-flow dynamics, subjects performed squat-stand maneuvers at 0.05 and 0.10 Hz. Beat-to-beat blood pressure, middle cerebral artery velocity, and end-tidal carbon dioxide were continuously measured during 5 minutes of seated rest and throughout the squat-stand maneuvers. Cardiac baroreceptor sensitivity gain and cerebral pressure-flow responses were assessed with linear transfer function analysis. Heart transplant recipients had reductions in R-R interval power and baroreceptor sensitivity low frequency gain (P<0.01) compared with both control groups; however, these changes were unrelated to transfer function metrics. Thus, in contrast to our hypothesis, the increased risk of cerebrovascular complication after heart transplantation does not seem to be related to alterations in cerebral pressure-flow dynamics. Future research is, therefore, warranted.

Abstract 315: Endothelial And Autonomic Dysfunctions Induced By High Fructose Intake Are Modulated By The Angiotensin Converting Enzyme (ACE) Gene Dosage

ACE gene polymorphism may be associated with different responses to physiological and pathological stimuli. Therefore, we tested whether low, normal or high levels of ACE gene dosage influence on the effects of chronic and excessive fructose intake (F). Male mice (22±1g) harboring 1, 2 or 3 copies of the ACE gene received F (100g/l) or tap water for 8 weeks. After this period, glucose tolerance (0-120 min after glucose load=1.5 g/Kg ip) and lipids were measured; blood pressure (BP) signals were recorded (Windaq, 4kHz), and BP variability was analyzed in frequency domain (FFT). After euthanasia, mesenteric resistance artery (MRA) was dissected out and rings were mounted in an isometric myograph (DMT,620M). MRA responses to noradrenaline (Nor; 0.1nM-1μM) and acetylcholine (Ach; 0.01nM-30μM) were studied. One-way ANOVA and p&lt;0.05 were used for statistical analysis F induced glucose intolerance (1 copy: 100±3 vs. F=198±5; 2 copies: 121±4 vs. F=201±8; 3 copies: 86±4 vs. F=212±5 mg/dl after 120 min) with no alterations in total cholesterol nor triglycerides. Systolic BP increased in 2 and 3-copy mice after F (1 copy: 119±2 vs. F=124±4; 2 copies: 120±3 vs. F=131±3; 3 copies: 121±3 vs. F=139±4 mmHg) and diastolic BP increased in all F-fed groups (1 copy: 80±2 vs. F=92±3; 2 copies: 83±2 vs. F=95±4; 3 copies: 84±2 vs. F=100±2 mmHg). The augment in systolic BP was significantly higher in 3-copy (17±1 mmHg) vs. 1 (6±1 mmHg) and 2-copy mice (10±1 mmHg). F also increased BP variability in all groups, with a more pronounced augment in 3-copy mice vs. other groups (1 copy: 39±3 vs. F=57±2; 2 copies: 37±2 vs. F=60±3; 3 copies: 40±3 vs. F=73±7 mmHg 2 ). Additionally, the sympathetic component of BP variability (LF %) presented a similar behavior (1 copy: 5±1 vs. F=12±3; 2 copies: 6±2 vs. F=19±3; 3 copies: 7±3 vs. F=31±5 %). Ach-induced relaxation was reduced in F mice (1 copy: 78 vs. F=58; 2 copies: 76 vs. F=47; 3 copies: 73 vs. F=36 %) and a hyperreactivity to Nor was also observed (1 copy: 92 vs. F=170; 2 copies: 107 vs. F=190; 3 copies: 101 vs. F=214 %). In both responses, 3-copy mice were significantly different than the other groups. ACE gene dosage seems to modulate the magnitude of MRA and autonomic dysfunctions caused by F consumption, inducing a more increased cardiovascular risk for 3-copy mice.

Blood pressure variability, impaired autonomic function and vascular senescence in aged spontaneously hypertensive rats are ameliorated by angiotensin blockade

ObjectiveElderly hypertensive patients are characterized by blood pressure (BP) variability, impaired autonomic function, and vascular endothelial dysfunction and stiffness. However, the mechanisms causing these conditions are unclear. The present study examined the effect of angiotensin receptor blockers (ARBs) on aged spontaneously hypertensive rats (SHR). MethodsWe surgically implanted telemetry devices in SHR and WKY at the age of 15 weeks (Young) and 80 weeks (Aged). Aged SHR were orally administered either olmesartan or valsartan once daily at 19:00 h (at the beginning of the dark period (active phase)) for 4 weeks to examine the effects on BP variability, impaired autonomic function, and vascular senescence. ResultsAging and hypertension in SHR additively caused the following: increased low frequency (LF) power of systolic BP, a decreased spontaneous baroreceptor reflex gain (sBRG), increased BP variability, increased urinary norepinephrine excretion, increased vascular senescence-related beta-galactosidase positive cells and oxidative stress. Treatment with olmesartan or valsartan significantly ameliorated these changes in aged SHR. However, olmesartan ameliorated these changes in aged SHR better than valsartan. The reductions in BP caused by olmesartan in aged SHR were sustained longer than reductions by valsartan. This result indicates longer-lasting inhibition of the AT1 receptor by olmesartan than by valsartan. ConclusionARBs ameliorated autonomic dysfunction, BP variability, and vascular senescence in aged SHR. Olmesartan ameliorated the aging-related disorders better than valsartan and was associated with longer-lasting AT1 receptor inhibition by olmesartan. Thus, the magnitude of improvement of these aging-related abnormalities differs for ARBs.