Australian National Blood Pressure Study Research Articles

Change in Blood Pressure Variability Among Treated Elderly Hypertensive Patients and Its Association With Mortality.

BackgroundInformation is scarce regarding effects of antihypertensive medication on blood pressure variability (BPV) and associated clinical outcomes. We examined whether antihypertensive treatment changes BPV over time and whether such change (decline or increase) has any association with long‐term mortality in an elderly hypertensive population.Methods and ResultsWe used data from a subset of participants in the Second Australian National Blood Pressure study (n=496) aged ≥65 years who had 24‐hour ambulatory blood pressure recordings at study entry (baseline) and then after a median of 2 years while on treatment (follow‐up). Weighted day‐night systolic BPV was calculated for both baseline and follow‐up as a weighted mean of daytime and nighttime blood pressure standard deviations. The annual rate of change in BPV over time was calculated from these BPV estimates. Furthermore, we classified both BPV estimates as high and low based on the baseline median BPV value and then classified BPV changes into stable: low BPV, stable: high BPV, decline: high to low, and increase: low to high. We observed an annual decline (mean±SD: −0.37±1.95; 95% CI, −0.54 to −0.19; P<0.001) in weighted day‐night systolic BPV between baseline and follow‐up. Having constant stable: high BPV was associated with an increase in all‐cause mortality (hazard ratio: 3.03; 95% CI, 1.67–5.52) and cardiovascular mortality (hazard ratio: 3.70; 95% CI, 1.62–8.47) in relation to the stable: low BPV group over a median 8.6 years after the follow‐up ambulatory blood pressure monitoring. Similarly, higher risk was observed in the decline: high to low group.ConclusionsOur results demonstrate that in elderly hypertensive patients, average BPV declined over 2 years of follow‐up after initiation of antihypertensive therapy, and having higher BPV (regardless of any change) was associated with increased long‐term mortality.

Night-time ambulatory blood pressure is the best pretreatment blood pressure predictor of 11-year mortality in treated older hypertensives.

Numerous studies have shown a stronger relationship between ambulatory blood pressure (ABP), particularly night ABP, and cardiovascular events/mortality than for office blood pressure (OBP). A previous clinical trial (Syst-Eur) showed that pretreatment ABP was only a better predictor of outcome than OBP in placebo-treated participants. The current study in treated elderly hypertensives from the Second Australian National Blood Pressure study (ANBP2) examined whether pretreatment ABP was a better predictor of mortality than OBP over long-term (∼11 years) follow-up. ANBP2 was a comparative outcome trial in 6083 off-treatment or previously untreated elderly hypertensives. In the ABP substudy, at study entry, participants had ABP and nurse-performed OBP measurements. Cox proportional hazards analysis assessed the relationships between both OBP and ABP at study entry and 11-year all-cause and cardiovascular mortality, with results pooled from both active treatment phases. In 702 participants, over a median of 10.8 years, including 6.7 years after the trial, 167 died (82 cardiovascular). Pretreatment 'night' systolic ABP and pulse pressure were the best predictors of '11-year' cardiovascular mortality (hazard ratios: 1.26; 95% confidence intervals: 1.10-1.45, P=0.001 and 1.18; 1.06-1.31, P=0.003, respectively) and all-cause mortality (hazard ratios: 1.15; 95% confidence intervals:1.05-1.28, P=0.005 and 1.09; 1.10-1.31, P=0.03, respectively). OBP was not a significant predictor of mortality. In actively treated elderly hypertensives participating in ANBP2, all-cause or cardiovascular deaths were significantly related to pretreatment ABP, particularly to night-time systolic ABP and pulse pressure, but not to OBP.

A7625 Change in blood pressure variability among elderly treated hypertensive population and its association with mortality

Objectives: Higher blood pressure variability (BPV) is associated with increased cardiovascular and all-cause mortality. We aimed to explore whether BPV changed overtime in response to treatment and whether such change (decline/increase) has any association with long-term mortality amongst an elderly hypertensive population. Methods: We used data from a subset of Second Australian National Blood Pressure study participants (n = 496) aged ≥65 years who had 24 hours ambulatory BP (ABP) recording at study entry (baseline) and then after a median 2-yrs while on-treatment (follow-up). Weighted 24hr systolic BPV was calculated for both baseline and follow-up as a weighted mean of daytime and nighttime BP records standard deviations (SD). The annual rate of change in BPV over-time was calculated from these BPV estimates. Further, we classified both BPV estimates into ‘high’ and ‘low’ based on the baseline median BPV value; and then classified BPV changes into ‘No-change: low’, ‘no-change: high’, ‘decline: high to low’ and ‘increase: low to high’. Association of BPV changes with mortality outcome was assessed over a median 8.5 years after the follow-up ABPM. Results: We observed a decline in average weighted 24hr systolic BPV (mmHg) between baseline (11.8 ± 2.9) and follow-up (11.2 ± 3.2) among the study cohort. The observed BPV annual decline rate (mean ± SD) was –0.78 ± 1.95 (range –7.36 to 9.87). Having a ‘high’ BPV at baseline was associated after adjustment with an increase in all-cause and cardiovascular mortality irrespective of any change in BPV (Table 1). For those with ‘low’ BPV at baseline was not associated with an increase in mortality. Conclusion: In Elderly hypertensives having BPV above baseline median was associated with increased long-term mortality irrespective of any change in BPV.

Short- and long-term association of lipid-lowering drug treatment and cardiovascular disease by estimated absolute risk in the Second Australian National Blood Pressure study

There is currently insufficient evidence to support the use of lipid-lowering drug treatment (LLT) for primary prevention of cardiovascular disease (CVD) in the elderly. We examined the relationship of early initiation of LLT with short- and long-term all-cause and CVD mortality in persons older than 65years in this post hoc study from the Second Australian National Blood Pressure study (ANBP2). This was an in- and post-trial observational study. About 4257 hypertensive participants aged 65 to 84years within Australian family practices were randomized to an angiotensin-converting enzyme inhibitor or a diuretic treatment group. After excluding participants with a prior history of CVD, the cohort was stratified into "LLT" and "no LLT" subgroups based on LLT status at randomization. At randomization, the participants had a mean age of 72years, average blood pressure of 168/91mm Hg and estimated 5-year CVD risk of 18.7±8.3%. In the overall study population, the association of LLT with long-term (11-years) all-cause and non-CVD mortality was significant (hazard ratio [HR] 0.78 [95% confidence interval {CI} 0.66-0.92, P=.003] and HR 0.70 [95% CI 0.54-0.90, P=.006], respectively). Magnitudes of the association of LLT with long-term mortality and the association with short-term mortality were similar; however, no statistically significant association with short-term mortality was observed. In the subgroup analysis by baseline 5-year CVD risk, LLT participants in the highest risk tertile had a substantially lower relative risk for short-term all-cause mortality (HR 0.31, 95% CI 0.13-0.71, P for interaction .02) compared to those with lower estimated CVD risk. All analyses were adjusted for baseline and in-trial characteristics. Our study showed a strong association between LLT and reduced long-term all-cause mortality. Thus, our findings support recommendations of the use of LLT in patients over 65 years, particularly those with high CVD risk who were more likely to obtain additional benefits in the short term. The findings also suggested that mortality benefits of LLT for the elderly may take longer to become evident.

Association of depression with mortality in an elderly treated hypertensive population

Data from 6,083 hypertensive patients aged ≥65 years enrolled in the Second Australian National Blood Pressure study were used. Participants were followed for a median of 10.8 years (including 4.1 years in-trial) and classified into: "no depression," "pre-existing" and "incident" depression groups based on either being "diagnosed with depressive disorders" and/or "treated with an anti-depressant drug" at baseline or during in-trial period. Further, we redefined "depression" restricted to presence of both conditions for sensitivity analyses. For the current study, end-points were all-cause and any cardiovascular mortality. 313 (5%) participants had pre-existing depression and a further 916 (15%) participants developed depression during the trial period (incidence 4% per annum). Increased (hazard-ratio, 95% confidence-interval) all-cause mortality was observed among those with either pre-existing (1.23, 1.01-1.50; p = 0.03) or incident (1.26, 1.12-1.41; p &lt; 0.001) depression compared to those without. For cardiovascular mortality, a 24% increased risk (1.24, 1.05-1.47; p = 0.01) was observed among those with incident depression. The sensitivity analyses, using the restricted depression definition showed similar associations. Incident depression was associated with being female, aged ≥75 years, being an active smoker at study entry, and developing new diabetes during the study period. This elderly cohort had a high incidence of depression irrespective of their randomised antihypertensive regimen. Both pre-existing and incident depression were associated with increased mortality.

Relation of Alcohol Consumption to Risk of Heart Failure in Patients Aged 65 to 84 Years With Hypertension

Although a high level of alcohol consumption is associated with cardiomyopathy, the benefit or risk of moderate alcohol consumption on incident heart failure (HF) is unknown. This study examined the association between alcohol consumption and risk for HF in older adults with hypertension. The study analyzed data from a cohort of 6,083 participants aged 65 to 84 years at baseline (1995 to 2001) followed for a median of 10.8 years during and after the Second Australian National Blood Pressure Study. Frequency and amount of alcohol consumption were self-reported at baseline and during the clinical trial. The percentages of current drinkers, former drinkers, and never-drinkers at baseline were 4,400 (72%), 394 (6%), and 1,289 (21%), respectively. Incident HF was diagnosed in 183 men and 136 women. After adjustment for multiple confounders, alcohol consumption was not significantly associated with HF. Compared with never-drinkers, the adjusted hazard ratios (95% confidence interval) for those who consume 1 to 7, 8 to 14, and >14 drinks/week at baseline were 0.87 (0.59 to 1.30), 0.96 (0.57 to 1.60), and 0.71 (0.25 to 2.02), respectively in women, and 0.81 (0.47 to 1.38), 0.77 (0.43 to 1.38), and 1.04 (0.59 to 1.84), respectively in men. The findings of lack of an association between alcohol consumption and risk of HF persisted in the analyses comparing the risk of HF across each level of drinking at baseline or at follow-up with never-drinkers. In the present study, there was no evidence for benefit or risk of alcohol consumption, reported at baseline or at follow-up, in relation to incident HF in both men and women.

Relationship of aortic excess pressure obtained using pressure-only reservoir pressure analysis to directly measured aortic flow in humans

Objectives: A reservoir pressure model describing left ventricular-large artery interaction has been proposed as a useful heuristic model providing insight into the propagation of the central blood pressure as well as providing clinical prognostic information. A pressure-only approach to calculation of reservoir pressure waves has been proposed but this assumes that the resultant excess pressure is proportional to the volume flow rate out of the left ventricle; this has not been tested in humans.Approach: We use non-invasively acquired central pressure and flow data obtained in the 2nd Australian National Blood Pressure Study to test this assumption and to investigate the use of flow approximations based on excess pressure or an assumed triangular flow pattern in calculation of forward and backwards waves in the aortic root.Main results: Results from 821 subjects showed close association between the shape of measured flow patterns and calculated excess pressure, with mean coefficient of determination R2 = 0.931 ± 0.046(SD). For directly measured versus triangular flow approximation R2 was 0.918 ± 0.057. Comparison of the peak amplitudes of forwards (Pf) and backwards (Pb) going pressure waves resulted in significant correlation between Pfmax and Pbmax using both measured flow and the triangular flow approximation (0.83 and 0.79 respectively) and using excess pressure as a flow approximation (Pfmax 0.86 and Pbmax 0.77). All associations for peak pressures and integrals were high with R-values between 0.70 and 0.95.Significance: Pressure-only reservoir wave analysis appears to conform to the inherent assumptions underpinning the mathematical approach employed: this provides support for use of reservoir analysis as a non-invasive method to describe potentially important features and functions of ventriculo-vascular interaction without the requirement for flow measurement.

Visit-to-visit (long-term) and ambulatory (short-term) blood pressure variability to predict mortality in an elderly hypertensive population.

To explore the association of different types of blood pressure (BP) variability measures estimated from either short-term ambulatory reading-to-reading or long-term clinic visit-to-visit BP records with long-term survival in an elderly treated hypertensive population. A subset of patients (n = 508) aged at least 65-years was studied from the Second Australian National Blood Pressure study. We estimated SBP and DBP BP variability as the SD of ambulatory (24-h, daytime, night-time) and clinic visit-to-visit BP directly from all corresponding on-treatment within-individual BP records. Ambulatory 'weighted day-night' variability was calculated as a weighted mean of daytime and night-time SD. Cox-proportional hazard models adjusted for baseline risk factors (Model 1) and corresponding on-treatment BP (Model 2) or average night-time SBP (best predictive BP measure for outcome) (Model 3) were used to determine the relationship between long-term outcome and BP variability. Over a median of 10.6 years, 101 patients died from any cause, of which 51 deaths were cardiovascular. We observed increase in 'daytime' and 'weighted day-night' SBP/DBP variability was significantly associated with increased all-cause mortality in all models. For cardiovascular mortality, only 'weighted day-night' SBP variability significantly predicted risk in all models (Model 3 hazard ratio: 1.09, 95% confidence interval: 1.00-1.19, P = 0.04). Long-term BP variability was not associated with any outcome. On direct comparison, both 'daytime' and 'weighted day-night' BP variability measures provided similar prognostic information. Short-term 'daytime' and 'weighted day-night' SBP variability from ambulatory BP recordings was a better predictor of mortality in elderly treated hypertensive patients than long-term BP variability from visit-to-visit BP recordings.

Effectiveness of blood pressure-lowering drug treatment by levels of absolute risk: post hoc analysis of the Australian National Blood Pressure Study

ObjectivesIn many current guidelines, blood pressure (BP)-lowering drug treatment for primary prevention of cardiovascular disease (CVD) is based on absolute risk. However, in clinical practice, therapeutic decisions are often based...

Long-term survival following the development of heart failure in an elderly hypertensive population.

Available data on the prognosis of heart failure (HF) patients are predominantly limited to patients diagnosed at time of hospitalization. To describe the long-term survival of incident HF patients and identify clinical characteristics associated with mortality. The Second Australian National Blood Pressure Study (ANBP2) randomized 6083 hypertensive subjects aged 65-84years to angiotensin-converting enzyme (ACE) inhibitor or thiazide diuretic-based therapy and followed them for a median of 4.1years. One hundred forty-five participants who developed HF and 5938 who remained free from HF during the trial period were followed for a median of 6.7years during a posttrial follow-up. Three quarters, 110 (76%) of HF patients had died at the end of the follow-up. The five- and ten-year survival rates following HF diagnosis during the trial period were 37% and 15%, respectively, in men, compared with 60% and 33%, respectively, in women. In non-heart failure participants, the five- and ten-year survival rates, following enrollment into the study, were 92% and 76%, respectively. Mortality following HF diagnosis increased with advancing age (HR=1.09, 95% CI: 1.04-1.33). In addition, male gender and preexisting diabetes were predictive of mortality, while ACE inhibitor-based therapy for the initial trial was associated with 39% decrease (HR=0.61, 95% CI: 0.41-0.91) in mortality compared with a thiazide diuretic-based regimen. Long-term survival in elderly HF patients is poor, especially in men. Mortality in HF patients increased progressively with advancing age, while allocation to the ACE inhibitor-based regimen for the initial trial significantly improved HF outcome.

Pet ownership and survival in the elderly hypertensive population.

To assess the association of pet ownership and all-cause and cardiovascular mortality over a long-term follow-up among elderly treated hypertensive participants. Pet-ownership data from a subcohort of the Second Australian National Blood Pressure study were used. Participants were aged 65-84 years at enrolment (1995-1997) and responded to a pet-ownership questionnaire during year 2000. Participants' survival information was determined over a median of 10.9 years that includes Second Australian National Blood Pressure in-trial period (median 4.2 years) together with posttrial follow-up period (median 6.9 years). For the current study, end points were any fatal cardiovascular event and all-cause fatal events. Of those who responded to a pet-ownership questionnaire (4039/6018 - 67%), 86% (3490/4039) owned at least one pet at any-time during their life (current or previous pet owner), with 36% (1456/4039) owning at least one pet at the time of the survey. During the follow-up period, 958 participants died including 499 deaths of cardiovascular origin. Using a Cox proportional hazard regression model adjusting for possible confounders, there was a 22 and 26% reduction in cardiovascular mortality observed among previous and current pet owners, respectively, compared with those who had never owned one. A similar nonsignificant trend was observed for all-cause mortality once adjusted for potential confounders. Pet ownership was associated with an improved cardiovascular disease survival in a treated elderly hypertensive population.

Prediction of 10-year Risk of Incident Heart Failure in Elderly Hypertensive Population: The ANBP2 Study.

Multivariable risk prediction models consisting of routinely collected measurements can facilitate early detection and slowing of disease progression through pharmacological and nonpharmacological risk factor modifications. This study aims to develop a multivariable risk prediction model for predicting 10-year risk of incident heart failure diagnosis in elderly hypertensive population. The derivation cohort included 6083 participants aged 65 to 84 years at baseline (1995-2001) followed for a median of 10.8 years during and following the Second Australian National Blood Pressure Study (ANBP2). Cox proportional hazards models were used to develop the risk prediction models. Variables were selected using bootstrap resampling method, and Akaike and Bayesian Information Criterion and C-statistics were used to select the parsimonious model. The final model was internally validated using a bootstrapping, and its discrimination and calibration were assessed. Incident heart failure was diagnosed in 319 (5.2%) participants. The final multivariable model included age, male sex, obesity (body mass index > 30kg/m2), pre-existing cardiovascular disease, average visit-to-visit systolic blood pressure variation, current or past smoking. The model has C-statistics of 0.719 (95% CI: 0.705-0.748) in the derivation cohort, and 0.716 (95% CI: 0.701-0.731) after internal validation (optimism corrected). The goodness-of-fit test showed the model has good overall calibration (χ 2 = 1.78, P = 0.94). The risk equation, consisting of variables readily accessible in primary and community care settings, allows reliable prediction of 10-year incident heart failure in elderly hypertensive population. Its application for the prediction of heart failure needs to be studied in the community setting to determine its utility for improving patient management and disease prevention.

OS 18-06 COMPARISON OF THE MORTALITY PREDICTION CAPABILITY OF VISIT-TO VISIT AND AMBULATORY BLOOD PRESSURE VARIABILITY

Objective: Differences in blood pressure (BP) reading between multiple measurements, known as BP variability, is a strong predictor of cardiovascular and all-cause mortality. Lack of consensus on quantifying and reporting BP variability has limited its use in clinical practice. We aimed to determine the best possible way to quantify BP variability that would improve predictability of long-term mortality among elderly hypertensive population. Design and Method: We used data from a subset of patients (n = 694) aged > 65 years from the Second Australian National Blood Pressure (ANBP2) study. To calculate Systolic BP (SBP) and Diastolic BP (DBP) variability, 24-hours ambulatory BP monitoring data at study entry and visit-to-visit clinic BP data over a median 4.1 years follow-up were used. BP variability was defined as within-individual standard deviations in BP across measurements for 24 hours, day-time, night-time and visit-to-visit. Cox-proportional hazard models were used to explore the relationship between outcome and BP variability. Results: Over a median of 10.8 years, 161 patients died from any cause, of which 81 deaths were due to cardiovascular causes. We observed an increased risk of all cause and cardiovascular mortality with per mm increase in BP variability on univariate analyses irrespective of 24hrs, day-time, night-time and visit-to-visit BP variability, except DBP visit-to-visit BP variability. However, only day-time SBP and DBP variability from 24-hours ABPM were a strong predictor of long-term all-cause and cardiovascular mortality, when adjusted for age, gender and other possible risk factors (Table 1). Conclusions: Day-time BP variability, both SBP and DBP, measured by 24-hours ambulatory BP monitoring is a better predictor of mortality over the long-term in elderly hypertensive patients than visit-to-visit clinic BP variability.

Ten-year legacy effects of baseline blood pressure 'treatment naivety' in the Second Australian National Blood Pressure study.

Current blood pressure (BP) management guidelines recommend that treatment thresholds for BP be based on absolute cardiovascular disease (CVD) risk rather than on elevated BP levels alone. Clinicians are concerned that delayed pharmacotherapy in individuals with high BP, but low CVD risk, may increase long-term CVD events. To investigate this, we examined differences in CVD events within the Second Australian National BP study (ANBP2) for those previously on pharmacotherapy and those who were not, as well as fatal events in the 6-year post-trial period. Population consisted of ANBP2 participants without a prior CVD event. Adjusted Cox-regression hazard models were used to assess the effects of prior BP pharmacotherapy use on cardiovascular endpoints within ANBP2. An extended 6-year follow-up analysis for cardiovascular and all-cause mortality was also conducted. We found a higher in-trial CVD and all-cause mortality rate and incidence of new-onset diabetes for those on previous treatment versus those who were treatment-naive. We investigated whether this was an effect of the in-trial protocol, but this did not explain the observed differences. No difference in CVD or all-cause mortality at 10 years was observed between 'treatment-naive' and 'previous treatment' groups. We found no long-term adverse mortality associated with treatment naivety of elevated BP in an elderly hypertensive cohort, but this finding is likely to be confounded as seen by the lower in-trial mortality in the 'treatment-naive' group. Legacy effects need to be explored in randomized trials of middle-aged populations where the clinical concern lies.

Incidence of heart failure in 6083 elderly hypertensive patients: the Second Australian National Blood Pressure Study (ANBP2).

Hypertension is a known risk factor for the development of heart failure (HF); however, few data are available on the magnitude of short- and long-term progression from hypertension to HF. The present study aims to determine the short- and long-term incidence of HF, and identify factors associated with onset of HF in elderly hypertensive patients. The incidence of HF was measured in 6083 hypertensive patients, in the Second Australian National Blood Pressure Study (ANBP2), followed for a median of 10.8 years (4.1 years during the trial and 6.7 years during post-trial follow-up). A total of 373 cases of HF were identified over 59 581 person-years of follow-up (PY). The overall cumulative incidence of HF was 6.26 per 1000 PY; 5.33 per 1000 PY during the ANBP2 clinical trial and 7.04 per 1000 PY during the post-trial follow-up. HF was 63% higher among men [incidence rate ratios (IRR) 1.63, P < 0.01]. Older age, male sex, obesity, and history of cardiovascular disease independently predicted HF during both the short- and long-term follow-up. In addition, diabetes and smoking were associated with onset of HF in the short-term follow-up, and higher systolic blood pressure in the long-term follow-up. Median survival following diagnosis with HF was 3.94 years, and women (6.06 years) had a survival advantage over men (3.32 years). Heart failure is a frequent long-term outcome in treated elderly hypertensive patients. Development of HF was predicted by patient characteristics and co-morbidities, with the effect of some predictors varying over the short- and long-term follow-up.

4B.04

Objective: To examine the cost-effectiveness of angiotensin-converting enzyme inhibitor-based (ACEI) treatment compared to thiazide diuretic-based treatment for hypertension in elderly Australians considering diabetes as an outcome along with cardiovascular outcomes from the Australian government perspective. Design and method: We used a cost-utility analysis to estimate the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained. Data on cardiovascular events and new-onset of diabetes were used from the Second Australian National Blood Pressure Study, a randomized clinical trial comparing diuretic-based (hydrochlorothiazide) versus ACEI-based (enalapril) treatment in 6083 elderly (age 65yrs or more) hypertensive patients over a median 4.1-year period. For this economic analysis, the total study population was stratified into two groups. Group A was restricted to participants diabetes-free at baseline (n = 5,642); and Group B was restricted to participants with pre-existing diabetes mellitus (Type I or Type II) at baseline (n = 441). Data on utility scores for different events were used from available published literatures; whereas, treatment and adverse event management cost were calculated from direct health care costs available from Australian Government reimbursement data. Quality of life and costs were discounted at 5% per annum. One-way and probabilistic sensitivity analyses were performed to assess the uncertainty around utilities and cost data. Results: After a treatment period of five years, for Group A the ICER was AUD 27,698 (Euro 18,004; AUD 1∼ € 0.65) per QALY gained comparing ACEI-based with diuretic-based treatment (sensitive to the utility value for new-onset diabetes). In Group B, ACEI-based treatment was a dominant strategy (both more effective and cost-saving). On probabilistic sensitivity analysis, the ICERs per QALY gained were always below AUD 50,000 for Group B; whereas for Group A the probability of being below AUD 50,000 was 85%. Conclusions: Although the dispensed price of diuretic-based treatment of hypertension in the elderly is lower, upon considering the potential enhanced likelihood of the development of diabetes in addition to the costs of treating cardiovascular disease, ACEI-based treatment may be a more cost-effective strategy in this population.

Abstracts From the 36th Annual Scientific Meeting of the HBPRCA

### CONTRIBUTION OF THE AREA POSTREMA TO THE INCREASED CARDIAC SYMPATHETIC NERVE ACTIVITY IN OVINE HEART FAILURE Abukar Y, Ramchandra R, May CN The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia Background : Heart failure (HF) is associated with an increase in cardiac sympathetic nerve activity (CSNA), which is directly linked to mortality in HF patients. The mechanisms responsible for the elevated CSNA remain unclear. Previous studies indicate that the area postrema (AP), a circumventricular organ in the brainstem, plays a role in the control of sympathetic nerve activity. We hypothesized that the elevated CSNA in HF is mediated by the AP and lesioning this region would reduce the increased CSNA in sheep with HF. Aims : To determine the effect of sham lesion or lesion of the AP on CSNA and hemodynamics in conscious sheep with HF. Methods : Studies were conducted in 2 groups of sheep with pacing-induced HF: sham (n=6) and AP lesion (n=6) sheep. Mean arterial blood pressure (MAP), heart rate (HR) and CSNA were recorded simultaneously in conscious sheep at least 4 days after surgery. Results : Heart failure was associated with a significant decrease in ejection fraction (from 74±2 % to 38±1 %; P<0.001), which was similar in both groups. There was a significant reduction in CSNA burst incidence in the AP lesion group compared with the sham group (45±10 and 89±3 bursts/100 heartbeats, respectively; P<0.01). Conclusions : In sheep with HF, the group with lesion of the AP had a significantly lower CSNA compared with the sham group. These data suggest that the AP plays a role in setting the detrimental high levels of CSNA in HF. ### G PROTEIN-COUPLED ESTROGEN RECEPTOR SIGNALING IMPROVES STROKE OUTCOME IN FEMALE MICE Broughton BRS, Jansen GL, Sobey CG Department of Pharmacology, Monash University, Clayton, Victoria, Australia Background: Estrogen has been assumed to provide neuroprotection following stroke entirely via classical estrogen receptors. Interestingly, there is recent evidence that activation of a novel G …

Rate of change in renal function and mortality in elderly treated hypertensive patients.

Evidence relating the rate of change in renal function, measured as eGFR, after antihypertensive treatment in elderly patients to clinical outcome is sparse. This study characterized the rate of change in eGFR after commencement of antihypertensive treatment in an elderly population, the factors associated with eGFR rate change, and the rate's association with all-cause and cardiovascular mortality. Data from the Second Australian National Blood Pressure study were used, where 6083 hypertensive participants aged ≥65 years were enrolled during 1995-1997 and followed for a median of 4.1 years (in-trial). Following the Second Australian National Blood Pressure study, participants were followed-up for a further median 6.9 years (post-trial). The annual rate of change in the eGFR was calculated in 4940 participants using creatinine measurements during the in-trial period and classified into quintiles (Q) on the basis of the following eGFR changes: rapid decline (Q1), decline (Q2), stable (Q3), increase (Q4), and rapid increase (Q5). A rapid decline in eGFR in comparison with those with stable eGFRs during the in-trial period was associated with older age, living in a rural area, wider pulse pressure at baseline, receiving diuretic-based therapy, taking multiple antihypertensive drugs, and having blood pressure <140/90 mmHg during the study. However, a rapid increase in eGFR was observed in younger women and those with a higher cholesterol level. After adjustment for baseline and in-trial covariates, Cox-proportional hazard models showed a significantly greater risk for both all-cause (hazard ratio, 1.28; 95% confidence interval, 1.09 to 1.52; P=0.003) and cardiovascular (hazard ratio, 1.40; 95% confidence interval, 1.11 to 1.76; P=0.004) mortality in the rapid decline group compared with the stable group over a median of 7.2 years after the last eGFR measure. No significant association with mortality was observed for a rapid increase in eGFR. In elderly persons with treated hypertension, a rapid decline in eGFR is associated with a higher risk of mortality.

Central Aortic Reservoir-Wave Analysis Improves Prediction of Cardiovascular Events in Elderly Hypertensives

Several morphological parameters based on the central aortic pressure waveform are proposed as cardiovascular risk markers, yet no study has definitively demonstrated the incremental value of any waveform parameter in addition to currently accepted biomarkers in elderly, hypertensive patients. The reservoir-wave concept combines elements of wave transmission and Windkessel models of arterial pressure generation, defining an excess pressure superimposed on a background reservoir pressure. The utility of pressure rate constants derived from reservoir-wave analysis in prediction of cardiovascular events is unknown. Carotid blood pressure waveforms were measured prerandomization in a subset of 838 patients in the Second Australian National Blood Pressure Study. Reservoir-wave analysis was performed and indices of arterial function, including the systolic and diastolic rate constants, were derived. Survival analysis was performed to determine the association between reservoir-wave parameters and cardiovascular events. The incremental utility of reservoir-wave parameters in addition to the Framingham Risk Score was assessed. Baseline values of the systolic rate constant were independently predictive of clinical outcome (hazard ratio, 0.33; 95% confidence interval, 0.13-0.82; P=0.016 for fatal and nonfatal stroke and myocardial infarction and hazard ratio, 0.38; 95% confidence interval, 0.20-0.74; P=0.004 for the composite end point, including all cardiovascular events). Addition of this parameter to the Framingham Risk Score was associated with an improvement in predictive accuracy for cardiovascular events as assessed by the integrated discrimination improvement and net reclassification improvement indices. This analysis demonstrates that baseline values of the systolic rate constant predict clinical outcomes in elderly patients with hypertension and incrementally improve prognostication of cardiovascular events.

Prediction of cardiovascular and all-cause mortality at 10 years in the hypertensive aged population.

We have previously developed a score for predicting cardiovascular events in the intermediate term in an elderly hypertensive population. In this study, we aimed to extend this work to predict 10-year cardiovascular and all-cause mortality in the hypertensive aged population. Ten-year follow-up data of 5,378 hypertensive participants in the Second Australian National Blood Pressure study who were aged 65-84 years at baseline (1995-2001) and without prior cardiovascular events were analyzed. By using bootstrap resampling variable selection methods and comparing the Akaike and Bayesian information criterion and C-indices of the potential models, optimal and parsimonious multivariable Cox proportional hazards models were developed to predict 10-year cardiovascular and all-cause mortality. The models were validated using bootstrap validation method internally and using the Dubbo Study dataset externally. The final model for cardiovascular mortality included detrimental (age, smoking, diabetes, waist-hip ratio, and disadvantaged socioeconomic status) and protective factors (female sex, alcohol consumption, and physical activity). The final model for all-cause mortality also included detrimental (age, smoking, random blood glucose, and disadvantaged socioeconomic status) and protective factors (female sex, alcohol consumption, body mass index, and statin use). Blood pressure did not appear in either model in this patient group. The C-statistics for internal validation were 0.707 (cardiovascular mortality) and 0.678 (all-cause mortality), and for external validation were 0.729 (cardiovascular mortality) and 0.772 (all-cause mortality). These algorithms allow reliable estimation of 10-year risk of cardiovascular and all-cause mortality for hypertensive aged individuals.