Paula J. Harvey

Short-Term Blood Pressure, Noradrenergic, and Vascular Effects of Nocturnal Home Hemodialysis

Abstract—Long-term nocturnal hemodialysis, which uses longer and more frequent sessions than conventional hemodialysis, lowers clinic blood pressure and left ventricular mass. We tested the hypotheses that short-term nocturnal hemodialysis would (1) reduce ambulatory blood pressure; (2) cause peripheral vasodilation; (3) lower plasma norepinephrine concentration; and (4) improve the arterial response to reactive hyperemia (a marker of endothelium-dependent vasodilation). We studied 18 consecutive patients (age, 41±2; [mean±SEM]) before and 1 and 2 months after conversion from conventional (three 4-hour sessions per week) to nocturnal (six 8-hour sessions per week) hemodialysis. As the dialysis dose per session (Kt/V) increased from 1.24±0.06 to 2.04±0.08 after 2 months (P =0.02), symptomatic hypotension developed and most antihypertensive medications were withdrawn. Nocturnal hemodialysis nonetheless lowered 24-hour mean arterial pressure (from 102±3 to 90±2 mm Hg after 2 months; P =0.01), total peripheral resistance (from 1967±235 to 1499±191 dyne · s · cm−5; P <0.01) and plasma norepinephrine (from 2.66±0.4 to 1.96±0.2 nmol; P =0.04). Endothelium-dependent vasodilation could not be elicited during conventional hemodialysis (−2.7±1.8%) but was restored (+8.0±1.0%; P =0.001) after 2 months of nocturnal hemodialysis. The brachial artery response to nitroglycerin also improved (from 6.9±2.8 to 15.7±1.6%; P <0.05). Nocturnal hemodialysis had no effect on weight or on stroke volume. Rapid reversal of these markers of adverse cardiovascular events with more intense hemodialysis may translate into improved outcome in this high-risk group of patients.

Hemodynamic after-effects of acute dynamic exercise in sedentary normotensive postmenopausal women.

Objectives To determine, in sedentary normotensive postmenopausal women, the after-effects of exercise on systemic and regional hemodynamics, and whether changes in total peripheral conductance after exercise relate to changes in brachial artery flow-mediated vasodilation (FMD). Methods In 13 sedentary postmenopausal women, the blood pressure (BP), cardiac output, total peripheral resistance and total peripheral conductance, calf vascular resistance and FMD were measured during baseline rest, and again commencing 45 min after treadmill exercise. Fourteen premenopausal women completed the identical protocol to obtain reference values for the after-effects of exercise in healthy females. Results In postmenopausal women, exercise was followed by falls in systolic BP (P < 0.01) and diastolic BP (P < 0.001). BP did not fall after exercise in premenopausal women. In both groups the cardiac output (P < 0.01) increased and the calf vascular resistance (P < 0.01) and total peripheral resistance (P < 0.05) decreased after exercise, but resistance fell more (P < 0.05) in postmenopausal women. Baseline FMD was greater in premenopausal women (12.1 ± 1.5 versus 5.3 ± 1.3%, P < 0.01), and similar before and after exercise, whereas prior exercise nearly doubled the FMD of postmenopausal women (to 9.9 ± 1.4%, P < 0.01). These increases in FMD correlated with baseline values (r = −0.75, P < 0.01) and with relative changes in total peripheral conductance (r = 0.72, P < 0.02). The latter relationship was absent in premenopausal women (r = −0.29). Conclusions In postmenopausal women, acute dynamic exercise elicits sustained increases in FMD that could facilitate post-exercise hypotension in this population. These observations reinforce the concept of exercise as an important non-pharmacological intervention to modify cardiovascular risk in postmenopausal women.

All-Cause Mortality and Serious Cardiovascular Events in People with Hip and Knee Osteoarthritis: A Population Based Cohort Study

Background Because individuals with osteoarthritis (OA) avoid physical activities that exacerbate symptoms, potentially increasing risk for cardiovascular disease (CVD) and death, we assessed the relationship between OA disability and these outcomes. Methods In a population cohort aged 55+ years with at least moderately severe symptomatic hip and/or knee OA, OA disability (Western Ontario McMaster Universities (WOMAC) OA scores; Health Assessment Questionnaire (HAQ) walking score; use of walking aids) and other covariates were assessed by questionnaire. Survey data were linked to health administrative data to determine the relationship between baseline OA symptom severity to all-cause mortality and occurrence of a composite CVD outcome (acute myocardial infarction, coronary revascularization, heart failure, stroke or transient ischemic attack) over a median follow-up of 13.2 and 9.2 years, respectively. Results Of 2156 participants, 1,236 (57.3%) died and 822 (38.1%) experienced a CVD outcome during follow-up. Higher (worse) baseline WOMAC function scores and walking disability were independently associated with a higher all-cause mortality (adjusted hazard ratio, aHR, per 10-point increase in WOMAC function score 1.04, 95% confidence interval, CI 1.01–1.07, p = 0.004; aHR per unit increase in HAQ walking score 1.30, 95% CI 1.22–1.39, p<0.001; and aHR for those using versus not using a walking aid 1.51, 95% CI 1.34–1.70, p<0.001). In survival analysis, censoring on death, risk of our composite CVD outcome was also significantly and independently associated with greater baseline walking disability ((aHR for use of a walking aid  = 1.27, 95% CI 1.10–1.47, p = 0.001; aHR per unit increase in HAQ walking score  = 1.17, 95% CI 1.08–1.27, p<0.001). Conclusions Among individuals with hip and/or knee OA, severity of OA disability was associated with a significant increase in all-cause mortality and serious CVD events after controlling for multiple confounders. Research is needed to elucidate modifiable mechanisms.

Endothelial function, carotid-femoral stiffness, and plasma matrix metalloproteinase-2 in men with bicuspid aortic valve and dilated aorta.

OBJECTIVES This study sought to examine the relationship between proximal aortic dilation and systemic vascular function in men with bicuspid aortic valve (BAV). BACKGROUND Proximal aortic dilation in subjects with BAV is associated with structural and functional abnormalities in the ascending aorta. METHODS We studied 32 men (median age 31 years [range 28 to 32 years]) with nonstenotic BAV categorized into 2 subgroups according to proximal ascending aorta dimensions (nondilated <or=35 mm and dilated >or=40 mm, respectively). Sixteen healthy men were studied as control subjects. Flow-mediated dilation in response to hyperemia (a marker of endothelial dysfunction) and carotid-femoral pulse wave velocity (an index of aortic stiffness) were assessed, and peripheral blood was sampled for matrix metalloproteinases (MMP-2 and -9) and their tissue inhibitors (TIMP-1 and -2), respectively. Cardiac chamber and aortic dimensions were assessed by echocardiography and cardiac magnetic resonance imaging, respectively. RESULTS Despite the similar severity of aortic stenosis, left ventricular mass, and function, men with dilated aortas had blunted brachial flow-mediated vasodilation to hyperemia (5% [interquartile range (IQR) 4% to 6%] vs. 8% [IQR 7% to 9%] change, p = 0.001), higher carotid-femoral pulse wave velocity (9.3 cm/s [IQR 9 to 10 cm/s] vs. 7 cm/s [IQR 6.9 to 7.4 cm/s], p = 0.001), and significantly higher plasma levels of MMP-2 (1,523 [IQR 1,460 to 1,674] vs. 1,036 [IQR 962 to 1,167], p = 0.001) compared with men with BAV and nondilated aorta. Values for MMP-9, TIMP-1 and -2 levels, and nitroglycerin-induced (endothelium-independent) vasodilation were similar in all 3 groups. CONCLUSIONS Young men with BAV and dilated proximal aortas manifest systemic endothelial dysfunction, increased carotid-femoral pulse wave velocity, and higher plasma levels of MMP-2. These observations could introduce new targets for screening and perhaps for therapeutic intervention.

The relation between total joint arthroplasty and risk for serious cardiovascular events in patients with moderate-severe osteoarthritis: propensity score matched landmark analysis

Objective To examine whether total joint arthroplasty of the hip and knee reduces the risk for serious cardiovascular events in patients with moderate-severe osteoarthritis. Design Propensity score matched landmark analysis. Setting Ontario, Canada. Participants 2200 adults with hip or knee osteoarthritis aged 55 or more at recruitment (1996-98) and followed prospectively until death or 2011. Main outcome measure Rates of serious cardiovascular events for those who received a primary total joint arthroplasty compared with those did not within an exposure period of three years after baseline assessment. Results The propensity score matched cohort consisted of 153 matched pairs of participants with moderate-severe arthritis. Over a median follow-up period of seven years after the landmark date (start of the study), matched participants who underwent a total joint arthroplasty during the exposure period were significantly less likely than those who did not to experience a cardiovascular event (hazards ratio 0.56, 95% confidence interval 0.43 to 0.74, P<0.001). Within seven years of the exposure period the absolute risk reduction was 12.4% (95% confidence interval 1.7% to 23.1%) and number needed to treat was 8 (95% confidence interval 4 to 57 patients). Conclusions Using a propensity matched landmark analysis in a population cohort with advanced hip or knee osteoarthritis, this study found a cardioprotective benefit of primary elective total joint arthroplasty.

Estradiol Induces Discordant Angiotensin and Blood Pressure Responses to Orthostasis in Healthy Postmenopausal Women

Postmenopausal estrogen replacement therapy (ERT) is reported to increase angiotensin II under resting conditions. To determine the implications of this increase for cardiovascular regulation during simulated orthostasis, blood pressure (BP), heart rate (HR), renin, angiotensinogen, angiotensin II, and aldosterone were measured at rest and during lower body negative pressure (LBNP; −10, −20, and −40 mm Hg). We studied 13 normotensive postmenopausal women (54±2 [mean±SE] years) before and after 1 month of oral estradiol 2 mg daily, and 14 premenopausal women. LBNP activated the renin-angiotensin system acutely in premenopausal but not postmenopausal women. Resting renin and aldosterone were unaffected by estradiol, whereas angiotensinogen (P<0.001) and angiotensin II (P<0.01) increased. Renin, aldosterone, and HR responses to LBNP (which tended to be less in postmenopausal women [P=0.06]) were not affected by estradiol. Importantly, angiotensin II was higher on estradiol during all stages of LBNP, and increased 70% above resting values at the end of this stimulus (P<0.05), yet BP was significantly lower, both at rest (P<0.05) and during LBNP (P<0.01). In summary, in normotensive postmenopausal women, estradiol increases angiotensin II, but not aldosterone, at rest and during orthostatic stress, yet lowers, rather than raises, BP under both conditions. Downregulation of vascular and adrenal responsiveness to angiotensin II may protect healthy women against this activation. Loss of such protection may elevate BP and have adverse implications for women with conditions that impair their capacity to counteract the pathological actions of angiotensin II. This may contribute to higher cardiovascular event rates reported in recent ERT trials.

Behavioral Neurocardiac Training in Hypertension A Randomized, Controlled Trial

It is not established whether behavioral interventions add benefit to pharmacological therapy for hypertension. We hypothesized that behavioral neurocardiac training (BNT) with heart rate variability biofeedback would reduce blood pressure further by modifying vagal heart rate modulation during reactivity and recovery from standardized cognitive tasks (“mental stress”). This randomized, controlled trial enrolled 65 patients with uncomplicated hypertension to BNT or active control (autogenic relaxation), with six 1-hour sessions over 2 months with home practice. Outcomes were analyzed with linear mixed models that adjusted for antihypertensive drugs. BNT reduced daytime and 24-hour systolic blood pressures (−2.4±0.9 mm Hg, P=0.009, and −2.1±0.9 mm Hg, P=0.03, respectively) and pulse pressures (−1.7±0.6 mm Hg, P=0.004, and −1.4±0.6 mm Hg, P=0.02, respectively). No effect was observed for controls (P>0.10 for all indices). BNT also increased RR-high-frequency power (0.15 to 0.40 Hz; P=0.01) and RR interval (P<0.001) during cognitive tasks. Among controls, high-frequency power was unchanged (P=0.29), and RR interval decreased (P=0.03). Neither intervention altered spontaneous baroreflex sensitivity (P>0.10). In contrast to relaxation therapy, BNT with heart rate variability biofeedback modestly lowers ambulatory blood pressure during wakefulness, and it augments tonic vagal heart rate modulation. It is unknown whether efficacy of this treatment can be improved with biofeedback of baroreflex gain. BNT, alone or as an adjunct to drug therapy, may represent a promising new intervention for hypertension.

Estrogen Status and the Renin Angiotensin Aldosterone System

The renin-angiotensin-aldosterone system (RAAS) is integrally involved in multiple cardiovascular physiological processes including arterial blood pressure (BP) regulation. Over activity of the RAAS has been implicated in the pathogenesis of a number of cardiovascular disease entities, including hypertension. Several lines of evidence suggest estrogen favorably modulates the RAAS. Conversely, estrogen deficiency due to menopause may contribute to over activity of the RAAS. Of importance, estrogen deficiency in women is not exclusive to the postmenopausal period. Functional hypothalamic amenorrhea is a reversible cause of premenopausal hypoestrogenemia. In contrast to postmenopausal women (PMW), premenopausal women with exercise-associated functional hypothalamic amenorrhea demonstrate decreased, not increased, resting BP compared with their estrogen-replete eumenorrheic counterpart. In this review we briefly examine the effects of estrogen status on the RAAS and present the hypothesis that the RAAS is altered in physically active women with functional hypothalamic amenorrhea.

Therapeutic benefit of preventive telehealth counseling in the Community Outreach Heart Health and Risk Reduction Trial.

We evaluated whether telehealth counseling augments lifestyle change and risk factor decrease in subjects at high risk for primary or secondary cardiovascular events compared to a recommended guideline for brief preventive counseling. Subjects at high risk or with coronary heart disease (35 to 74 years of age, n = 680) were randomized to active control (risk factor feedback, brief advice, handouts) or telehealth lifestyle counseling (active control plus 6 weekly 1-hour teleconferenced sessions to groups of 4 to 8 subjects). Primary outcome was questionnaire assessment of adherence to daily exercise/physical activity and diet (daily vegetable and fruit intake and restriction of fat and salt) after treatment and at 6-month follow-up. Secondary outcomes were systolic and diastolic blood pressures, ratio of total to high-density lipoprotein cholesterol, and 10-year absolute risk for coronary disease. After treatment and at 6-month follow-up, adherence increased for telehealth versus control in exercise (29.3% and 18.4% vs 2.5% and 9.3%, respectively, odds ratio 1.60, 95% confidence interval 1.2 to 2.1) and diet (37.1% and 38.1% vs 16.7% and 33.3%, respectively, odds ratio 1.41, 95% confidence interval 1.1 to 1.9). Telehealth versus control had greater 6-month decreases in blood pressure (mean ± SE, systolic -4.8 ± 0.8 vs -2.8 ± 0.9 mm Hg, p = 0.04; diastolic -2.7 ± 0.5 vs -1.5 ± 0.6 mm Hg, p = 0.04). Decreases in cholesterol ratio and 10-year absolute risk were significant for the 2 groups. In conclusion, telehealth counseling augments therapeutic lifestyle change in subjects at high risk for cardiovascular events compared to a recommended guideline for brief preventive counseling.

Low-dose diuretic and/or dietary sodium restriction when blood pressure is resistant to ACE inhibitor.

AIM To compare the efficacy of indapamide (1.25 mg daily) and low-salt diet (<100 mmol/day) separately and in combination in essential hypertensive patients with inadequate BP response to perindopril. DESIGN AND METHODS Randomized double-blind, double-dummy, crossover design. The randomized treatments were indapamide 1.25 mg daily, sodium chloride 80 mmol daily, the combination of indapamide and sodium chloride and placebo. All patients received perindopril 4 mg daily and maintained a low-sodium diet. RESULTS 19 patients entered and 17 completed the study. Prior to randomization, average clinic sitting blood pressure was 162/101 mm Hg and average 24-h urine sodium excretion was 157 mmol/day. Compared to the phase in which patients received perindopril with sodium repletion, clinic and ambulatory BPs were significantly reduced (p<0.01) in all the other phases. Indapamide had a greater effect on BP than dietary sodium restriction, and in combination their effects were additive. The effect of indapamide on ambulatory BP persisted throughout 24 h, but the effect of the low-salt diet was predominantly observed during waking hours. CONCLUSIONS In hypertensives with BP resistant to the angiotensin converting enzyme (ACE) inhibitor perindopril, the diuretic indapamide had greater additional efficacy and longer duration of action than dietary sodium restriction. In combination they had additive effects on BP.