Orthostatic hypotension (OH) is a major health problem

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1 Arterial Stiffness Is Associated with Orthostatic Hypotension in Elderly Subjects with History of Falls Jacques Boddaert, MD, w Hani Tamim, MD, Marc Verny, MD, w and Joël Belmin, MD OBJECTIVES: To test the hypothesis that impaired hemodynamic orthostatic changes commonly observed in the elderly may be related to age-related increase in arterial wall stiffness. DESIGN: Convenience sample of consecutive patients admitted for falls. SETTING: Acute- and intermediate-care geriatric ward of a French hospital. PARTICIPANTS: Fifty-seven elderly patients (46 women) consecutively admitted to a geriatric ward with a history of recent falls. MEASUREMENTS: Orthostatic hypotension (OH) was assessed using blood pressure measurements in the supine position and 1, 2, and 3 minutes after standing. Arterial wall stiffness was assessed using upper-limb and aortic pulse-wave velocities, measured with an external pressure transducer connected to a computer. RESULTS: OH was present in 18 patients with a mean age standard deviation of (5 men, 13 women) and absent in 39 patients aged (6 men, 33 women). Upper-limb pulse-wave velocity was significantly higher, by 16%, in patients with OH than those without (9.91 vs 8.53 m/s; Po.02). Significant correlations were found between upper-limb pulse-wave velocity and systolic blood pressure changes after 1 minute of standing (r , Po.05) and maximal diastolic blood pressure change after standing (r , Po.01). CONCLUSION: Upper-limb arterial wall stiffness was significantly greater in elderly patients with OH than in patients without OH and was significantly related to blood pressure changes after standing. These results highlight the possible role of age-related changes in the arterial tree in the hemodynamic response to orthostatic challenges. JAm Geriatr Soc 52: , Key words: elderly; orthostatic hypotension; arterial stiffness From the Service de Médecine Interne Gériatrique, Hôpital Charles Foix et Université Paris 61, Ivry-sur-Seine, France; and w Centre de Gériatrie, Hôpital Pitié-Salpétrière, Paris, France. Address correspondence to Prof. Joël Belmin, Service de Médecine Interne Gériatrique, Hôpital Charles Foix et Université Paris 613, Ivry-sur-Seine, France. joel.belmin@cfx.ap-hop-paris.fr Orthostatic hypotension (OH) is a major health problem in the elderly and is extremely common in older individuals. It affects 6% to 33% of community-dwelling people aged 65 and older and much larger proportions of elderly institutionalized patients. 1 4 OH can cause dizziness and falls and may lead to functional impairment, hospitalization, altered quality of life, and vital complications. 5 9 It is also considered to be a risk factor for stroke. 10 The hemodynamic response to orthostatic challenge involves many factors, grouped together in the baroreflex arch. Orthostatic challenge is responsible for blood redistribution in the lower parts of the body and for decreases in blood pressure (BP) and cardiac preload. In response, carotid and aortic arterial wall receptors activate the baroreflex, which reduces parasympathetic activity and increases sympathetic nervous system activity. Stimulation of the a-adrenergic component leads to vasoconstriction and increased peripheral arterial resistance and stimulation of the b-adrenergic component of increased heart rate and contractility. The hemodynamic response to orthostatic challenge involves several organs, which all play a significant part in regulating BP. They include the arterial tree, heart, and nervous system, particularly the autonomic nervous system. The arterial tree plays a crucial part in this mechanism, first because the detection of BP changes involves sensors located in the arterial wall, and second because the hemodynamic response mostly relies on vasomotion, which depends on effectors also located in the arterial wall. Many researchers have investigated the age-related changes in the autonomic nervous system in an attempt to understand why the hemodynamic response to orthostatic challenge is altered in the elderly, 11 but few have explored the role of arterial aging. Because several defects in the arterial wall, especially arterial stiffening, which reduces its elasticity and contractility, characterize senescence, 12,13 it was postulated that age-related arterial stiffness might be involved in the hemodynamic response to orthostatic challenge. In particular, it was hypothesized that pulse-wave velocity, a reliable marker of arterial stiffness, might be correlated with the magnitude of BP change during postural testing. METHODS Subjects Consecutive patients admitted for falls to an acute- and intermediate-care geriatric ward of a French hospital were JAGS 52: , 2004 r 2004 by the American Geriatrics Society /04/$15.00

2 JAGS APRIL 2004 VOL. 52, NO. 4 ARTERIAL STIFFNESS AND ORTHOSTATIC HYPOTENSION 569 considered for participation in the study. Patients were eligible if they had a history of recent falls and were able to transfer from bed to standing and remain upright. Moreover, exclusion criteria were unstable medical conditions, including anemia, dehydration, heart failure, or infections, and recent change in drug regimen. Fifty-seven elderly patients comprising 11 men and 46 women were studied (mean age standard deviation (SD) ). Orthostatic Tests Blood pressure was measured in the nondominant arm using an automatic oscillometric monitor (Dinamap, Critikon model 1846 SX, GE Medical Systems, Fairfield, CT) and a size-adapted arm cuff. Supine BP was measured after patients had rested for 10 minutes or more in a quiet environment in the presence of the physician, without talking, moving, or smoking. Three successive measurements were made to ensure that resting supine BP was stable and to accustom patients to the automatic device. The last measurement was the one considered for the study. Upon completion of these measurements, the patient was asked to stand up, and BP was measured at 1, 2, and 3 minutes after orthostatic challenge. According to the Consensus Committee of the American Autonomic Society and the American Academy of Neurology, 14 OH was defined as patients who exhibited a drop of 20 mmhg or more in systolic BP (SBP) or 10 mmhg or more in diastolic BP (DBP) at any of the three standing BP measurements. The key measure of this study, the hemodynamic response to an orthostatic challenge, was determined by calculating the changes in SBP and DBP from baseline (DSBP and DDBP, respectively), at 1, 2, and 3 minutes after orthostatic challenge. For example, a SBP increase of 40 mmhg at 2 minutes was expressed as DSBP mmhg. Because the largest drop in BP is believed to determine the largest reduction in cerebral blood flow and symptoms, and because kinetics of BP change during orthostatic challenge varies between individuals, the largest changes from baseline in SBP and DBP (DSBP max and DDBP max) were studied. Pulse-Wave Velocity Measurements With the contraction of the left ventricle, the ejection of blood into the ascending aorta generates a pulse wave that is propagated through the arterial tree. The measurement of the pulse-wave velocity is a well-recognized way of evaluating arterial distensibility: the stiffer the arterial wall, the faster the pulse wave. Here, the pulse waves were recorded using pressure-sensitive transducers, and pulsewave velocity was measured just before the orthostatic challenge in supine resting conditions, using the Complior device (Colson, Garges-les-Gonesse, France). Aortic pulsewave velocity was first measured by applying two external pressure transducers to the carotid and femoral pulses. The arterial pulse waves were recorded simultaneously and processed by software specially designed to automatically determine the interval between pulse waves (Colson). Pulsewave velocity was calculated as the ratio of the distance between the transducers to the interval between two pulse waves. The average for each patient was based on 10 pulsewave recordings. 15 Upper-limb pulse-wave velocity was determined using the same methodology, except that a transducer was placed on the brachial artery pulse at the wrist instead of the femoral pulse. Statistical Analysis Univariate regression analyses were performed to evaluate the relations between the studied parameters. Repeatedmeasures analysis of variance was used to compare mean changes before and after orthostatic challenge in patients with and without OH. All data are expressed as mean SD. The significance level was set at Po.05. RESULTS Subjects Baseline characteristics of the subjects are shown in Table 1. Under resting conditions, SBP values were significantly higher in patients with OH than in those without ( vs mmhg; Po.01). No significant differences were found between the two groups for DBP ( vs mmhg), pulse pressure ( vs mmhg), or heart rate ( vs beats/min). BP and Heart Rate Responses to Orthostatic Challenge BP responses during the orthostatic challenge are shown in the Table 2. According the definition detailed in the Table 1. Baseline Characteristics of Elderly Patients with or without Orthostatic Hypotension (OH) Characteristic Without OH (n 5 39) With OH (n 5 18) Age, mean standard deviation Men/women 6/33 5/13 Hypertension, 22 (56) 13 (72) Ischemic heart 12 (31) 2 (11) disease, Atrial fibrillation, 4 (10) 6 (33) Heart failure, 4 (10) 2 (11) Stroke, 5 (13) 3 (17) Diabetes mellitus, 3 (8) 1 (6) Alcohol, 2 (5) 3 (17) Dementia, 12 (31) 4 (22) Depression, 9 (23) 2 (11) Nitrates, 8 (21) 6 (33) Calcium channel blockers, 4 (10) 6 (33) Angiotensin converting 8 (21) 0 (0) enzyme inhibitor, Others antihypertensive 6 (15) 5 (28) drugs, Psychotropic drugs, 21 (54) 7 (39) Po.05.

3 570 BODDAERT ET AL. APRIL 2004 VOL. 52, NO. 4 JAGS Table 2. Hemodynamic Characteristics of Elderly Patients with or without Orthostatic Hypotension (OH) Without OH (n 5 39) With OH (n 5 18) Mean Standard Characteristic Deviation Systolic blood pressure, mmhg Diastolic blood pressure, mmhg Pulse pressure, mmhg Heart rate, bpm Upper-limb pulse wave velocity, m/s Aortic pulse wave velocity, m/s DSBP-1, mmhg w DSBP-2, mmhg w DSBP-3, mmhg w DDBP-1, mmhg w DDBP-2, mmhg DDBP-3, mmhg w DSBP max, mmhg w DDBP max, mmhg w Po.05; w Po.0001 compared with elderly patients without OH. DSBP 5 change in systolic blood pressure; DDBP 5 change in diastolic blood pressure from supine to standing for 1 minute (DSBP-1, DDBP-1), 2 minutes (DSBP-2, DDBP-2), and 3 minutes (DSBP-3, DDBP-3). DSBP max and DDBP max are the maximal SBP and DBP changes from supine to standing. Methods section, subjects had OH. A drop in SBP of 20 mmhg or more or a drop in DBP of 10 mmhg or more was found in 17 of these patients after 1 minute standing, in 12 after 2 minutes standing, and in 11 after 3 minutes standing. Pulse-Wave Velocity Upper-limb pulse-wave velocity was 16% higher in patients with OH than in those without (9.91 vs 8.53 m/s, Po.02) (Table 2). Similarly, aortic pulse-wave velocity was 9% higher in patients with OH, but this difference was not significant (14.86 vs m/s) (Table 2). Upper-limb pulsewave velocity correlated with resting SBP (r , Po.01, y x15.285), resting DBP (r , Po.01, y x14.924), and resting pulse pressure (r , Po.01, y x14.444). No significant relationship was found between aortic pulse-wave velocity and baseline blood pressure. Correlates of Orthostatic BP Changes There was no significant correlation between DSBP max and baseline SBP, DBP, or pulse pressure, but DDBP max correlated with resting SBP (r , Po.01, y x ) and resting DBP (r , Po.05, y x 13.38). Significant correlations were also found between upperlimb pulse-wave velocity and both DDBP max (r , P o.01, y x ) and DSBP-1 (r , Po.05, y x ) but not other standing parameters (Figure 1). Similarly, aortic pulse-wave velocity correlated with DDBP max (r , Po.01, y x ) but not with other standing parameters. DISCUSSION The main new finding in this study was that upper-limb pulse-wave velocity was significantly greater in elderly patients with OH than in patients with a history of falls but without OH. In addition, a significant correlation was found between the hemodynamic response to orthostatic challenge and upper-limb and aortic pulse-wave velocity, which are recognized indicators of arterial stiffness. These findings support the view that arterial stiffness plays an important role in the hemodynamic response to orthostatic challenge, especially in elderly patients with OH. This conclusion is consistent with prior research. In the Systolic Hypertension in the Elderly Program cohort of 4,736 healthy community-dwelling older persons aged 60 and older with isolated systolic hypertension, OH was found to be highly prevalent and was associated with higher mean SBP under resting conditions. 3 This suggested a link between OH and reduced arterial compliance, because isolated systolic hypertension is known to be mainly due to arterial wall stiffening and because patients with isolated systolic hypertension were found to have significantly decreased arterial compliance. 16 One study subsequently suggested that vascular and neural deficits contribute to the age-related decline in cardiovagal baroreflex gain. 17 Furthermore, in 47 healthy men aged 19 to 76, another study found a significant univariate correlation between cardiovagal baroreflex sensitivity and both age and carotid artery compliance. 18 The current study was able to detect only strong links between the hemodynamic response to orthostatic challenge or OH and pulse-wave velocity. Because of the small number of patients, the possibility cannot be excluded that more-subtle associations might have been missed because of insufficient statistical power. In addition, frail elderly inpatients who presented with several comorbid conditions and were not drug free were studied. An important limitation of this observational study was that all factors were not controlled. Thus, any no causal relationship can be drawn from the results. There were significant differences between the characteristics of the two groups. In particular, baseline SBP was higher and atrial fibrillation and the use of antihypertensive drugs were more common in the patients with OH than in patients without. Moreover, one cannot exclude that these factors or another unrecorded confounding factor might intervene in the pathophysiology of OH. Several mechanisms might account for the links between arterial stiffness and the hemodynamic response to orthostatic challenge. The activation of carotid and aortic baroreceptors is a first step in the baroreflex response and generates sympathetic/parasympathetic regulation. Because these baroreceptors are located inside the arterial wall and are triggered by stretch, arterial stiffness may interfere with their activation, thus explaining the decline in baroreceptor sensitivity. 11 In addition, because orthostatic challenge generates sympathetic-dependent vasoconstriction,

4 JAGS APRIL 2004 VOL. 52, NO. 4 ARTERIAL STIFFNESS AND ORTHOSTATIC HYPOTENSION 571 A (mmhg) 30 Maximal orthostatic change in DBP B (mmhg) 40 SBP change at 1 min Upper limb pulse wave velocity (m.sec-1) Figure 1. Correlation between upper-limb pulse-wave velocity and the maximal drop on diastolic blood pressure (DBP) (Panel A) and systolic blood pressure (SBP) drop for 1 minute standing (Panel B). arterial stiffness might reduce the vasoconstricting potential of the arterial wall. Nevertheless, this study was not designed to elucidate the mechanisms involved in this decline. Age-related changes in the nervous system have been implicated as the main factor responsible for the impaired hemodynamic response to orthostatic challenge that occurs with aging and for the frequent occurrence of OH in the elderly. Many authors reported a decline in baroreceptor sensitivity, 11,19 a reduced sympathetic nervous system activation to orthostatic challenge, or a diminished vasomotor response to sympathetic nervous system activation with aging, 20,21 but there is a large body of data supporting the concept that the basal activity of the sympathetic nervous system increases with aging, a paradox that has been attributed to the uncoupling of beta-adrenergic receptors. 26 Moreover, there is a recent report that indicates that the vestibulosympathetic reflex declines with age and suggests that this plays a role in OH in the elderly. 27 Arterial stiffening might also contribute to the age-related impairment of the hemodynamic response to orthostatic challenge and to OH in the elderly and might constitute an additive mechanism in relation to the changes in the autonomic nervous system. The hypothesis that arterial stiffening is a determinant factor in the hemodynamic response to orthostatic challenge implies that it should be considered as a therapeutic target. If so, interventions capable of reducing arterial stiffness could be expected to improve the hemodynamic response to orthostatic challenge and diminish the occurrence of OH. The benefit of a regular aerobic-endurance exercise regimen was reported for central arterial compliance 28 and for cardiovagal baroreflex sensitivity and carotid artery compliance. 18 Other types of interventions might be capable of improving arterial compliance, but their effect on the hemodynamic response to orthostatic challenge is not known. In rats, aminoguanidine was found to prevent the formation of advanced glycation endproducts involved in arterial stiffening with aging and to lessen the age-related decrease in carotid distensibility. 29 Similar results were subsequently found in humans, using an advanced glycation end-product cross-link-breaker regimen, 30 but their effects on the hemodynamic response to orthostatic challenge have not been reported. The involvement of arterial stiffness in age-related hemodynamic homeostatic changes is a relatively new and interesting concept that may help improve understanding of the hemodynamic response to orthostatic challenge and the occurrence of OH in the elderly. In addition, interventions might be capable of improving arterial compliance, but their effects on hemodynamic response to orthostatic challenge are not known. ACKNOWLEDGMENTS The authors thank Prof. Gabriel Gold (Geneva, Switzerland) for his help in the preparation of the manuscript. REFERENCES 1. 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