Some people who feel dizzy or lightheaded when they stand up may have an increased risk of developing dementia years later, according to a new study published in Neurology.
The condition, called orthostatic hypotension, occurs when people experience a sudden drop in blood pressure when they stand up.
The study found the link with dementia only in people who have a drop in their systolic blood pressure, not in people with only a drop in their diastolic blood pressure or their blood pressure overall.
Systolic is the first, or top, number in a blood pressure reading and systolic orthostatic hypotension was defined as a drop of at least 15 mmHg after standing from a sitting position.
“People’s blood pressure when they move from sitting to standing should be monitored,” said study author Laure Rouch, Pharm.D., Ph.D., of the University of California, San Francisco.
“It’s possible that controlling these blood pressure drops could be a promising way to help preserve people’s thinking and memory skills as they age.”
The study involved 2,131 people who were an average age of 73 and did not have dementia when they enrolled.
Their blood pressure readings were taken at the start of the study and then one, three and five years later.
A total of 15% had orthostatic hypotension, 9% had systolic orthostatic hypotension and 6% had diastolic orthostatic hypotension.
Over the next 12 years, the participants were evaluated to see if anyone developed dementia. A total of 462 people, or 22%, did develop the disease.
The people with systolic orthostatic hypotension were nearly 40% more likely to develop dementia than those who did not have the condition.
Fifty of the 192 with systolic orthostatic hypotension, or 26%, developed dementia, compared to 412 of the 1,939 people without it, or 21%.
When researchers adjusted for other factors that could affect dementia risk, such as diabetes, smoking and alcohol use, those with systolic orthostatic hypotension were 37% more likely to develop dementia.
The researchers also found that people whose sitting-to-standing systolic blood pressure readings changed the most from visit to visit were more likely to develop dementia years later than people whose readings were more stable.
The people were divided into three groups based on how much their readings changed over time.
A total of 24% of people in the group with the most fluctuation in systolic readings later developed dementia, compared to 19% of the people in the group with the least fluctuation.
When researchers adjusted for other factors affecting dementia risk, those in the highest group were 35% more likely to develop dementia than those in the lowest group.
Rouch noted that the study is observational and does not show cause and effect. It only shows an association between the blood pressure readings and the development of dementia.
Another limitation of the study was that the diagnosis of dementia was made without distinction between Alzheimer’s disease and vascular dementia.
In healthy adults, blood pressure is remarkably well preserved throughout a range of positions. An abnormal fall in blood pressure on standing has been described as either postural hypotension or the more often used term, orthostatic hypotension (OH). OH is then the failure of cardiovascular reflexes to maintain blood pressure on standing from a supine or sitting position.
A widely used consensus guideline has defined OH as a decrease in systolic blood pressure (SBP) of at least 20mmHg and/or a diastolic blood pressure (DBP) of at least 10mmHg within 3min of standing.1
Over the last decade, these criteria have become the research standard for epidemiologic and investigative studies.2–8 Many epidemiologic studies involving OH have only measured standing blood pressure between 1 and 3min of standing,3,6–9 potentially missing clinically significant OH that occurs within 1min10 and after 3min11 of standing.
OH has, in the past, been exclusively linked to the presence of symptoms: positional dizziness or syncope. Detection of OH has thus depended on the measurement of standing blood pressure in symptomatic patients.
Recent population studies have demonstrated that asymptomatic OH (AOH) accounts for the vast majority of OH when compared with the symptomatic form.3–5 Additionally, the orthostatic response can vary over time and more frequent assessment can distinguish between transient OH and persistent OH, which each carry different risk profiles.12
The clinical implications for AOH are not fully defined. Episodic reductions in blood pressure may be detrimental for vulnerable populations, especially the elderly and, in particular hypertensive elderly groups.
This review summarizes the pathophysiology, epidemiology, and associated risk of AOH in relation to hypertension and its treatment, especially in older patients.
Going from a supine to a standing position invokes gravitational force to pool 500–1,000ml of blood into the lower extremities.13–16 There is a rapid decrease in both venous return and ventricular filling causing a transient reduction in cardiac output and blood pressure.
This transient fall in blood pressure and cardiac output rapidly triggers cardiopulmonary, carotid sinus, and aortic arch baroreceptors resulting in an increase sympathetic tone and decrease in parasympathetic tone.13–16
These normal baroreflex responses cause an increase in heart rate and vascular resistance restoring normal blood pressure, cardiac output, and cerebral perfusion.13–16
OH is the consequence of a failure of the human circulatory system and neural pathways to maintain blood pressure on standing.
The mechanisms of this failure include a decreased blood volume secondary to intravascular volume loss, failed carotid sinus baroreflex activation secondary to normal aging and arteriosclerosis and loss of sympathetic output as a consequence of neuropathies and many drugs including calcium-channel blockers, nitrates, diuretics, antiparkinson drugs, α-receptor blockers, β-blockers, and tricyclic antidepressants.13,15,17
OH and Symptoms
In epidemiologic studies of middle-aged and older populations, the majority of patients with OH do not have symptoms of dizziness on standing.3–5 The Cardiovascular Health Study (CHS) was a population-based longitudinal study of coronary heart disease (CHD) and stroke in 5,201 adults 65 and older.
In a cross-sectional analysis of the CHS evaluating OH risk, the study reported that only 2% of participants had symptomatic OH, whereas 16.2% had asymptomatic OH.
Two studies on OH risk from Atherosclerosis Risk in Communities (ARIC) study (described in detail in the subsequent section), reported that dizziness was unrelated to the presence or absence of OH.4,5
AOH accounts for the vast majority of OH. Thus, if patients are screened on the basis of symptoms alone, clinic or office detection of OH will greatly underestimate its prevalence.
OH: Dementia and Falls
The morbidity associated with OH is not limited to mortality and cardiovascular outcomes. Some evidence suggests OH is linked to dementia30,31 and falls3,32,33 which carry serious morbidity and mortality risk in the elderly population.
In a cross-sectional analysis of a population-based cohort study of 2,321 community dwelling adults aged 55 years and above, hypotensive patients (SBP <120mmHg or DBP <70mmHg) with OH had significantly increased risk of having cognitive impairment at baseline (cognitive impairment defined as a mini-mental status exam score <24),31 however, OH was not shown to be predictive of cognitive decline over a 1–2-year follow-up.
A small longitudinal cohort study of 27 healthy women aged 75–95 reported that drops in SBP on tilt table testing at baseline were associated with cognitive decline (defined as symptoms of dementia or mini-mental status score of <27) over a 5-year follow-up period.30
Falls are multifactorial and can lead to fractures and head trauma that can result in serious morbidity for an elderly adult. Orthostatic blood pressure measurements are often included in clinical investigations evaluating fall risk and prevention.32,34–36 Nevertheless, the association between AOH and unexplained falls is not well defined.
In the cross-sectional analysis of the CHS, frequent falls and difficulty walking were both strongly correlated with OH, with risk ratios of 1.52 (confidence interval: 1.04–2.22) and 1.23 (confidence interval: 1.02–1.49) respectively, after adjustment for age and clinic-site.3
Some studies have found that OH does not predict falls in all elderly persons,37,38 however, two prospective studies of the elderly have reported that OH is a risk factor for falls in elderly persons with a history of falling.32,33
Hypertension and OH
In experimental models, an abrupt rise in arterial pressure initially causes an increase in baroreceptor afferent activity.39 Over 24–48h, the baroreceptor firing decreases significantly and a new (higher) set point for activation is generated.19,39,40 The role of the baroreceptor reflexes in the regulation of chronic clinical hypertension is less well defined.39 Several studies have shown that the effectiveness of the baroreceptor response to acute changes in blood pressure diminishes with age41,42 and chronic hypertension.19,40,43,44 This results in part from diminished carotid distensibility related to atherosclerotic arterial disease that includes increased wall thickness, stenosis, fibrosis, and calcification.19,40,41,43–46 In another analysis from the Rotterdam study, arterial stiffness and the BRS were analyzed in conjunction with postural blood pressure changes. The study reported that arterial stiffness is an independent determinant of impaired BRS and impaired BRS was associated with postural decreases blood pressure.44
In one of the earliest studies, Mancia et al. studied the baroreflex in hypertensive patients using vasoactive drugs and neck chamber techniques to apply direct positive and negative pressures to the carotid sinus. They demonstrated that BRS is inversely correlated with blood pressure variability and positively with heart rate variability.43 Thus, as BRS diminishes with aging and hypertension, there are wider fluctuations in blood pressure with a diminished ability to increase the heart rate.43,47
Recent studies have shown that surgical interventions, such as carotid stenting and carotid endarectomy can result in diminished BRS and long-term impairment of baroreflex function.48 Given the increased frequency of these interventions, OH prevalence may increase, especially in patients who already have risk factors for baroreflex dysfunction.
Prevalence of OH in Hypertension
OH is strongly associated with hypertension; prevalence rates for OH and hypertension range from 13.4 to 32.1% depending on the age and comorbid medical conditions of the population.3,24,49
The ARIC, the Rotterdam study and the MPP all found that patients with OH had significantly higher rates of hypertension as well as higher resting mean SBP and DBP compared to the patients without OH.2,4,5,7,8 In an additional analysis of the MPP cohort in combination with the Malmo Diet and Cancer Study, Fedorowski et al. evaluated OH in genetically related hypertensive and normotensive individuals.
The study selected 469 middle-aged hypertensive patients and 453 of their normotensive first-degree relatives and reported an OH prevalence of 13.4% in hypertensives and 5.5% prevalence in the first-degree normotensive relatives.49 The authors inferred that OH was correlated with hypertension rather than shared familial traits.
Antihypertensive Therapy and OH
The history of antihypertensive drug treatment begins with agents that interrupted sympathetic transmission, the ganglionic blockers (hexamethonium) and neuron depleters (guanethidine).50 OH was a frequent and limiting adverse effect for the use of these agents. In recent years, antihypertensive drug treatment has shifted to lower doses for diuretics and use of other drug classes: β-receptor blockers, angiotensin-converting enzyme inhibitors, calcium-channel blockers and angiotensin receptor antagonists.
Current guidelines for treatment of hypertension emphasize lower treatment goals than in the past and frequent use of drug classes in combination to achieve these goals.51,52 The consequences of these prescribing patterns for OH during treatment of hypertension are described below.
The ARIC study and the HHP found strong associations of OH with hypertension, but did not show a statistically significant correlation with the use antihypertensive drugs.2,4–6
The ARIC study also found that among hypertensive patients using their medications, the patients with OH were more likely to have worse blood pressure control with higher baseline blood pressures,2,4,5 suggesting that these patients were in fact resistant hypertensives.
In contrast to the ARIC and HHP, the Rotterdam study and the MPP found a significant association between the use of antihypertensive medication and the presence of OH.7,53 In the study by Fedorowski et al. of genetically related hypertensives, there was an association between different antihypertensive drug treatment and OH.49
The sample sizes for patients taking the various antihypertensives were small, but OH was associated with spironolactone, and less associated with use of angiotensin-converting enzyme inhibitors, β-receptor blockers and calcium-channel blockers.49 Thiazide diuretics were prescribed infrequently in this population.
The British Women’s Heart and Health Study (BWHHS) is a prospective cohort study of 4,286 women (aged 60–80) in 23 different UK towns. In an analysis of OH, based on changes in blood pressure on standing alone (AOH), medication exposure, and comorbidities,23 there was a highly significant relationship between the number of antihypertensives taken and prevalence of AOH.
As a single components β-blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors, and α-blocking drugs had significant correlations with OH in an unadjusted model. After adjustment for age, other medications and comorbid conditions only β-blockers had a significant association with OH, with nonsignificant trends for the other medications.
Poon et al. conducted a retrospective chart review of 505 male veterans over 75-years old and evaluated for OH and for the number of medications each patient was reported as taking.21 The study categorized medications as “causative medications” if they were known to be associated with OH.
The “causative” medications included α-blockers, antihypertensives, diuretics, tricyclic antidepressants, and antipsychotics. In the study, the number of “causative medications” positively correlated with the presence of OH. The prevalence of OH in patients receiving zero, one, two, and three causative medications was 35, 58, 60, and 65%.
This study reported that OH is not only related to specific “causative drugs” but to the overall number of causative drugs prescribed, most likely due to additive effects of different drug classes.
In a study of 47 elderly patients with persistent OH and hypertension, Fotherby and Potter withdrew antihypertensive medication, and found a significant decrease in the prevalence of OH at 1-year follow-up, 23–11%.54
In a separate study of patients without OH, the same investigators demonstrated that aggressive nondrug interventions could replace drug treatment for selected elderly patients.55
These results suggest that greater use of nondrug treatment (lifestyle changes) may prevent OH during treatment of hypertension in the elderly, if outcome trials confirm this approach.
How Does AOH Increase Cardiovascular Risk in Treatment of Hypertension?
Therapeutic trials of drug treatment for hypertension in older patients have revealed that those with the lowest diastolic pressures may have less favorable outcomes than those whose diastolic pressures are somewhat higher, the J-curve effect.56,57
A recent report analyzing the results of the ONTARGET trial identifies a J-curve for SBP.58 Thus far, all J-curve analyses have used seated clinic pressures for their conclusions. AOH is, however, a recurring and transient form of episodic reduction in pressure.
Episodic reductions in pressure detected by 24-h ambulatory blood pressure monitoring have, in a small series of high-risk participants, been linked to concurrent electrocardiographic ischemic cardiac events.29
Thus, a causal relationship between AOH and risk of future CE can be suggested. Alternatively, other characteristics of those with AOH, such as subclinical autonomic dysfunction, unrecognized arterial disease, or frailty that is not clinically evident might also account for higher risk.
Enrollment and follow-up pressures for most recent clinical trials have also relied on seated clinic pressures.58,59–74 The Systolic Hypertension in Europe (Syst-Eur) trial in the elderly73,75 and the hypertension in the very elderly trial (HYVET) trial of the old–old,76–78 however, took standing blood pressure into account for enrollment.
Those with sitting SBP >160mmHg and standing pressures of SBP <140mmHg were excluded, eliminating some OH positive participants. In HYVET, the treatment goal was to reduce SBP to <150mmHg.
However, up titration of antihypertensive medication to achieve this goal was deferred for those with seated SBP >150mmHg, if standing SBP were <120mmHg. No information is yet available from HYVET regarding the frequency or management of symptomatic or asymptomatic OH in placebo and treated groups.
Recent advice for treatment of symptomatic OH emphasizes the need to preserve function and avoid falls through individualized care.79,80
Whether or not recognition of AOH, by subgroup analysis, would alter conclusions from recent clinical trials remains an unknown. Could there be a J-curve for standing blood pressure or for the magnitude of the decrease in pressure on standing?
Future therapeutic trials, especially in older participants, might benefit from taking AOH into consideration to provide better guidance for management.
AOH, is an often present, independent risk factor for mortality and CVD. AOH is also a manifestation of underlying disease and its prevalence increases with age, hypertension, diabetes, and the use of antihypertensive medications. AOH is easily determined and should be assessed in clinic visits.
It takes only a few minutes for measurement of seated and standing blood pressures that can be performed by trained physician extenders while waiting for the primary provider.
When AOH is found, the time for counseling and the increased complexity of decision making may appropriately add to the charge for the visit according to current medicare policies.
Thus the effort to detect AOH need not affect appropriate reimbursement. However, a thorough cost-effectiveness analysis is far beyond the scope of this review.
In the current clinical practice, the frequency of assessment for AOH is unknown but is likely to be uncommon when no related symptoms are recognized. Guidelines for treatment of hypertension recommend the periodic assessment for postural hypotension, without providing advice for changing strategy when OH is identified.51,52
For older patients, the HYVET strategy of withholding up titration of antihypertensive medications when AOH is present may be reasonable.
When OH is associated with nocturnal hypertension, change in dosing patterns may reduce nighttime pressure and OH as well.81–83 Replacement of antihypertensive medication with more attention to lifestyle improvement may have potential to benefit some patients at increased risk due to AOH.
Until more evidence is available, we recommend the routine assessment of AOH, attention to those drugs that might cause or aggravate AOH and caution in increasing antihypertensive medications when AOH is found.
In future clinical trials for hypertension and perhaps high-risk states for CVD, assessment of AOH should be included and correlated to the risk of mortality and CVD. This recommendation will elucidate the risk of AOH with different antihypertensive therapies and it will provide more information on how episodic, but asymptomatic, hypotension correlates with CVD morbidity and mortality. Potentially, this may lead to improved and more careful management of hypertension.