Authors: Sean W. Dooley (1.Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts), Fredrick Larbi Kwapong (1.Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts), Hannah Col (1.Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts), Ruth-Alma N. Turkson-Ocran (1.Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 2.Harvard Medical School; Boston, MA), Long H. Ngo (1.Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 2.Harvard Medical School; Boston, MA), Jennifer L. Cluett (1.Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts), Kenneth J. Mukamal (1.Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 2.Harvard Medical School; Boston, MA), Lewis A. Lipsitz (1.Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 3.Hebrew SeniorLife Marcus Center), Mingyu Zhang (1.Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 2.Harvard Medical School; Boston, MA), Natalie R. Daya (4.Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland), Elizabeth Selvin (4.Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland), Pamela L. Lutsey (5.University of Minnesota), Josef Coresh (6.New York University, Grossman School of Medicine), Beverly Gwen Windham (7.University of Mississippi), Lynne Wagenknecht (8.Wake Forest University School of Medicine), Stephen P. Juraschek (1.Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 2.Harvard Medical School; Boston, MA)
Categories: Article, Orthostatic hypertension, coronary heart disease, heart failure, stroke, mortality, cohort
Source: Hypertension (Dallas, Tex. : 1979)
Authors: Sean W. Dooley, Fredrick Larbi Kwapong, Hannah Col, Ruth-Alma N. Turkson-Ocran, Long H. Ngo, Jennifer L. Cluett, Kenneth J. Mukamal, Lewis A. Lipsitz, Mingyu Zhang, Natalie R. Daya, Elizabeth Selvin, Pamela L. Lutsey, Josef Coresh, Beverly Gwen Windham, Lynne Wagenknecht, Stephen P. Juraschek
Orthostatic hypertension (OHTN) is an emerging risk factor for adverse events. Recent consensus statements combine an increase in blood pressure (BP) upon standing with standing hypertension, but whether these two components have similar risk associations with cardiovascular disease (CVD) is unknown.
The Atherosclerosis Risk in Communities (ARIC) Study measured supine and standing BP during visit 1 (1987–1989). We defined systolic orthostatic increase (a rise in SBP≥20 mmHg, standing minus supine BP) and elevated standing SBP (standing SBP≥140 mmHg) to examine the new consensus statement definition (rise in SBP≥20 mmHg and standing SBP≥140 mmHg). We used Cox regression to examine associations with incident CHD, heart failure, stroke, fatal CHD, and all-cause mortality.
Of 11,369 participants (56% female, 25% Black adults, mean age 54 years) without CVD at baseline, 1.8% had systolic orthostatic increases, 20.1% had standing SBP≥140 mmHg, and 1.3% had systolic orthostatic increases with standing SBP≥140 mmHg. During up to 30 years of follow-up, orthostatic increases were not significantly associated with any of the adverse outcomes of interest, while standing SBP≥140 mmHg was significantly associated with all endpoints. In joint models comparing systolic orthostatic increases and standing SBP≥140 mmHg, standing SBP≥140 mmHg was significantly associated with higher risk of CVD and associations differed significantly from systolic orthostatic increases.
Unlike systolic orthostatic increases, standing SBP≥140 mmHg was strongly associated with CVD outcomes and death. These differences in CVD risk raise important concerns about combining systolic orthostatic increases and standing SBP≥140 mmHg in a consensus definition for OHTN.
Orthostatic hypertension (OHTN) is an emerging hypertension phenotype^1^ characterized by a rise in blood pressure (BP) upon assuming an upright posture. There is considerable interest in appropriately characterizing OHTN as it is strongly associated with cardiovascular disease (CVD), stroke, kidney disease, cognitive impairment, and all-cause mortality.^2–5^ However, its definition remains controversial.
Recent consensus statements have recommended that OHTN encompass both systolic orthostatic increases in BP and exceed a standing BP threshold of systolic BP ≥140 mm Hg.^6,7^ However, combining orthostatic increase with standing SBP ≥140 mm Hg in a single definition raises the question of whether these components have similar or distinct associations with CVD. If the systolic orthostatic increase in BP and standing SBP ≥140 mm Hg have different relationships with CVD then combining the two might obscure critical distinctions in their pathophysiology, risk factors, and clinical outcomes. This potential blending of distinct phenotypes could have meaningful implications for risk stratification and the development of targeted interventions for this emerging phenotype.
We conducted a prospective cohort analysis of data from the Atherosclerosis Risk in Communities (ARIC) study. The ARIC Study has followed middle-aged adults in community settings for over 30 years to monitor for the occurrence of CVD events. In previous ARIC studies, orthostatic hypotension (OH), defined as a decrease in BP (systolic ≥20 mm Hg or diastolic ≥10 mm Hg) from the supine to standing position, was identified as a predictor for CVD, including coronary heart disease (CHD), stroke, heart failure (HF), falls, and syncope, even when considered independently of other relevant risk factors.^8–11^ However, the specific associations between distinct orthostatic phenotypes, such as components of OHTN, and adverse events have not been examined in ARIC.
Our objectives were to determine the prevalence of traditional and alternative definitions of OHTN and to determine the associations of these definitions with incident CVD. We postulated that there would be differences in outcomes when comparing orthostatic increases and standing hypertension with CVD events. Accordingly, we argue against combining the two conditions for clinical characterization and in future research endeavors focusing on OHTN.
The ARIC study is a population-based prospective cohort of 15,792 adults. Participants aged 45 to 64 years were enrolled between 1987 and 1989 (visit 1) from 4 US communities (Forsyth County, North Carolina; Jackson, Mississippi; suburbs of Minneapolis, Minnesota, and Washington County, Maryland) and then followed to the present day. The baseline ARIC protocol involved physical examinations, medical interviews, laboratory tests, and orthostatic BP measurements.^12–14^
We excluded participants who did not participate in the standing BP protocol (N=2,548). We also excluded participants with a history of CHD (N=766), HF (N=750), or stroke (N=286). In addition, we excluded those who were missing a covariate of interest or rare ethnic groups (N=493) (note some participants were excluded for more than one reason), such that our study population included 11,369 participants.
All participants provided written informed consent. The study protocol was approved by Institutional Review Boards at all study sites. The Beth Israel Deaconess Medical Center Institutional Review Board designated the present study as human subjects exempt research.
Supine and standing BPs were measured during ARIC visit 1 (1987–1989) in over 13,000 ARIC participants as part of an ancillary protocol on orthostatic hypotension.^15^ Supine BP was measured up to five times after a 20-minute rest, using a Dinamap 1846 SX, an automated BP device. Measurement occurred every 20–30 seconds over a 2-minute period without a scheduled pause between deflation and re-inflation. After the supine measurement was complete, participants were instructed to stand up as quickly and safely as possible and stand with their arm supported at heart level, using a bedside table. In the standing position they underwent up to five measurements (there were at least 4 measurements for 91% of participants) in similar fashion to the supine measurement (i.e., every 20–30 seconds without a scheduled pause between measurements) during the first two minutes of standing.
An orthostatic increase was defined as a rise in SBP of ≥20 mm Hg or DBP of ≥10 mm Hg when moving from supine to standing. We also examined the following systolic orthostatic increase (a rise in SBP of ≥20 mm Hg), standing SBP ≥140 mm Hg, diastolic orthostatic increase (a rise in DBP of ≥10 mm Hg), and standing DBP ≥90 mm Hg.^2,3,6,7,16,17^ Moreover, we examined two combined systolic orthostatic increase with standing SBP ≥140 mm Hg (the new orthostatic consensus definition),^6,7^ and diastolic orthostatic increase with standing DBP ≥90 mm Hg. We also defined OH as a change in SBP ≤−20 mm Hg or DBP ≤−10 mm Hg.
Active surveillance for CVD events and mortality was available through December 31, 2019, except the Jackson site, where follow-up data was unavailable after December 31, 2017. Surveillance involved reviewing local hospital discharge lists, conducting regular telephone check-ins (yearly before 2012 and twice-yearly thereafter) with participants, and linking data with state and national death indexes. Medical records and death certificates were abstracted by ARIC staff for endpoint classification. Comprehensive details on event ascertainment and adjudication are available elsewhere.^14^ The five outcomes of interest in this study (1) CHD, (2) HF, (3) stroke, (4) fatal CHD, and (5) all-cause mortality. Incident CHD was adjudicated and based on a composite definition that included fatal CHD, having undergone a coronary procedure, or silent myocardial infarction based on electrocardiogram (ECG) abnormalities or changes. Incident HF was defined by the initial hospitalization or HF-related death, indicated by an International Classification of Diseases, Ninth Revision (ICD-9) code of 428.x or International Classification of Diseases, Tenth Revision (ICD-10) code I50 in any position on the hospital discharge list or death certificate.^18^ Incident stroke events (including ischemic and hemorrhagic strokes) were identified through active surveillance of hospitalizations, cohort follow-up, and linkage with death registries, including both definite and probable stroke events adjudicated by committee review. Fatal CHD was defined as death related to CHD with CHD defined as above. Death was determined by reviewing hospitalization discharge records, coroner reports, linkage with local death records, the National Death Index, and next-of-kin interviews.
Baseline data from visit 1 were collected by trained study personnel using standardized protocols with predetermined quality control measures. Self-reported covariates included age, sex (male or female), race (White or Black), alcohol use (never, former, or current), education level (less than high school degree; high school degree or equivalent or vocational school; or any college or professional school), smoking status (never, former, or current), and antihypertensive or cholesterol-lowering medication use during the prior 2 weeks based on medications brought to the clinic and/or self-report (yes or no). Physical activity was assessed via the ARIC Study/Baecke Physical Activity questionnaire,^19^ which uses leisure index as a self-reported measure of non-sport related exercise during leisure time (e.g. physical activity not at work). Race and clinic center were jointly classified to reflect the composition of the Forsyth County, NC (White participants); Forsyth County, NC (Black participants); Jackson, MS (Black participants); suburbs of Minneapolis, MN (White participants); and Washington County, Maryland (White participants).
Diabetes mellitus status was defined as having a fasting blood glucose ≥126 mg/dL, a non-fasting blood glucose ≥200 mg/dL, a self-report of diabetes diagnosed by a physician, or self-reported diabetes mellitus medication use. Seated BP measurements were based on sitting SBP and DBP levels estimated from a mean of the second and third of 3 measurements obtained after 5 minutes of seated rest using a Hawksley random-zero sphygmomanometer. Serum creatinine was measured by the modified kinetic Jaffé method and was used to calculate the estimated glomerular filtration rate via the updated 2021 Chronic Kidney Disease Epidemiology Collaboration equation.^20^ Body mass index was determined using height and weight measurements. Resting heart rate was measured from an ECG performed at rest. Lipids (total and high-density lipoprotein cholesterol) were measured in plasma. Prevalent CHD at baseline was determined by self-reported history of myocardial infarction, heart or arterial surgery, coronary bypass, balloon angioplasty, or angioplasty of coronary artery, and by past myocardial infarction from adjudicated ECG data from visit 1. Prevalent HF at baseline was determined by Gothenburg Criteria^21^ and self-reported use of HF medications in the last two weeks. Prior stroke was determined by a standardized questionnaire.^22^
We summarized baseline characteristics of the population at the time of the orthostatic BP assessment overall and by orthostatic increases status, using means and proportions. We also determined baseline characteristics by the presence or absence of systolic orthostatic increases or standing SBP ≥140 mmHg as these were a focus of the recent consensus statement.^6,7^ We determined the prevalence of orthostatic increases and a number of alternate definitions (systolic and diastolic components, as well as standing SBP ≥140 mmHg, standing DBP ≥90 mm Hg, systolic orthostatic increases and standing SBP ≥140 mmHg, and diastolic orthostatic increases and standing DBP ≥90 mm Hg) using proportions with logit-transformed confidence intervals. This approach was also used to examine the prevalence of seated hypertension (based on measured seated BP or antihypertensive medication use) by definition of OHTN component. We used Lowess curves and scatter plots of SBP or DBP in the standing, supine, and seated positions to compare the relationship between standing and supine as well as standing and seated BP across the study population.
Using Cox regression, we determined the association between orthostatic increase and alternate OHTN definitions with incident CHD, incident HF, incident stroke, fatal CHD, and all-cause mortality. The primary models were adjusted for age, sex, race-center, eGFR, BMI, heart rate, HDL cholesterol, total cholesterol, diabetes mellitus, cholesterol-lowering medication use, alcohol, education, leisure index, and smoking status, consistent with our prior work.^23,24^ Absolute risk was visualized using cumulative incidence plots by orthostatic increase, standing SBP ≥140 mm Hg, neither condition, or both conditions. In sensitivity analyses we also examined the association between standing SBP ≥140 mm Hg and outcomes adjusted for supine SBP and DBP as well as seated SBP and DBP. The continuous association between change in SBP or DBP with each outcome was examined via restricted cubic splines by standing SBP ≥140 mm Hg status adjusted for the covariates above. In addition, we examined the relationship between continuous change in SBP or DBP in Cox models adjusted for the covariates above in the overall population and among the population without OH.
In addition, we used Cox regression models with both a covariate for systolic change ≥20 mm Hg and a covariate for standing SBP ≥140 mm Hg in relation to our outcomes, adjusted as above. We compared both these components of the consensus definition via Wald tests. These analyses were repeated with models that included a diastolic change ≥10 mm Hg and standing DBP ≥90 mm Hg and in sensitivity with adjustment for supine or seated BP.
All analyses were conducted using Stata 15.1 (Stata Corp, College Station, TX); a two-tailed P-value < 0.05 was considered statistically significant.
The study sample (N=11,369) was 56% women and 25% Black adults with a mean (SD) age of 53.9 (5.7) years at baseline (Table 1; see Supplement Table ST1–ST2 for characteristics by systolic orthostatic increase or standing SBP ≥140 mm Hg). Standing SBP and supine SBP had a strong positive correlation (Pearson’s r = 0.869) (Figure 1). Similarly, standing DBP and supine DBP were positively correlated (Pearson’s r = 0.856). Seated SBP ≥130 or DBP ≥80 mm Hg was highly prevalent among adults with standing SBP ≥140 mm Hg (Supplement Table ST3).
Among the participants, the prevalence of orthostatic increase was 10%, with 2% exhibiting a systolic orthostatic increase and 10% displaying a diastolic orthostatic increase (Table 2). Twenty percent of the participants had standing SBP ≥140 mmHg while 9% had standing diastolic DBP ≥90 mm Hg. The prevalence of the combined phenotypes was lower with only 1% having both systolic orthostatic increase and standing SBP ≥140 mmHg, while only 3% had diastolic orthostatic increases and standing DBP ≥90 mm Hg.
Median follow-up time ranged from 24 to 28 years. Among the four OHTN components examined, standing SBP ≥140 mm Hg was associated with the highest cumulative incidence of any CHD, HF, fatal CHD, and all-cause mortality. Having both an orthostatic increase and standing SBP ≥140 mm Hg was associated with the highest cumulative incidence of stroke (Supplement Figure SF1–SF2). In contrast, orthostatic alone was associated with a lower cumulative incidence of HF, stroke, and all-cause mortality. These findings were consistent with adjusted Cox proportional hazards models where standing SBP ≥140 mm Hg was significantly associated with all outcomes and death in the overall population (Table 3) and the population without OH (Supplement Table ST4). In contrast, orthostatic increase was not positively associated with any outcomes, but was inversely associated with HF (HR 0.85; 95% CI: 0.74, 0.97). In sensitivity analyses with models adjusted for supine SBP and DBP or seated SBP or DBP, the association between standing SBP ≥140 mm Hg and outcomes was significantly attenuated (Supplement Tables ST5–ST6).
Generally, increases in BP with standing were not associated with higher cardiovascular risk, unlike decreases in BP. Examination of the continuous relationship between change in SBP (Figure 2) or DBP (Supplement Figure SF5) showed that in general, a larger drop in BP was associated with a higher risk of CVD outcomes regardless of standing SBP ≥140 mm Hg status. Of note, continuous changes in either SBP or DBP were inversely associated with CVD outcomes even after excluding those with OH (Supplement Table ST7).
In models with both systolic orthostatic increase and standing systolic HTN, systolic orthostatic increase (versus no systolic orthostatic increase) was associated with a lower risk of CHD (HR: 0.63; 95% CI: 0.45, 0.89) and was not associated with other outcomes, while standing SBP ≥140 mm Hg was positively associated with all outcomes (Table 4). Comparison of the coefficients for systolic orthostatic increase and standing SBP ≥140 mm Hg were significantly different (P <0.05). Similarly, in models with both diastolic orthostatic increase and standing DBP ≥90 mm Hg, diastolic orthostatic increase was inversely associated with HF, while standing DBP ≥90 mm Hg was positively associated with all CVD outcomes. Moreover, coefficients all differed significantly from each other (P <0.05). Associations were attenuated when adjusted for supine or seated BP (Supplement Tables ST8–ST9).
In this population-based sample of 11,369 middle-aged adults without prior CVD, standing SBP ≥140 mm Hg was more common than orthostatic increases in BP. While orthostatic increase was not associated with risk for CVD or death, standing SBP ≥140 mm Hg was strongly associated with greater risk for CVD or death. Moreover, in joint models, standing SBP ≥140 mm Hg or DBP ≥90 mm Hg was associated with higher risk of CVD or death, while orthostatic increases in SBP were inversely associated with CHD and orthostatic increases in DBP were inversely associated with HF. These results question the combination of these two BP measures in a consensus definition for OHTN.
There is substantial heterogeneity in reports on the prevalence of OHTN in the general population with estimates ranging as low as 1% to as high as 28%.^25^ This range likely reflects differences in underlying study populations with older populations having a greater prevalence of OHTN.^26,27^ Additional factors driving differences in prevalence include varying diagnostic criteria. In recent reviews, definitions for OHTN varied substantially, including any increase in SBP or DBP with standing to a sustained increase (lasting greater than one minute) in SBP ≥20 mm Hg or above 140/90 mm Hg if the patient was normotensive in the supine position.^2,16^ Our study is consistent with the literature in that our orthostatic prevalence estimate ranged from 1.3 to 20.1% depending on the component used. Given this spread in prevalence estimates, long-term clinical events play an important role in informing definitions of this BP phenotype in order to identify, study, and treat patients with orthostatic increases or standing elevations in BP.
A growing body of evidence identifies orthostatic increases in BP as a potentially pathologic hypertension phenotype. While some studies have shown associations with higher risk of CVD, dementia, chronic kidney disease progression, and all-cause mortality,^5,28^ other studies have not.^26,29–32^ We did not find orthostatic increase to be associated with a risk of CVD events in the ARIC cohort. The observed discrepancy between our findings and prior studies is unclear. Differences in the study population, such as variations in age, comorbidities, or medication use, may explain why previous research demonstrated stronger associations. In addition, older or frail populations may exhibit more pronounced cardiovascular risks than younger, healthier cohorts. Moreover, orthostatic increases may be inversely related to CHD and HF, particularly after accounting for standing SBP ≥140 mm Hg, suggesting that BP augmentation after standing may represent a normal physiologic response. However, others have noted that orthostatic increases in BP upon standing are associated with masked hypertension.^33^ Moreover, secondary analyses of SPRINT suggest that more intensive BP treatment did not reduce CVD events among adults with orthostatic increases in BP upon standing, suggesting that it may be a novel phenotype, requiring a unique treatment approach.^17^ Our study underscores the lack of data to guide treatment for OHTN. Future studies may address this gap, particularly for patients with controlled seated BP and exaggerated orthostatic responses, through a separate study pooling orthostatic data from clinical trials. Delineating when and with what populations orthostatic increases may be harmful represents an important topic for future research.^34^
There are few studies in the literature on standing BP with respect to long-term outcomes.^23,24^ In contrast to orthostatic increases in BP, standing SBP ≥140 mm Hg was associated with a higher risk for CVD events in this cohort. We also found that standing BP was highly correlated with supine and seated BP, such that those with elevated BP while standing were more likely to have elevated BP in other body positions. Given that seated hypertension is an important risk factor for CVD, it is possible that the strong positive association between standing SBP ≥140 mm Hg and CVD events merely mirrors CVD risk related to hypertension while supine or sitting. Indeed, in sensitivity analyses, after adjustment for supine or seated BP measurements, the positive association between standing SBP ≥140 mm Hg and outcomes was largely attenuated. More work is needed to establish a clinical role for the assessment of BP in distinct body positions to characterize their independent association with CVD events.
This study has limitations. First, there were only a few adults with both systolic orthostatic increases and standing SBP ≥140 mm Hg, which may have reduced our power to detect associations between the new consensus definition and outcomes. Moreover, we adjust for many covariates. Despite this, orthostatic increase alone was inversely related to some CVD events (e.g., CHD or HF), suggesting that its risk relationship differed from standing SBP ≥140 mm Hg and the two should not be combined. Second, our study included middle-aged adults. As orthostatic increase may be more prevalent in older adults, it could have different implications among different populations. Thus, our findings should be replicated in other cohorts. Third, our analyses are based on a single visit with standing BP. Repeated assessments could be useful to confirm the presence of orthostatic increases and the presence of related underlying pathophysiology. Moreover, longitudinal assessments could better characterize changes over time. A fourth limitation of the study is the relatively low prevalence of both orthostatic increases, standing hypertension, and potentially seated hypertension compared to more contemporary populations. While this may affect our power to detect associations with some outcomes, the adjusted hazard ratios for orthostatic increases versus standing hypertension showed opposite trends for several outcomes, which is reassuring. Finally, this was an observational study, which could be subject to residual confounding.
This study also has strengths. First, the inclusion of a sizable sample of middle-aged, community-dwelling Black and White adults in the ARIC study enhances the generalizability of our findings to a diverse ambulatory population. Second, the ARIC staff received thorough training to carefully implement the study’s standardized supine, standing, and seated BP measurements. Moreover, their detailed collection of other covariates permitted robust adjustment for potential confounders. Finally, CVD events were the primary focus of the ARIC study and adjudicated with careful ascertainment over multiple decades of surveillance.
Our study has important implications for the characterization and definition of OHTN in subsequent research and clinical care. In some sense, the new consensus definition addresses one of the primary limitations of the OH consensus definition, i.e., it is not tethered to an actual hypotensive state, such that one may have a drop in BP upon standing, but still have elevated BP in both supine and standing positions.^7^ With the new OHTN definition, linking the rise in BP after standing with a threshold of standing SBP ≥140 mm Hg addresses this issue, ensuring that a state of hypertension is always present. However, our study raises concerns with this approach as an orthostatic increase in BP was not consistently related to CVD events and was potentially a healthier finding for some conditions (e.g., CHD or HF), while standing SBP ≥140 mm Hg was always related to higher risk for CVD events. While it has yet to be seen if similar discordance in risk association might be observed among older adults or adults with higher risk conditions (for example, chronic kidney disease or diabetes), our evidence does not support the combination of these two BP components and rather suggests that they be considered separately for the study of OHTN in subsequent research.
In conclusion, in this middle-aged, community-based cohort, systolic orthostatic increase in BP and standing SBP ≥140 mm Hg differed substantially in their risk associations with CVD and death. Unlike orthostatic increases in BP, standing elevations in BP demonstrated a robust positive association with CVD events and mortality. Contrary to the recent consensus definition, this finding underscores the importance of distinguishing between orthostatic increases and standing SBP ≥140 mm Hg in clinic care and subsequent research.
Orthostatic hypertension is related to adverse outcomes, and hypertension treatment may not be as effective among patients with orthostatic hypertension. However, definitions for orthostatic hypertension have varied. A recent consensus statement recommended combining orthostatic increases in blood pressure upon standing with standing hypertension, but there has been limited evidence characterizing the relationship of this definition with cardiovascular disease events. In the present analysis of community-dwelling, middle-aged adults with blood pressure measured in both the supine and standing position, we found that increases in blood pressure after standing were not consistently associated with cardiovascular disease and may be inversely related to some cardiovascular events. In contrast, hypertension in the standing position was consistently associated with cardiovascular disease events. A combined definition with both orthostatic increase and standing hypertension, obscured the risk associations between orthostatic increases in blood pressure or standing hypertension with cardiovascular disease. These findings raise concerns about combining these two components into a single definition, as the two may have distinct risk factors, underlying physiology, and downstream implications for cardiovascular disease.