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00004872-201401000-0001100004872_2014_32_75_fedorowski_cardiovascular_1article< 94_0_17_5 >Journal of Hypertension© 2014 Wolters Kluwer Health | Lippincott Williams & WilkinsVolume 32(1)January 2014p 75–81Systolic and diastolic component of orthostatic hypotension and cardiovascular events in hypertensive patients: the Captopril Prevention Project[ORIGINAL PAPERS: Orthostatic hypotension]Fedorowski, Artura,b; Wahlstrand, Björnc; Hedner, Thomasc; Melander, OlleaaDepartment of Clinical Sciences, Lund University, Clinical Research CenterbArrhythmia Department, Skåne University Hospital, MalmöcInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenCorrespondence to Artur Fedorowski, MD, PhD, Arrhythmia Department, Inga Marie Nilssons gata 46, Skåne University Hospital, 205 02 Malmö, Sweden. E-mail: Artur.fedorowski@med.lu.se Abbreviations: BP, blood pressure; CAPPP, The Captopril Prevention Project; CCB, calcium channel blocker; CVD, cardiovascular disease; MI, myocardial infarctionReceived 20 March, 2013Revised 31 July, 2013Accepted 13 August, 2013AbstractObjective: Impact of SBP vs. DBP decrement during orthostasis on cardiovascular events in hypertension is not clear.Methods: We assessed prospective association of orthostatic hypotension with mortality and major cardiovascular events [myocardial infarction (MI) and stroke] among 8788 treated hypertensive patients (52.2% men; mean age 52 years, mean BP 161/99 mmHg) without history of MI or stroke at baseline. Orthostatic hypotension was defined according to combined international consensus criteria, and as either systolic (decrease ≥20 mmHg) or diastolic orthostatic hypotension (decrease ≥10 mmHg). Final Cox regression model was adjusted for age, sex, supine SBP and DBP, diabetes, smoking, and total cholesterol.Results: A total of 1060 (12.1%) study participants fulfilled combined orthostatic hypotension criteria, of these 886 (10.1%) met systolic and 290 (3.3%) diastolic criterion. In the crude analysis, combined orthostatic hypotension criteria were predictive of the composite endpoint, major cardiovascular event, total mortality, and stroke but not MI. After full adjustment, combined orthostatic hypotension criteria and systolic orthostatic hypotension were independently associated with stroke only (hazard ratio: 1.48, 1.07–2.05, P = 0.019, and 1.53, 1.08–2.15, P = 0.015, respectively), whereas the composite endpoint tended in the same direction (hazard ratio: 1.21, 0.98–1.51, P = 0.075, and 1.24, 0.99–1.55, P = 0.066, respectively). In contrast, diastolic orthostatic hypotension was associated with increased risk of MI (hazard ratio: 2.04, 1.20–3.46, P = 0.008).Conclusion: Orthostatic hypotension has a dual role in cardiovascular events among hypertensive patients: SBP fall indicates higher risk of stroke, whereas DBP fall confers higher risk of MI.INTRODUCTIONIn the longitudinal population-based studies, orthostatic hypotension has been consistently identified as an independent predictor of total mortality and cardiovascular morbidity [1–4]. Among traditional cardiovascular risk factors, orthostatic hypotension strongly correlates with hypertension and antihypertensive treatment [5,6]. Although a causal relationship between increased blood pressure (BP) and orthostatic hypotension is still disputable, their concurrence represents a potent combination of cardiovascular risk. However, the prospective association of prevalent orthostatic hypotension with premature death and cardiovascular events has been hitherto poorly studied in hypertensive patients. In the Captopril Preventive Project (CAPPP) [7], a large randomized trial comparing captopril with β-blockers and/or diuretics, mortality and cardiovascular morbidity did not differ between the therapeutic groups. The assessment of orthostatic BP response at baseline, though included in the study protocol, has not been previously analyzed. In an earlier study, we observed that orthostatic hypotension predicted all-cause mortality and coronary events in predominantly normotensive individuals, though its association with stroke was uncertain [6], in contrast to results reported by other authors [8,9]. Moreover, we found that DBP fall during orthostasis was a relatively stronger predictor of coronary events in general population as compared with the SBP fall [6]. Consequently, we designed a model to analyze the predictive role of orthostatic hypotension, classified as overall, and its systolic and diastolic components, separately, in long-term mortality and cardiovascular events in a cohort consisting of hypertensive patients under systematic BP-lowering treatment.MATERIALS AND METHODSThe rationale, design, and the main outcomes of the CAPPP trial were reported in detail previously [7]. Briefly, men and women aged 25–66 years who had treated or untreated hypertension were enrolled at 536 health centers in Sweden and Finland, if their DBP was 100 mmHg or higher measured on two separate occasions prior to the recruitment. Exclusion criteria were secondary hypertension, serum creatinine concentration at least 150 μmol/l, and indication for treatment with β-blockers other than hypertension. Eligible patients were randomly assigned captopril or conventional antihypertensive treatment with diuretics, β-blockers, or both according to the Prospective Randomized Open Blinded Endpoint (PROBE) design criteria [10]. The goal of antihypertensive treatment was a supine DBP of 90 mmHg or less. The investigators were free to increase the dose of antihypertensive agent, and choose a suitable conventional treatment among the respective classes of β-blockers or diuretics. A calcium antagonist could be added in both treatment groups to achieve the presumed treatment goal.Blood pressure measurements and orthostatic hypotensionSupine BP was measured after 10-min rest using a conventional mercury sphygmomanometer with an appropriate cuff size. Standing BP was measured after 1 min in the upright standing position and arm hanging down along the chest with cuff placed at the heart level. A mean of two measurements was calculated to the nearest 2 mmHg. Overall orthostatic hypotension was defined according to the international consensus criteria as a decrease in SBP at least 20 mmHg and/or decrease in DBP at least 10 mmHg on standing [11]. Systolic and diastolic orthostatic hypotension was defined according to systolic or diastolic criterion only, respectively.EndpointsThe primary endpoint in CAPPP was a major cardiovascular event defined as fatal or nonfatal myocardial infarction (MI) and stroke, or other cardiovascular death. For the purpose of this study, we separately analyzed the relationship of overall, systolic and diastolic orthostatic hypotension with the primary endpoint (major cardiovascular event), and the following secondary endpoints: MI, stroke, all-cause mortality, and the composite endpoint (death, MI, or stroke). The assessment of study endpoints was thoroughly described in a previous publication [7].Statistical methodsAll individuals from the original CAPPP population who had reported history MI or stroke at randomization were excluded. Groupwise differences in continuous variables between orthostatic hypotension-positive and orthostatic hypotension-negative individuals were compared using one-way analysis of variance (ANOVA) test, whereas categorical variables were compared using Pearson's χ2 test.For each patient, only the first occurrence of the adequate endpoint was included in the analysis. At the initial stage, in order to test the proportional hazard assumption, we graphically assessed the relationship between orthostatic hypotension and the composite endpoint using the Kaplan–Meier method. Then, we applied crude and adjusted Cox regression models using follow-up period since randomization as a time variable. In the adjusted model 1, we entered age at randomization and sex as covariates, whereas a more comprehensive model 2 also included supine SBP and supine DBP at randomization, diabetes, smoking, and total cholesterol. The positive associations were then tested in a model including the presence or absence of antihypertensive treatment at randomization.Potential interactions between orthostatic hypotension and the type of antihypertensive treatment on specific endpoints were evaluated by including interaction terms [orthostatic hypotension × captopril, orthostatic hypotension × β-blocker, orthostatic hypotension × diuretic, and orthostatic hypotension × calcium channel blocker (CCB)] in the multivariate model. All analyses were performed using IBM SPSS Statistics version 20 for Windows (SPSS Inc., Chicago, Illinois, USA). All tests were two-sided, whereby P <0.05 was considered statistically significant for noninteraction terms, and P <0.10 for interaction terms.RESULTSA total of 10 985 patients were enrolled in CAPPP, of these 8788 had complete orthostatic BP data and no history of MI or stroke The systolic orthostatic hypotension criterion was met by 886 patients (10.1%), the diastolic criterion by 290 patients (3.3%), and 1060 patients (12.1%) were classified as having orthostatic hypotension based on the combined criteria. Characteristics of study population stratified according to orthostatic hypotension status at randomization are presented in Table 1. A higher proportion of patients with orthostatic hypotension were women (53.4 vs. 46.9%), and orthostatic hypotension was associated with higher age, higher supine SBP and DBP, higher total cholesterol, and current antihypertensive treatment at randomization. Study participants were followed up for a mean period of 72 ± 17 months with the composite endpoint incidence rate of 12.7/1000 person-years. The specific incidence of all study endpoints is summarized in Table 2. As can be seen in Fig. 1, the proportional hazard assumption between orthostatic hypotension and the composite endpoint, that is, death, MI, or stroke, was satisfied during the entire follow-up period.TABLE 1 Characteristics of the Captopril Preventive Project study population (n = 8788) according to orthostatic hypotension status at baseline presented as means with standard deviation or percentagesTABLE 2 Total mortality and incidence of cardiovascular events among the Captopril Preventive Project participants with available orthostatic hypotension data and no history of myocardial infarction or stroke (n = 8788)FIGURE 1. Kaplan–Meier curves for the cumulative incidence (%) of the composite endpoint (death, myocardial infarction, or stroke) in the Captopril Preventive Project (CAPPP) study according to the orthostatic hypotension status at randomization (n = 8788). OH, orthostatic hypotension.Relations between prevalent orthostatic hypotension according to the combined criteria and study endpoints in different Cox regression models are presented in Fig. 2, whereas those regarding systolic and diastolic orthostatic hypotension are presented in Table 3. In the crude analysis, orthostatic hypotension was predictive of the composite endpoint, major cardiovascular event, total mortality, and stroke but not MI. After full adjustment, combined orthostatic hypotension criteria and systolic orthostatic hypotension were independently associated with stroke only (hazard ratio: 1.48, 1.07–2.05, P = 0.019, and 1.53, 1.08–2.15, P = 0.015, respectively), whereas the composite endpoint tended in the same direction (hazard ratio: 1.21, 0.98–1.51, P = 0.075, and 1.24, 0.99–1.55, P = 0.066, respectively). In contrast, diastolic orthostatic hypotension was associated with increased risk of MI (hazard ratio: 2.04, 1.20–3.46, P = 0.008). Further adjustment for the presence or absence of antihypertensive treatment at randomization did not alter these results, although previous antihypertensive treatment was weakly associated with the risk of MI (hazard ratio: 1.33, 0.99–1.79, P = 0.062) but not with the risk of stroke (hazard ratio: 1.09, 0.82–1.46, P = 0.54). In parallel, in the fully adjusted model 2, supine SBP was independently of orthostatic hypotension associated with the risk of MI and stroke (hazard ratio per 10 mmHg: 1.16, 1.08–1.24, P <0.001, and 1.12, 1.04–1.21, P = 0.003, respectively), whereas supine DBP was inversely associated with the risk of MI and was not associated with stroke risk (hazard ratio per 10 mmHg: 0.76, 0.69–0.90, P = 0.001, and 0.92, 0.79–1.08, P = 0.29, respectively). Further, exclusion of participants who developed heart failure (n = 121) or atrial fibrillation (n = 206) during the follow-up period did not substantially change relationship between systolic orthostatic hypotension and stroke (hazard ratio: 1.50, 1.04–2.18, P = 0.031). There were no significant interactions between orthostatic hypotension and the group of antihypertensive drugs on any of the study endpoints (data not shown).FIGURE 2. Association between overall orthostatic hypotension at randomization and study endpoints according to three Cox regression models: crude; model 1, adjusted for age and sex; model 2, adjusted for age, sex, supine SBP and DBP, total cholesterol, current smoking, and diabetes (n = 8 788). CV, cardiovascular; MI, myocardial infarction.TABLE 3 Relative risk of unfavorable eventa predicted by baseline systolic and diastolic orthostatic hypotension in the Captopril Preventive Project study (n = 8788)DISCUSSIONIn the last two decades, population-based epidemiological studies have identified orthostatic hypotension as an independent predictor of cardiovascular morbidity. Here, we present a new observation derived from a large cohort of hypertensive patients systematically treated with BP-lowering drugs in a randomized and controlled manner. The prevalence of orthostatic hypotension in the study population was in concordance with that previously found among middle-aged hypertensive individuals [5]. In general, after adjustment for traditional risk factors, the presence of orthostatic hypotension according to the combined systolic and diastolic criteria was associated with the increased risk of incident cerebrovascular event and tended to predict the composite event of death and manifest cardiovascular disease. Interestingly, adjustment for the type of antihypertensive drug used in the study did not alter these relations. When analyzed separately, a decrease in SBP was even more strongly associated with the higher incidence of stroke (↑53%), and composite endpoint (↑24%), whereas decrease in DBP indicated the higher incidence (↑100%) of MI. Thus, the systolic variation of BP during orthostasis had greater impact on cerebral circulation, whereas the diastolic variation mainly affected the coronary circulation. The overall effect of orthostatic hypotension was probably driven by the systolic component as three times more patients with hypertension met the systolic criterion compared with those who met the diastolic criterion of orthostatic hypotension, with only a fraction (≈12%) meeting the combined criteria.Systolic orthostatic hypotension and strokeAmong traditional risk factors for stroke, orthostatic hypotension is rarely mentioned in the current literature, in contrast to elevated resting BP [12]. Although the presence of orthostatic hypotension correlates with history of stroke in hypertensive patients [13], the longitudinal association between orthostatic hypotension and stroke has never been consistently explored in such settings. Previously, we reported that in the general population, SBP drop during early orthostasis of not less than 20 mmHg may be a better indicator of stroke risk than the combined criteria of orthostatic hypotension [14]. In parallel, some authors observed that an orthostatic SBP but not DBP decrease was associated with greater lacunar stroke incidence, whereas occurrence of nonlacunar ischemic stroke, including cardioembolic etiology, was more strongly related to systolic than diastolic orthostatic hypotension [9]. The relationship between cardioembolic events and orthostatic hypotension is supported by the fact that orthostatic hypotension correlates both with incident atrial fibrillation [15] and heart failure [16,17]. Moreover, both carotid intima–media thickness and fibrinogen, well established indicators of elevated stroke risk [18,19], are increased in orthostatic hypotension [20] as is also arterial stiffness [21]. Further, in the prospective Atherosclerosis Risk in Communities study, the increased risk of ischemic stroke associated with orthostatic hypotension was exclusively found among those individuals who were on antihypertensive treatment [8]. Thus, the present study not only adds to the available evidence but it also expands our understanding of interaction between arterial hypertension and orthostatic hypotension suggesting that elevated resting BP and concomitant antihypertensive treatment augment the cerebrovascular effects of SBP instability during orthostasis. Most probably, hypertension acts synergistically with systolic orthostatic hypotension to produce critical damages in the heart and vasculature leading directly (e.g., through plaque rupture) or indirectly (by inducing such stroke substrates as atrial fibrillation and heart failure) to the increased occurrence of cerebrovascular events. It is interesting to note that exclusion of incident atrial fibrillation and heart failure did not alter these results, so the direct action is more likely.Diastolic orthostatic hypotension and myocardial infarctionThe diastolic orthostatic hypotension was three times less frequent than systolic orthostatic hypotension, but conferred almost a doubled risk of MI. The nature of causal coupling between diastolic orthostatic hypotension and coronary events is still unclear. The orthostatic volume shift results in an instant redistribution of circulating blood by pooling of 500–1000 ml below the diaphragm. Consequently, the venous return diminishes, while autonomic reflexes compensate to maintain the mean arterial pressure in the upper body at the preorthostatic level [22,23]. In a healthy person, SBP remains substantially unchanged, whereas DBP slightly increases by about 10–15% [22]. Thus, decrement of DBP on standing indicates not only an absolute reduction of BP relative to supine position, but also a lack of its compensatory increase. It is a well known fact that the diastolic component of BP reflects the real pressure of coronary perfusion as the coronary flow is substantially reduced during systole [24]. Repeated and pronounced decreases in DBP may lead to periodic myocardial hypoperfusion and exacerbation of the coexisting atherosclerosis. In the general population, decrement of diastolic but not systolic component of orthostatic BP is associated with the increased long-term incidence of coronary events [6]. Similar observations were made among elderly adults [25]. As indicated by our results, coronary effects mediated by diastolic orthostatic hypotension seem to be reinforced in hypertensive patients with a nontreated supine DBP of not less than 100 mmHg. Here, we can also infer that hypertension, an established risk factor for coronary heart disease [26], and diastolic orthostatic hypotension synergistically affect coronary circulation both by a direct action on vasculature (i.e. via promotion of atherosclerosis and systemic inflammation [20]) and by inducing structural changes in myocardium, such as left ventricular hypertrophy and dysfunction [16,17,27]. Consequently, presence of diastolic orthostatic hypotension in hypertensive individuals is more detrimental for coronary circulation than in the normotensive population. Indeed, in the final multivariate-adjusted model, supine DBP was inversely associated with the risk of MI. Thus, whereas high supine SBP is a strong predictor of MI, increased DBP seems to protect from MI. Consequently, DBP decrease on standing acts in the opposite direction by limiting the protective effect of the DBP component.Study limitationsOrthostatic BP was measured only once 1 min after standing, which may have limited the accuracy of the measurement. In a recent study of elderly patients, the prospective cardiovascular risk associated with systolic orthostatic hypotension increased from the measurement immediately after standing, to 1 and 2 min after standing, and the relative risk of cardiovascular event was highest for the systolic orthostatic hypotension based on the average of three measurements. In contrast, the diastolic orthostatic hypotension was only significant immediately after standing [28]. Further, the overall orthostatic hypotension prevalence may have been underestimated as patients with initial (within the first minute of standing) [29] and delayed orthostatic hypotension (after 3 min of standing) [30] were not detected by the study protocol.In conclusion, the impairment of orthostatic hemodynamics plays a dual role among hypertensive patients: decrement of SBP indicates an increased risk of stroke, whereas decrement of DBP confers an increased risk of myocardial infarction.ACKNOWLEDGEMENTSThis study was supported by grants from the European Research Council (StG 282225), Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Malmö University Hospital, the Care North Consortium, the Albert Påhlsson Research Foundation, the Crafoord Foundation, the Ernhold Lundströms Research Foundation, the Region Skane, the Hulda and Conrad Mossfelt Foundation, the King Gustaf V and Queen Victoria Foundation, the Wallenberg Foundation, and the Lennart Hanssons Memorial FundConflicts of interestThere are no conflicts of interest.Reviewers’ Summary Evaluations Reviewer 1The authors conclude, from a posthoc analysis of the CAPPP trial, that systolic and diastolic orthostatic hypotension (OH) confer a high risk for, respectively, stroke or myocardial infarction in hypertensive patients. The prognostic significance of OH has been shown repeatedly but is rarely mentioned among cardiovascular risk factors. This may at least partly be due to the 17-year old vague definition of OH, resulting in different applications in the literature. In the current study OH was assessed only 1 min after standing. Therefore to make OH acceptable as a risk factor in clinical practice, a more precise and uniform definition of OH is needed.Reviewer 2In the CAPPP study, the authors investigated whether orthostatic hypotension (found in 1060 subjects) is a risk of cardiovascular outcomes. 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[CrossRef] [Full Text] [Medline Link] [Context Link] hypertension; mortality; myocardial infarction; orthostatic hypotension; strokeovid.com:/bib/ovftdb/00004872-201401000-0001100002057_2000_13_571_rose_atherosclerosis_|00004872-201401000-00011#xpointer(id(R2-11))|11065213||ovftdb|SL0000205720001357111065213P58[CrossRef]10.1016%2FS0895-7061%2899%2900257-5ovid.com:/bib/ovftdb/00004872-201401000-0001100002057_2000_13_571_rose_atherosclerosis_|00004872-201401000-00011#xpointer(id(R2-11))|11065405||ovftdb|SL0000205720001357111065405P58[Medline 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