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Computer models in bedside physiology
Zhang, Y.
Publication date
2013
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Citation for published version (APA):
Zhang, Y. (2013). Computer models in bedside physiology.
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Chapter 5
A subgroup of Brugada patients shows low orthostatic blood
pressures as a sign of decreased sympathetic outflow
Yanru Zhang and John M. Karemaker
(to be submitted)The results in this chapter have been obtained by Y. Zhang’s analysis of recordings
made by DA van Hoeijen, M.D. and MT Blom, M.D. in patients of HL Tan, M.D, PhD. Dr.
Tan is cardiologist and Principal Investigator at the Heart Failure Research Center of
the AMC.
A full, final report of this study will follow.
Abstract
Background: Patients with Brugada syndrome have an increased risk to develop life‐threatening ventricular fibrillation (VF). Various studies have shown involvement of the autonomic nervous system in eliciting these attacks. We tested autonomic control of the circulation in a 10 minutes supine, 10 minutes upright standing test in 28 established Brugada patients and compared those to 25 healthy, matched control subjects. Methods: Measurement of continuous non‐invasive blood pressure. Analysis of heart rate variability, changes in blood pressure, baroreflex sensitivity and pulse‐contour derived cardiac output and systemic vascular resistance in the upright posture. Results: In addition to low values of LF/HF in supine posture, indicating relatively increased vagal outflow, we found a subgroup of Brugada patients who showed low values of upright/supine diastolic blood pressure, caused by low increase or even decrease in estimated systemic vascular resistance in the upright posture. Conclusions: A subgroup of Brugada patients exhibits low sympathetic outflow in the upright posture. This may lead, on longer duration standing, to an increased risk of vasovagal syncope. An association with increased risk of VF remains to be established.Introduction
After its first description in 1992 (3), the Brugada syndrome (BrS) has been recognized as a major risk for sudden death in young adults, particularly in some south‐east Asian countries (1). BrS patients may develop a variety of cardiac arrhythmias; the worst of those being ventricular fibrillation (VF). In some BrS patients the ECG shows the characteristic ‘saddleback’ ST elevation (23); however in many patients this may turn up only after pharmacological provocation (12). In recent years a relationship between symptomatic BrS and autonomic nervous system (ANS) imbalance/‐dysfunction has been suggested, with increased parasympathetic activity and withdrawal of sympathetic activity (14, 15, 22) or even presynaptic sympathetic dysfunction (14, 15, 22) as risk factors in established BrS. Some of patients have syncopal events which are due to neurogenic (vasovagal) syncope; this is considered a benign condition (20). If, however, the syncope cannot (retrospectively) be characterized as such, due to lack of prodromal events, the association with self‐terminating VF becomes more likely, necessitating therapeutic intervention like the implantation of an ICD(18). In the present study we included 28 Brugada patients who came to the outpatient clinic of the AMC between March 2011 and August 2012 for a full evaluation of their disease status, including assessment of their ‘autonomic balance’ as judged from the heart rate variability in LF/HF and other parameters in a simple test designed to mimic every‐day life conditions. Patients were 10 minutes in a supine resting condition followed by 10 minutes active standing while continuous finger blood pressure was measured. The patients’ recordings were compared to those from 25 matched healthy control subjects. The ultimate goal of this pilot study was to decide which of the parameters to evaluate ANS activity may be useful to point out those BrS patients who might be more at risk due to abnormal autonomic control of the circulation (14‐16).Methods and materials
Patients, control subjects and recordings We included 28 Brugada patients who were consecutively admitted between March 2011 and August 2012 to the outpatient clinic of the Academic Medical Center for assessment of their disease status. In addition to a full cardiologic evaluation, including a pharmacological provocation test to establish the existence of a Brugada(‐like) condition, they underwent an autonomic function test by 10 minutes supine resting followed by 10 minutes active standing.Continuous non‐invasive finger blood pressure was measured by a Nexfin® cardiovascular monitor (BMEye, Amsterdam, The Netherlands). The hand was held at heart level, when necessary supported by a sling around the neck while in the standing position. Nexfin shows continuous reconstituted upper arm blood pressure, heart rate (HR) and online computed stroke volume (SV) by pulse contour analysis; from HR*SV cardiac output (CO) and, finally, it computes systemic vascular resistance (SVR) from mean arterial pressure (MAP) divided by CO. These online presented parameters helped in patient monitoring during the stand test and they were used for offline evaluation. Since this supine/stand test has been in use in the Academic Medical Center for a couple of years now, an anonymized set of recordings in healthy control subjects is available who originally had been recruited for various (other) studies. All controls are non‐smokers in good health, free of cardiovascular disease. We matched 25 subjects from this set for age and gender to the Brugada patients. All subjects participated after written informed consent; the study protocol had been approved by the local review board. This also holds true for the subjects whose recordings were chosen from the anonymized database. Analyses Since we measured the heart period as the interval between blood pressure waves, we use the term interbeat interval or IBI (in seconds); instantaneous HR is calculated as 60/IBI. From steady state periods in the supine and upright recordings we derived the classical measures, i.e. mean‐IBI, SD‐IBI (standard deviation), rMSSD (root mean square of successive differences), pIBI‐50 (fraction of pairs of successive IBI’s that differ by more than 50 ms). Finally we performed frequency analysis of HR variability over those periods, resulting in a contribution of low frequency LF (0.04‐0.15 Hz) and of high frequency HF (0.15‐0.4 Hz) and the quotient LF/HF as measure of vasovagal balance (21). From the Nexfin cardiovascular monitor data we derived for the same periods the averaged blood pressure data (per beat: systolic, diastolic and mean pressure) and CO, SV, and SVR. From the coherent power in LF for systolic pressures and IBI we computed baroreflex sensitivity (BRS) in ms/mmHg (4). To allow for age‐related effects, subjects were divided into two groups as follows: 20 ≤ age < 40 and 40 ≤ age < 60. On the basis of their clinical background, BrS patients were classified in one of three groups: asymptomatic, syncopal (including vasovagal syncope), i.e. having experienced at least one syncopal event, and VF, if one or more documented VF’s had occurred. An overview of basic data is presented in Table 1.
Table 1 Demographics
[20,40) yrs [40,60) yrs
Control Asympt Syncopal Control Asympt Syncopal VF
Group size 12 4 6 13 7 8 3 Age (years) 31.1±5.9 27.5±5.2 30.8±7.1 51.1±6.9 52±2.1 48.5±5.3 53.7±6.8 Gender (m/f) 10/2 4/0 2/4 10/3 3/4 7/1 3/0 BMI 24.4±3.3 22.6±3.7 22.3±2.2 25.7±3.8 28.1±6.3 25.3±2.2 24.1±3.0 Ratio between supine and upright state To quantify the change in autonomic condition with standing, the ratios between standing and supine parameters were calculated. The distributions of the resulting quotients upright/supine and LF/HF were normalized by a log‐transformation before statistical testing. Statistics For the various parameters averages ± SD are given, unless the underlying distribution is not‐normal, then the median and range [min‐max] are presented. After testing for normality, groups were compared using a one way ANOVA or the Kruskal‐Wallis H test where appropriate. In case of significant differences (p<0.05) a post‐hoc test was used to determine which two groups are significantly different.
Results
Comparison between BrS patients and healthy controls in steady state supine and upright posture Table 2 summarizes all parameters in patients and control subjects in the supine and upright posture. The only significant differences between patients and healthy controls were found in the younger age group in the supine position [20, 40). Post‐hoc analysis showed that the symptomatic BrS patients had significantly lower LF, higher HF and, accordingly, a lower LF/HF than healthy controls. Moreover, supine SVR was significantly lower in healthy controls and standing blood pressure was, albeit marginally, lower in the younger patient group as well. The supine values of asymptomatic young patients were in‐between those of healthy controls and symptomatic patients; therefore they did not differ significantly from either group. Comparison of the upright to supine ratios The upright/supine ratio defines the reaction of a person’s cardiovascular control system to this daily challenge. If the supine value is maintained, the ratio will be 1, decreases in the upright posture result in ratios lower than 1. Table 3 summarizes all upright/supine ratios. Striking is the (slight, but significant) lowering of upright blood pressure in the group of BrS patients rather than the normal response, i.e. the increase that is observed in the control group. When BrS‐patients stand up, their HR is increased and SV is decreased, as in healthy controls; however in the younger age group [20, 40) CO is significantly increased in contrast to healthy controls and at the same time their SVR is not increased, but even decreased. In the older age groups these effects are tending in the same direction, but do not reach statistical significance to the same degree. Of note, only one patient had presyncopal signs after 8 minutes of standing, and had to return to the sitting posture. This patient belonged to the older group and was known to have experienced both VF’s and vasovagal syncope’s. This combination of effects points to a changed cardiovascular control in (some of) the BrS patients. Figure 1 shows how these statistical effects on LF/HF and diastolic pressure (Pdia) come into being: there is subgroup of patients who have a combination of low Pdia‐ratio (i.e. the value upright/supine) and low supine LF/HF. The histogram of LF/HF values for patients is only shifted to lower values compared to controls; the histogram of Pdia‐ratios in patients shows a bimodal distribution. Figures 2A and 2B demonstrate these effects. Having a Pdia‐ratio < 1.0 is not restricted to the younger age group of BrS patients: as Figure 3 demonstrates, neither is it restricted to any patient subgroup, as shown in Table 3.
Figure 1 LF/HF values as a function of the ratio upright/supine diastolic blood pressure. Red triangles: BrS patients; grey squares: healthy controls. Dividing line at Pdia‐ratio = 1.0 separates the low responders to the left from the normal responders to the right. In the lower left corner of the figure a conspicuous group of patients is observed, with both low LF/HF and low Pdia‐ratio.
Table 2 Hemodynamics and autonomics
[20,40) yrs [40,60) yrs
Supine control asympt syncopal p-value control asympt Syncopal VF p-value
Sys 119±12 121±17 127±6 0.429 125±17 146±15 127±22 126±12 0.094 Dia 70±8 75±10 76±5 0.356 70±7 79±8 76±10 68±4 0.092 MAP 88±9 91±13 94±5 0.383 92±10 103±8 96±14 89±6 0.118 SV 110±15 102±11 99±15 0.311 95±13 94±22 91±15 105±10 0.618 CO 7.5±1.2 6.7±1.5 6.3±1.2 0.154 5.3 [4.0-9.0] 5.3±1.3 5.7±1.4 6.1±1.4 0.830 SVR 964±179 1116±213 1238±250 0.044 1332±358 1482 [1126-2941] 1404±294 1199±206 0.486 dP/dt 836±182 1010±210 924±147 0.237 877±263 1000±212 882±357 903±140 0.794 IBI 0.90±0.17 0.94±0.12 0.97±0.20 0.718 1.01±0.21 1.07±0.07 0.94±0.19 1.06±0.16 0.578 SD-IBI 0.05±0.02 0.04±0.01 0.05±0.02 0.813 0.05±0.02 0.05±0.03 0.03±0.004 0.06±0.01 0.128 rMSSD 0.03±0.02 0.04±0.02 0.05±0.02 0.523 0.04±0.03 0.04±0.02 0.03±0.01 0.04±0.02 0.540 pIBI-50 0.17±0.17 0.22±0.23 0.32±0.24 0.347 0.21±0.23 0.17±0.18 0.09±0.12 0.18±0.14 0.745 BRS 13 [9-34] 10±2 12±4 0.262 8±5 8±6 8±4 12±4 0.675 LF 0.33±0.13 0.25±0.06 0.15 [0.14-0.32] 0.023 0.21 [0.07-0.69] 0.13 [0.09-0.46] 0.19±0.12 0.2±0.10 0.982 HF 0.22 ±0.07 0.33 [0.30-0.55] 0.46±0.14 0.002 0.31±0.20 0.31±0.16 0.26 [0.12 0.78] 0.10±0.04 0.156 LF/HF 1.66±0.88 0.74±0.29 0.34 [0.20-1.19] 0.006 0.77 [0.21-4.86] 0.86±0.78 0.79±0.60 1.98±0.16 0.221 Upright Sys 124±10 114±15 112±6 0.046 128±16 130±13 123±21 129±14 0.842 Dia 80±6 73±6 73±5 0.055 78±5 76±8 78±9 78±8 0.917 MAP 96±8 88±8 87±5 0.050 97±9 95±8 95±14 102 [84-102] 0.833 SV 84±15 85±8 69 [61-103] 0.083 74±11 80±22 74±14 76±8 0.813 CO 7.0±1.2 6.9 [6.2-7.8] 6.5±1.2 0.630 5.6±1.2 5.5±1.2 5.2±1.2 5.7±1.2 0.900 SVR 1119±202 1012±48 1100±176 0.596 1455±341 1458±369 1497±306 1368±172 0.952 dP/dt 960±224 987±273 845±171 0.514 928±282 934±215 902±323 1031±215 0.922 IBI 0.73±0.12 0.74±0.08 0.69±0.17 0.793 0.81±0.14 0.87±0.08 0.87±0.18 0.81±0.09 0.717 SD-IBI 0.04±0.01 0.04±0.01 0.04±0.02 0.759 0.05±0.02 0.04±0.01 0.04±0.01 0.05±0.02 0.624 rMSSD 0.02±0.01 0.02±0.01 0.02±0.01 0.795 0.03±0.02 0.02±0.005 0.02±0.004 0.02±0.01 0.881 pIBI-50 0.03 [0.005-0.18] 0.03±0.02 0.02 [0.003-0.22] 0.681 0.04 [0.002-0.42] 0.03±0.03 0.03±0.02 0.03±0.04 0.826 BRS 7±1 8±2 6±3 0.478 5±3 4±2 5±2 5±3 0.845 LF 0.40±0.11 0.47±0.06 0.25 [0.22-0.48] 0.175 0.34±0.19 0.33±0.17 0.36±0.18 0.31±0.17 0.986 HF 0.09 [0.04-0.34] 0.13±0.04 0.19±0.08 0.395 0.15±0.07 0.20±0.14 0.16 [0.07-0.34] 0.05±0.01 0.074 LF/HF 4.5±3.4 3.96±1.77 2.01±1.04 0.214 2.43 [0.98-7.07] 3.35±3.41 3.35±3.23 6.66±4.59 0.469
Sys: systolic pressure [mmHg]; Dia: diastolic pressure [mmHg]; MAP: mean arterial pressure [mmHg]; SV: stroke volume [mL]; CO: cardiac output [L/min]; SVR: systemic vascular resistance [dyn·s/cm5]; dP/dt: maximal value of the
time-derivative of pressure [mmHg/s]; IBI: interbeat interval [s]; BRS: baroreflex sensitivity [ms/mmHg]; LF: Low Frequency power in HRV [nu] ; HF: High Frequency HRV [nu] ; LF/HF: quotient.
Table 3 Hemodynamics and autonomics: upright / supine ratios
[20,40) yrs [40,60) yrs
control asympt syncopal p-value control asympt syncopal VF p-value
Sys 1.05±0.06 0.94±0.03 0.88±0.05 0.000# 1.03±0.08 0.89±0.05 0.97±0.12 1.02±0.04 0.019 * Dia 1.14±0.097 0.99±0.06 0.97±0.06 0.000 # 1.12±0.09 0.97±0.09 1.03±0.10 1.15±0.06 0.004 # MAP 1.09±0.06 0.97±0.05 0.93±0.04 0.000 # 1.06±0.07 0.92±0.07 1.00±0.11 1.08±0.05 0.005 # SV 0.77±0.10 0.83±0.10 0.74±0.09 0.320 0.78 ±0.08 0.85 ±0.10 0.82±0.08 0.72 ±0.04 0.145 CO 0.94±0.07 1.06±0.15 1.04±0.11 0.047 * 0.96 ±0.09 1.04 ±0.09 0.93 ±0.08 0.94 ±0.02 0.088 SVR 1.16±0.09 0.93±0.15 0.90±0.13 0.000 # 1.11 [0.97-1.52] 0.90 ±0.12 1.08 ±0.15 1.15 ±0.09 0.026 * dP/dt 1.15±0.13 0.97±0.09 0.92±0.12 0.002 # 1.07±0.16 0.94±0.15 1.07±0.25 1.14±0.06 0.337 IBI 0.82±0.09 0.79±0.07 0.71±0.08 0.084 0.81 ±0.07 0.82 ±0.08 0.88 ±0.07 0.77 ±0.04 0.076 SD-IBI 0.96±0.27 0.99±0.32 0.86±0.26 0.718 0.94 ±0.31 0.85 ±0.34 1.11 ±0.23 0.83 ±0.16 0.493 rMSSD 0.73±0.23 0.62±0.22 0.45±0.19 0.067 0.70 ±0.32 0.62 ±0.19 0.78±0.23 0.52 ±0.09 0.481 pIBI-50 0.55±0.44 0.27±0.25 0.27±0.33 0.278 0.30 [0.01-2.22] 0.17 [0.04-1.11] 0.58 ±0.50 0.16±0.12 0.423 BRS 0.50±0.16 0.85±0.33 0.50±0.14 0.076 0.67±0.16 0.45 [0.35-2.34] 0.74±0.19 0.39±0.14 0.042 * LF 1.00 [0.61-3.67] 1.94 ±0.59 2.01 ±1.16 0.476 1.58[ 0.82-8.63] 1.93 ±0.93 2.25±1.10 1.55 ±0.43 0.544 HF 0.57 [0.20-2.22] 0.37 ±0.15 0.47 ±0.33 0.554 0.63 [0.12 2.82] 0.41 [0.38-1.63] 0.56 [0.11-2.43] 0.45 [0.45-0.93] 0.949 LF/HF 2.44 [0.34-15.03] 6.13 ±3.14 6.44 ±4.55 0.316 4.10 ±3.57 3.91 ±2.77 4.47 [0.64-31.5] 3.33 ±2.34 0.990 Abbreviations as in Table 2
In age group [20, 40), by one-way ANOVA test there is significance in Sys (p=0.000), Dia (p=0.000), MAP (p=0.000),
CO (p=0.047), SVR (p=0.000), and dP/dt (p=0.002).
# Sys after post-hoc test (Gabriel test) significant difference between control and asympt group (p=0.009), between control and syncopal group (p=0.000).
# Dia after post-hoc test (Gabriel test) significant difference between control and asympt group (p=0.002), between control and syncopal group (p=0.000).
# MAP after post-hoc test (Gabriel test) significant difference between control and asympt group (p=0.003), between control and syncopal group (p=0.000).
# SVR after post-hoc test (Gabriel test) significant difference between control and asympt group (p=0.004), between control and syncopal group (p=0.000).
# dP/dt after post-hoc test (Gabriel test) significant difference between control and asympt group (p=0.043), between control and syncopal group (p=0.003).
* CO after post-hoc test (Gabriel test) no significant difference between two groups.
In age group [40, 60), by one-way ANOVA test (or one-way Kruskal-Wallis test) there is significance in Sys (p=0.019),
Dia(p=0.004), MAP(p=0.005), SVR (p=0.000), and BRS (p=0.042).
# Dia after post-hoc test (Gabriel test) significant difference between control and asympt group (p=0.006), between asympt and fibr group (p=0.035).
# MAP after post-hoc test (Gabriel test) significant difference between control and asympt group (p=0.005).
* SVR after post-hoc test ((t-test/Mann-Whitney test)) significant difference between control and asympt group (p=0.005), between asympt and Vfib group (p=0.012). (t--test/Mann-Whitney test as post-hoc test p<0.008 as significance).
Figure 2 A: Histograms of Pdia‐ratios for BrS patients (red bars) and healthy controls (grey bars). To linearize the distribution we computed the 2log of the values. The patients show a bimodal distribution, with a subgroup definitely below 0, indicating a ratio < 1.0, the histogram of healthy controls is unimodal and above zero. B: Histograms of LF/HF for BrS patients and healthy controls. Values have been linearized by 2log‐transformation. The two distrbutions show no obvious differences other than that the patients have lower values. Colors as in Figure2A.
Figure 3. Pdia‐ratios as a function of age for BrS patients and healthy controls. Colors as in Figure1. BrS patients with ratios below 1.0 are observed at all ages. Only 2 healthy controls have ratios around the divisor line at Pdia‐ratio = 1.0.
Discussion
This study was set up to test which parameters that evaluate the autonomic nervous system can be used to single out those BrS patients who might be more at risk due to abnormality in their autonomic control of the circulation. The, as yet unproven, idea being that the patients whose numbers deviate most from healthy controls might be those that are most at risk for the fatal complications of the disease. Patients describe the odds against them as ‘one strike you’re out’ and, although not every tachycardia attack ends in unstoppable VF, there is truth in that saying. In literature earlier studies have pointed to over‐activity of the parasympathetic system, particularly during sleep, as involved in eliciting a fatal attack (2, 7, 10, 13). Our study was limited to 2x10 minutes recording during daytime as part of a diagnostic workup. Even in this short period a subgroup of patients in the younger group stood out as having a low supine LF/HF ratio, as expression of increased parasympathetic activity (Table 2). But in addition thesame subjects exhibited another peculiarity in cardiovascular control: their upright diastolic pressure did not rise, even decreased in the upright posture (Table 3, Figures 1‐3). The same pattern in upright diastolic pressure regulation was observed in the older group (Table 3, Figure 3). The underlying abnormality is an insufficient increase in systemic peripheral resistance, as shown in Table 3. Even though the resistance effects were stronger than the pressure effects, we chose to emphasize the diastolic pressure effects, as being better suited for general praxis: even with a simple sphygmomanometer this can be measured, as long as supine and upright pressure are measured taking caution to keep the arm cuff at heart level both supine and upright. This study confirms earlier observations that showed a decreased sympathetic (cardiac) activity in BrS patients (15, 17, 20) and extends it to decreased vasomotor activity. In the standing posture sympathetic activity to the resistance vessels must, of necessity, increase to maintain sufficient blood pressure at the level of the brain (9, 21). Alternatively, orthostatic cardiac output should increase, or at least not decrease as much as it mostly does (6, 19). Upregulation of blood pressure is both by way of the systemic baroreflex and the ‘low‐pressure’‐reflex. The carotid sinus pressure receptors, being above heart level, signal a lowering of standing blood pressure and consequently vagal outflow to the heart is diminished (HR rises) and inhibition of sympathetic outflow is lessened. The low‐pressure receptors in the pulmonary vessels and atria are also less stimulated by the decreased venous return, which results in sympathetic activation as well. The present study does not allow a further interpretation of the lack of sympathetic outflow in BrS patients. The baroreflex sensitivity (BRS) is not changed as shown in Table 2. However, that number just relates to the vagal effect on heart rate and is only remotely related to the sympathetic effects on the vasculature. Alternatively we should consider an overall decrease in sympathetic drive in BrS patients, which might tally with the observed increase in vagal outflow and low LF/HF in the supine position (Table 2, Figures 1 and 2B) In earlier studies an increased propensity to orthostatic syncope in BrS patients has been documented (8, 24). These authors used a classical tilt table test, till actual syncope was induced; maximum 45 minutes of standing, followed by sublingual nitroglycerine spray. Makita et al.(11) showed a novel SCN5A mutation that gave rise to a Brugada‐type ECG combined with frequent neurocardiogenic syncopal attacks. In the broad spectrum of genetic diseases that go under the name of Brugada syndrome this underpins the relationship between the ECG‐abnormalities and other changes in cardiovascular control.
In a subgroup of BrS‐patients orthostatic blood pressure is maintained at a lower level than in control subjects. Question is, if this sign is indicative of them being more at risk than other bearers of the syndrome. It might predispose this subgroup to orthostatic syncope; however, as yet we do not know if this implies a predisposition to VF’s as well.
Limitations
This study includes only 28 patients, the results should be confirmed in a larger group before measurement of the upright/supine Pdia‐ratio may become a standard part of BrS‐workup. Moreover, follow‐up studies should show the significance of the present findings: it might very well be that the observed alteration in orthostatic blood pressure control is unrelated to the risk of VF in BrS‐patients. Finally, when judging orthostatic BP the reference level is of paramount importance. Any error in the measurement, as it might be induced by keeping the measured finger or arm above or below level of the aortic valves, may result in spurious outcomes. Since all investigators involved, both for the control group and the BrS‐patients, have been trained by the same instructor (JMK) on how to perform the supine‐stand test, we consider this unlikely.Conclusions
This study was designed to find indices of ANS activity that may be of use in the risk assessment of Brugada patients. We found a subgroup of Brugada patients who have lower than normal upright/supine diastolic blood pressure ratios, due to a deficient increase in systemic vascular resistance. This points to an alteration in cardiovascular control that may add to the well‐known problem of increased vagal outflow, all increasing the risk of a fatal VF. This outcome requires follow‐up studies to determine the value of this newly found trait for general risk assessment. We used a setting that can easily be copied: 10 minutes supine followed by 10 minutes active standing, measure at heart level a number of blood pressure values in each posture to compute reliable averages. We consider a Pdia‐ratio lower than 1.0 indicative of poor cardiovascular control.References
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