Background
Elevated blood pressure (BP) and related cardiovascular (CV) complications are leading causes of morbidity and mortality, and early recognition of individuals with increased CV risk is of foremost importance [
1]. All new cases of CV disease cannot be predicted using classical risk factors like family history, obesity, smoking, hypertension, diabetes, or dyslipidaemias. Therefore, studies aiming at the discovery of novel risk factors are still needed [
2,
3]. Furthermore, also psychosocial factors, like hostility and anger, have been linked with worse cardiovascular outcome [
4].
The CV phenotype in clinical practice has mainly been determined by measuring brachial BP and HR, even though the value of repeated single BP measurements in the diagnosis of hypertension has been questioned [
5,
6]. The haemodynamic changes causing similar elevations of BP may differ between patients and disorders. For example, systemic vascular resistance is typically elevated in essential hypertension [
7], while changes in fluid and electrolyte balance are characteristic causes of elevated BP during chronic kidney disease [
8].
The age-related decrease in large arterial compliance is accelerated in various CV disorders [
9,
10]. Increased large arterial stiffness is an acknowledged CV risk factor in both general populations and subjects with medical disorders [
9,
11]. Increased arterial stiffness also predisposes to exaggerated upright decrease in central BP and orthostatic hypotension [
12,
13]. The determination of pulse wave velocity (PWV) is the gold standard when evaluating large arterial stiffness [
10].
The assessment of CV status is usually performed at rest, but several studies have shown that haemodynamic reactivity to physical stimuli provides further information about CV risk. Enhanced BP response to cold pressor test, or to 4-min 2-step exercise test, predicted the development of hypertension in Japanese populations [
14,
15]. Reduced heart rate (HR) recovery after bicycle ergometer testing predicted mortality in a Finnish study [
6]. As the change in body posture from supine to upright induces changes in autonomic tone and arterial resistance, orthostatic challenge can also be regarded as a stress test addressing CV reactivity [
16,
17].
In the course of our studies on haemodynamics, we have observed that there are reproducible individual variations in the changes in cardiac output and systemic vascular resistance in response to upright posture [
17‐
19]. The objective of the present study was to examine the hypothesis whether functional differences exist in CV responses to upright posture, and whether these differences are associated with known determinants of cardiovascular risk. The results show that not only age, body mass index (BMI), and the presence of hypertension, but also the phenotype of the haemodynamic response to upright posture is associated with arterial stiffness.
Discussion
The evaluation of the CV status only in the supine or seated position gives rather limited information about haemodynamics [
16,
17,
22]. Although head-up tilt for 5 min is a short period of observation, we found that haemodynamic adaptation differed between individuals of similar age who only showed small differences in BP (Additional files
2 and
3). The type of haemodynamic reaction to upright posture was also related to PWV, an acknowledged measure of large arterial stiffness [
9‐
11]. Previously, the majority of studies utilizing head-up tilt have been performed to examine the mechanisms of syncope [
33,
34], and differences in upright haemodynamics have not been systematically investigated in non-syncopal subjects.
Subjects with increased CV risk should be identified before the manifestations of a clinical disease [
1]. In addition to the classical risk factors, efforts have been made to identify novel risk factors to increase the sensitivity of risk evaluation. For example, haemodynamic responses to physical challenge (bicycle exercise test, step exercise test, cold pressor test) can predict CV outcome [
6,
15,
35]. As change in posture from supine to upright activates sensory and neurogenic responses in the body, with subsequent changes in autonomic tone, cardiac function, and peripheral arterial resistance, passive head-up tilt can be regarded as a clinical haemodynamic stress test [
12,
16,
17].
Here we used systemic vascular resistance and cardiac index, the principal determinants of BP [
17,
23,
29], in the classification of haemodynamic response to upright posture into three phenotypes. The constrictor phenotype showed highest increase in SVRI, greatest decrease in cardiac output, and highest upright HF power as an indicator of parasympathetic cardiac autonomic tone [
28,
32]. The sustainers showed lowest increase in vascular resistance and smallest decrease in cardiac output, and greatest upright LF/HF ratio indicating highest sympathovagal balance [
28,
32]. The constrictors were also characterised by a more favourable CV risk profile than the sustainers, with lower total and LDL cholesterol, triglycerides and glucose (Table
1). However, in analyses adjusted for the differences in gender distribution, BMI and BP, the differences in the lipid and glucose values were no more significant.
In multivariate analysis including BMI, age, BP, gender, haematocrit, plasma glucose and lipid profile, the sustainer and intermediate phenotypes were associated with higher PWV, i.e. increased large arterial stiffness, than constrictors. Of note, the statistical coefficients relating the intermediate and sustainer phenotypes to higher PWV corresponded to those of increased BMI and elevated BP (Table
2). Higher PWV has been recognised as an independent CV risk factor in hypertensive subjects, elderly subjects, diabetics, and even in the general population [
9,
36,
37]. The close relation between PWV and the well-known CV risk factors, increased BMI and BP, has been repeatedly shown [
17,
38,
39]. As ageing is a strong determinant of PWV [
37,
40], it is important to note that the average age did not differ between the three phenotypes in the present study.
In supine position, HRV analysis showed a higher LF/HF ratio (increased symphatovagal balance) in the sustainers than in the constrictors [
28,
32]. Supine SVRI was also highest in the sustainers, who were characterised by male predominance, and highest BMI and BP, all factors associated with increased sympathetic tone [
41‐
43]. The head-up tilt uncovered differences in cardiac autonomic tone that largely resulted from the suppression of cardiac parasympathetic tone (decrease in HF power) in response to upright posture in the intermediate and sustainer phenotypes (Fig.
4b). Subsequently, the sustainers showed the highest upright LF/HF ratio, which corresponds to the smallest upright decrease in cardiac output in this phenotype. Previously, sympathovagal imbalance in young prehypertensive subjects has been attributed to increased sympathetic and decreased parasympathetic tone [
44].
Increased arterial stiffness is known to influence the control of autonomic tone. Higher arterial stiffness has been associated with reduced heart rate variability (HRV) [
45‐
47]. As baroreceptors are located in the arterial wall, arterial stiffening attenuates baroreceptor responses to changes in BP [
48]. Increased large arterial stiffness and impaired cardiac baroreflex control are also typical features of hypertension, and haemodynamic changes in hypertensive subjects have been attributed to reduced vagal inhibitory influence and overdrive of the sympathetic nervous system (for a review, see [
49]). Yet, reduced baroreflex sensitivity in the elderly can persist during methodological elimination of the influence of the stiffness of the vessel wall [
50]. Therefore, increased arterial stiffness is not the sole explanation for baroreflex changes, and these may also result from changes in the control of neural baroreflex pathways [
50].
In the present study, a putative explanation for the association between the sustainer phenotype and increased arterial stiffness would be alterations in baroreflexes, and this topic is a subject for further studies. However, it should be noted that the differences in HF power and LF/HF ratio were no more significant in adjusted analyses. This indicates that the demographic differences (sex distribution, BMI, and presence of hypertension) between the phenotypes largely explained the observed deviations in cardiac autonomic tone. Importantly, the differences in PWV between the phenotypes persisted after the adjustments, indicating that the deviations in autonomic tone did not explain the differences in arterial stiffness. The cross-sectional design of our study does not allow conclusions about causality, and an unanswered question is whether modifications in the associating risk profiles (like weight reduction) would result in changes of the functional cardiovascular phenotype.
Gender distribution was different between the phenotypes, with male predominance in the sustainers. Previously, haemodynamic differences between men and women have been observed in central wave reflections [
51], but the functional CV differences have been less thoroughly characterized. In women, autonomic responses to orthostasis may be attenuated due to lower baroreceptor sensitivity [
52]. Smaller body size and lower centre of gravity have been suggested to increase venous pooling of blood to lower extremities in women during orthostatic challenge [
53]. In the present study, the decrease in cardiac index during upright posture was greatest in the constrictors with female predominance, which could imply an increase in venous pooling of blood during head-up tilt. However, BP was well maintained in the constrictors, probably due to the pronounced increase in vascular resistance. Despite the differences in gender distribution between the groups, PWV was significantly associated with the functional phenotype, while the association of PWV with sex was only found as an interaction in the intermediate phenotype.
The present non-invasive methods have been validated against invasive methods [
23,
29,
54], and the repeatability and reproducibility of the measurements are good [
22]. The non-invasive nature of the recordings is a limitation, as the calculation of cardiac output from the bioimpedance signal requires mathematical equations and simplification of physiology [
24]. Invasive haemodynamic measurements, however, are not justified in humans without a clinical reason. The tonometric measurement of carotid-femoral PWV is considered as the gold standard for the assessment of arterial stiffness [
55], and the lack of this method in our study can be considered as a limitation. The impedance cardiography-derived PWV shows good correlation with PWV measured with Doppler ultrasound [
25], and the method has also been found to be a practical approach for the evaluation of arterial stiffness in 799 individuals aged 25–76 years [
26]. The median BMI in the study population was 26.3 kg/m
2, which corresponds to the average BMI in Finnish men (27.4 kg/m
2) and women (26.9 kg/m
2) in a large Finriski 2007 survey [
56]. The present median office BP (138/89 mmHg) was slightly lower than the reported average BP in the Finnish population (145-148/85-90 mmHg) [
57]. Importantly, subjects taking medications with known influences on haemodynamics were excluded from the present study.
Abbreviations
BMI, body mass index; BP, blood pressure; CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; HF, high frequency; HR, heart rate; HRV, heart rate variability; LDL, low-density lipoprotein; LF, low frequency; LF/HF, low frequency/high frequency ratio; MDRD, modification of diet in renal disease; PWV, pulse wave velocity; SD, standard deviation; SVRI, systemic vascular resistance index.
Acknowledgements
The authors are deeply grateful to Reeta Kulmala, RN and Paula Erkkilä, RN for invaluable contribution in subject recruitment and haemodynamic measurements. This study was supported by Aarne Koskelo Foundation, Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital, Finnish Cultural Foundation, Finnish Foundation for Cardiovascular Research, Finnish Medical Foundation, Paavo Nurmi Foundation, Sigrid Jusélius Foundation, and Tampere Tuberculosis Foundation.