Perceived stress is inversely related to ideal cardiovascular health: The Paris Prospective Study III

IJCA-26589; No of Pages 7 International Journal of Cardiology xxx (2017) xxx–xxx

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Perceived stress is inversely related to ideal cardiovascular health: The Paris Prospective Study III☆ L. Poirat a,b,⁎, B. Gaye a,b, M.C. Perier a,b, F. Thomas c, C. Guibout a,b, R.E. Climie a,d,e, L. Offredo a,b, M. Tafflet a,b, C. Lemogne b,f,g, B. Pannier c, P. Boutouyrie a,b,h, X. Jouven a,b,i, J.P. Empana a,b,⁎ a

INSERM, U970, Paris Cardiovascular Research Center, Department of Epidemiology, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France Preventive and Clinical Investigation Center, Paris, France d Baker Heart and Diabetes Institute, Melbourne, Australia e Menzies Institute for Medical Research, University of Tasmanian, Hobart, Australia f AP-HP, Georges Pompidou European Hospital, Psychiatry Department, Paris, France g INSERM, U894, Psychiatry and Neuroscience Center, Paris, France h AP-HP, Georges Pompidou European Hospital, Pharmacology Department, Paris, France i AP-HP, Georges Pompidou European Hospital, Cardiology Department, Paris, France b c

a r t i c l e

i n f o

Article history: Received 3 November 2017 Received in revised form 26 March 2018 Accepted 11 June 2018 Available online xxxx Keywords: Perceived stress Cardiovascular health Primordial prevention Depression Deprivation

a b s t r a c t Background: We hypothesized that subjects with a high level of perceived stress would be less likely to have ideal cardiovascular health (CVH). Methods: CVH was estimated using the 7-item tool developed by the American Heart Association. Perceived stress was measured using the validated 4-item Perceived Stress Scale at baseline and after 4 years of followup. Linear and polytomous logistic regression analysis were conducted. Results: 8914 volunteers (38% women) free from a history of cardiovascular disease and aged 50 to 75 were recruited in the framework of The Paris Prospective Study III between 2008 and 2012. At baseline, higher perceived stress was associated with lower global CVH score (regression coefficient of highest vs. lowest quartile of perceived stress: β: −0.20, p b 0.001). Perceived stress was associated only with the behavioral CVH score (smoking, physical activity, diet, body mass index) but not the health CVH score (fasting glycemia, total cholesterol, blood pressure, smoking). On the other hand, higher global CVH score at baseline was associated with lower level of perceived stress (OR for being in the highest vs. the lowest quartile of perceived stress per unit increase in the CVH score: 0.95; CI 95%: 0.93; 0.98). Again, the association only existed for the behavioral CVH score. Finally, baseline behavioral CVH score was inversely associated with perceived stress at 4 years, even after adjustment for perceived stress measured at baseline (p b 0.001). Conclusion: Our study demonstrates a clear association between higher perceived stress and lower CVH, in particular behavioral CVH, which has implications for CVD prevention. Clinical Trial Registration: NCT00741728 © 2017 Elsevier B.V. All rights reserved.

1. Introduction The importance of primordial prevention, that is preventing the development of risk factors in the first place, has been recently reemphasized by the American Heart Association (AHA) [1]. To this end, the AHA has developed a 7-item tool including behavioral (smoking, body mass index, physical activity and diet) and biological metrics

☆ Taxonomy: Risk Factor; Epidemiology. ⁎ Corresponding authors at: Paris Cardiovascular Research Center, INSERM, U970, 56 rue Leblanc, 75015 Paris, France. E-mail addresses: [email protected], (L. Poirat), [email protected] (J.P. Empana).

(blood pressure, total cholesterol, fasting glycaemia) to promote an ideal CVH. There is accumulating evidence showing that ideal CVH, as opposed to poor, is associated with substantially lower risk of mortality and morbidity from cardiovascular disease (CVD) [2–5]. Nevertheless, the prevalence of ideal CVH remains low in the population [2, 6]. Thus, identification of factors that may limit attainement of an ideal CVH is a major healthcare priority. Psychosocial factors may represent one of these limiting factors [7]. We, and others, have recently shown that depressive symptoms and individual socioeconomic deprivation were inversely related to ideal CVH [8–10]. Psychological stress, henceforth referred to as stress, is highly frequent in the population and should be considered as well. Objectively measured stress including work-related stress or negative life

https://doi.org/10.1016/j.ijcard.2018.06.040 0167-5273/© 2017 Elsevier B.V. All rights reserved.

Please cite this article as: L. Poirat, et al., Perceived stress is inversely related to ideal cardiovascular health: The Paris Prospective Study III, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.06.040

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events and subjective stress such as perceived stress have both been associated with an increased risk of CVD morbidity and mortality [11–14]. However, to our knowledge, no prior studies have investigated whether stress is related to CVH. Prior studies have mainly investigated stress at work and looked at their association with one single risk factor and much more seldom with combinations of risk factors such as the metabolic syndrome [15, 16]. Furthermore, stress usually coexists with depression and individual socioeconomic deprivation [17]. Hence, the extent to which stress is related to CVH independently from depression and individual socioeconomic deprivation needs to be investigated. We hypothesized that a high level of perceived stress would be inversely related to CVH and thus could represent a barrier to obtaining an ideal CVH status, beyond the effect of depressive symptoms and individual socioeconomic deprivation. We addressed this hypothesis in the Paris Prospective Study III (PPSIII). 2. Methods 2.1. Study population The PPSIII is an ongoing prospective cohort investigating determinants of CVD phenotypes in initially healthy subjects [18]. Our study was registered in the World Health Organization international clinical trial registry platform (NCT00741728) in 25/08/2008. The protocol was approved by the Ethic Committee of the Cochin Hospital and was conformed to the Declaration of Helsinki. Between June 2008 and May 2012, 10,157 subjects aged 50 to 75 were recruited in a preventive care center in Paris (the Centre d'Investigations Préventives et Cliniques: IPC) after signing an informed consent form [19]. This age range was chosen to maximize the number of expected incident CVD events and to detect arterial stiffness, but also to minimize any difficulties in measuring arterial aging associated with older age. The standard health check-up at the IPC involved a complete clinical examination with standardized measures of blood pressure, height, weight, and was coupled with biological tests for glycaemia and lipid profile following an overnight fasting. Subjects also provided information about their professional activity, education, individual socioeconomic deprivation, lifestyle, personal and family medical history, and medication consumption via a questionnaire. 2.2. Perceived stress Perceived stress was measured at baseline and at 4 years of follow-up with the French version of the 4-item Perceived Stress Scale (PSS4) (Internal Consistency: α = 0.73) [20, 21]. As shown in Supplementary 1, this questionnaire evaluates the degree to which a situation in one's life is perceived as stressful. Subjects were asked to rate from 0 (never) to 4 (very often) their feelings in the past month regarding 4 stressful situations. The PSS4 score ranges from 0 to 16, higher score indicating higher perceived stress. In the absence of clinically relevant thresholds, PSS4 was treated in quartiles for statistical analysis. We chose the PSS4 for its simplicity and shortness, since we had limited time for assessments at the IPC. 2.3. Cardiovascular health The CVH score comprises 7 metrics including 4 behavioral (body mass index [BMI], smoking status, physical activity and diet), and 4 health metrics (blood pressure, glycemia, total cholesterol and smoking status) [22]. Following the AHA recommendations, given the importance of smoking for CVD risk, this metric was counted twice as a behavioral and health metric [1]. Each metric was categorized as poor, intermediate and ideal using the AHA criteria, and weighted as 0, 1 and 2 respectively [1, 9, 10]. The definitions of each metric are detailed in Supplementary 2. 2.3.1. Global, behavioral and health CVH scores CVH scores were obtained by summing the weight of each metric. Global CVH score ranged from 0 to 14 with a higher score indicating increased likelihood of ideal CVH. Both the behavioral and the health CVH score ranged from 0 to 8. Consistently with previous studies, a global CVH score greater or equal to 12, between 8 and 11 and lower or equal to 7 respectively was used to define an ideal, intermediate or poor CVH status [2]. 2.4. Other covariates Low, middle and high levels of education were defined as people without a diploma, people who had less than a bachelor degree and people who had at least a bachelor degree or above, respectively. Individual socioeconomic deprivation was determined via the Evaluation de la Précarité et des Inégalités dans les Centres d'Examens de Santé (EPICES) score, a deprivation index routinely used in French health care centers [23]. The EPICES score is an 11-item score that considers an individual's socioeconomic characteristics, health care insurance

and leisure activities and ranges from 0 to 100 (lower score indicating lower likelihood of deprivation). Depressive symptoms were measured using the 13-items Questionnaire of Depression 2nd version Abridged (QD2A) [24]. A QD2A score ≥ 7 and/or being on antidepressants indicated depressed participants. Occupational status was categorized according to the French Occupations and Sociooccupational Categories as 4 classes: high, medium, low and unemployed [25]. As French laws prevent ethnicity to be collected, we used the participants and their parents' country of birth as proxy. 2.5. Statistical analyses The main analysis consisted of exploring the association between quartiles of perceived stress (exposure) and global, behavioral and health CVH scores (outcome) via linear regression analysis. Models were adjusted for sex, age, education and depression (model 1) and then for individual socioeconomic deprivation (model 2). We adjusted for education as it is well known that education impacts access to healthcare and awareness on prevention in general. Given that we have previously shown that depression and socioeconomic deprivation are inversely related to ideal CVH [8–10] and depression and stress usually coexists, we adjusted for both covariates to assess whether the anticipated relationship between perceived stress and CVH would be independent from these two covariates. To provide clinical/public health relevance, we also estimated the odds of being in intermediate or ideal vs. poor CVH according to increasing quartiles of perceived stress (first quartile as the reference category) employing multivariable polytomous logistic regression. Polytomous logistic regression analysis was also used to explore the association between quartiles of perceived stress and each level (intermediate and ideal compared to poor) of the 7 CVH metrics. To explore whether age (below and above the median), sex, occupational status and country of birth could modify the association between stress and CVH, analyses were stratified based on these variables. Interactions with these variables were also tested. We also examined the association between baseline CVH score (main exposure) and perceived stress (outcome). Firstly, we investigated the association between CVH score with increasing quartiles of perceived stress at baseline using polytomous logistic regression, the first quartile of perceived stress being the reference category. Secondly, we computed the association between baseline CVH score and the score of perceived stress at 4 years adjusting for perceived stress at baseline and other baseline covariates, in linear regression analysis. All statistical analyses were performed using R studio Software.

3. Results 3.1. Participants' characteristics Among the 10,157 subjects enrolled in the PPSIII, 86 had missing data for perceived stress, 846 for at least one CVH metric, 119 for at least one covariate, and 208 had prevalent CVD, leaving 8914 subjects for the final analysis. Compared to included subjects, excluded subjects were more often women, less educated, more likely to be deprived and stressed (for all p b 0.001) and also depressed (p = 0.05) (Supplementary 3). Among the included subjects, 3431 were women (38.5%). The mean age was 59.44 (SD: 6.21) and the mean perceived stress score was 3.88 (SD: 2.78), 3.51 (SD: 2.66) in men and 4.47 (SD: 2.86) in women (p b 0.001). Poor (CVH score b 8), intermediate (CVH score 8–11) and ideal CVH status (CVH score 12–14) was observed in 34.9%, 60.1% and 5.0% of the study population respectively. Baseline characteristics of the study subjects by increasing quartiles of perceived stress are reported in Table 1. Subjects in the higher quartile of perceived stress were more often women (p b 0.001), depressed (p b 0.001) and deprived (p b 0.001) and were less educated (p b 0.001). The mean behavioral CVH score decreased with increasing quartiles of perceived stress (p for trend b0.001). Accordingly, the proportion of poor behavioral metrics increased with increasing quartile of perceived stress. There was no significant relationship between health CVH score and quartiles of perceived stress (p = 0.645). Other than fasting serum glucose (p = 0.018), no other health CVH metrics were associated with quartiles of perceived stress. The characteristics of the subjects by CVH status are reported in Supplementary 4. As expected, participants with ideal CVH were more often women (p b 0.001), less stressed (p b 0.001) and less deprived (p b 0.001). The borderline significant association between depressive symptoms and CVH status in the overall population (p = 0.057) became

Please cite this article as: L. Poirat, et al., Perceived stress is inversely related to ideal cardiovascular health: The Paris Prospective Study III, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.06.040

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Table 1 Characteristics of Paris Prospective Study III (PPSIII) participants by level of perceived stress. Variables n = 8914

First quartile of perceived stressd n = 2184

Second quartile of perceived stressd n = 1397

Third quartile of perceived stressd n = 2159

Fourth quartile of perceived stressd n = 3174

p-Value⁎

Age Women High level of educationa High level of depressive symptomsb Socioeconomic deprivationc Global CVH score (0–14) Behavioral CVH score (0–8) Health CVH score (0–8)

59.8 (6.20) 631 (28.9%) 964 (44.1%) 46 (2.11%) 13.6 (15.9) 8.39 (2.05) 5.06 (1.54) 5.04 (1.41)

59.1 (6.03) 475 (34%) 609 (43.6%) 61 (4.37%) 14.1 (15.8) 8.32 (2.05) 4.93 (1.51) 5.09 (1.41)

59.5 (6.16) 821 (38.0%) 904 (41.9%) 99 (4.59%) 17.9 (17.7) 8.23 (2.12) 4.86 (1.58) 5.03 (1.41)

59.3 (6.33) 1504 (47.4%) 1134 (35.7%) 591 (18.6%) 21.2 (20.5) 8.19 (2.12) 4.79 (1.60) 5.04 (1.41)

0,004 b0.001 b0.001 b0.001 b0.001 0,003 b0.001 0,645

281 (12.9%) 79 (3.62%) 1824 (83.5%)

198 (14.2%) 32 (2.29%) 1167 (83.5%)

312 (14.5%) 111 (5.14%) 1736 (80.4%)

496 (15.6%) 128 (4.03%) 2550 (80.3%)

b0.001

172 (7.88%) 901 (41.3%) 1111 (50.9%)

121 (8.66%) 564 (40.4%) 712 (51.0%)

210 (9.73%) 869 (40.3%) 1080 (50.0%)

318 (10.0%) 1157 (36.5%) 1699 (53.5%)

0,002

626 (28.7%) 417 (19.1%) 1141 (48.8%)

429 (30.7%) 313 (22.4%) 655 (46.9%)

987 (31.7%) 406 (18.8%) 1066 (49.4%)

1089 (34.3%) 596 (18.8%) 1489 (46.9%)

b0.001

852 (39.0%) 1172 (53.7%) 160 (7.33%)

574 (41.1%) 739 (52.9%) 84 (6.01%)

951 (44.0%) 1071 (49.6%) 137 (6.35%)

1484 (46.8%) 1526 (48.1%) 164 (5.17%)

b0.001

643 (29.4%) 1082 (49.5%) 459 (21.0%)

394 (28.2%) 693 (49.6%) 310 (22.2%)

624 (28.9%) 406 (18.8%) 1066 (49.4%)

1089 (34.3%) 596 (18.8%) 1489 (46.9%)

0,395

606 (27.7%) 1125 (51.5%) 453 (20.7%)

385 (27.6%) 714 (51.1%) 298 (21.3%)

585 (27.1%) 1094 (50.7%) 480 (22.2%)

885 (27.9%) 1578 (49.7%) 711 (22.4%)

0,783

67 (3.07%) 980 (44.9%) 1137 (52.1%)

38 (2.72%) 600 (42.9%) 759 (54.3%)

60 (2.78%) 995 (46.1%) 1104 (51.1%)

92 (2.90%) 1308 (41.2%) 1774 (55.9%)

0,018

Status of behavioral metrics Smoking Poor Intermediate Ideal Body mass index Poor Intermediate Ideal Physical activity Poor Intermediate Ideal Healthy diet Poor Intermediate Ideal Status of health factors Fasting total cholesterol Poor Intermediate Ideal Blood pressure Poor Intermediate Ideal Fasting serum glucose Poor Intermediate Ideal

Data are reported as n (%) for categorical variables and as mean (standard deviation) for continuous variables. CVH stands for cardiovascular health status. ⁎ p value for a chi-squared test or ANOVA when appropriate. a Subjects with at least a bachelor degree or above. b High level of depressive symptoms defined as Questionnaire of Depression 2nd version ≥7 or being under antidepressants [24]. c Socioeconomic deprivation measured by the EPICES Score from 0 to 100 [23]. d Perceived stress measured by the PSS4 scale [20, 21].

statistically significant for women (p b 0.001) and borderline significant for men (p = 0.071). 3.2. Cross-sectional association between quartiles of perceived stress (exposure) and CVH scores (outcome) The multivariable associations of quartiles of perceived stress (exposure) with global, behavioral and health CVH scores (outcome) are reported in Table 2. There was a progressive decrement of global CVH score with increasing quartile of perceived stress that persisted even after adjustment for age, sex, education, depression and individual socioeconomic deprivation (linear regression coefficient of the fourth vs. the first quartile of perceived stress: −0.19; p for trendb0. 01). Sex, education, depression and deprivation were the other covariates significantly associated with global CVH score (Supplementary 5). This association existed with the behavioral CVH score, but not with the health CVH score (Table 2). Similarly, as shown in Table 3, the odds of being in intermediate or ideal CVH progressively decreased with increasing quartiles of

perceived stress. In particular, compared to the first quartile of perceived stress, those from the third and fourth quartile had a significant 16% (OR = 0.84; 95%CI: 0.74–0.96) and 17% (OR = 0.83; 95%CI: 0.73– 0.94) decreased odds of being in intermediate as compared to poor CVH. A similar trend was observed for ideal CVH status but it is likely that the lack of a statistically significant association was due to the small size of the subgroups. Analysis by behavioral CVH metrics (Supplementary 6) indicated that subjects in the fourth, compared to the first, quartile of perceived stress were significantly less likely to have an ideal status for physical activity (OR = 0.85; 95% CI: 0.73–0.97) and diet (OR = 0.44, 95% CI: 0.34–0.57), while the association with ideal smoking and ideal BMI was no longer significant after adjusting for confounding variables. Higher perceived stress was not associated with any of the health CVH metrics, except with higher odds for ideal total cholesterol (Supplementary 7). Stratified analyses (Supplementary 8) indicate that sex, age, occupational status or country of birth did not modify the association between perceived stress and CVH (all p for interaction ≥0.49).

Please cite this article as: L. Poirat, et al., Perceived stress is inversely related to ideal cardiovascular health: The Paris Prospective Study III, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.06.040

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Table 2 Regression coefficients of quartiles of perceived stress (exposure) for global, behavioral and health CVH scores (outcome). Model 1a

Unajusted model Perceived stressc Global CVH score (0–14) Second vs. first quartile Third vs. first quartile Fourth vs. first quartile

Behavioral score (0–8) Second vs. first quartile Third vs. first quartile Fourth vs. first quartile

Health CVH score (0–8) Second vs. first quartile Third vs. first quartile Fourth vs. first quartile

Model 2b

β⁎

p value⁎

β⁎

p value⁎

β⁎

p value⁎

−0,07 −0,16 −0.20 p for trend b0.001 R2 = 0.0016

0,33 b0.01 b0.001

−0.10 −0,22 −0,26 p for trend b0.001 R2 = 0.0517

0,17 b0.001 b0.001

−0,1 −0,17 −0,19 p for trend b0.01 R2 = 0.0585

0,17 b0.01 b0.01

−0,13 −0,19 −0,26 p for trend b0.001 R2 = 0.0043

0,017 b0.001 b0.001

−0,12 −0,22 −0,27 p for trend b0.001 R2 = 0.0775

0,02 b0.001 b0.001

−0,14 −0,19 −0,21 p for trend b0.001 R2 = 0.0883

0,01 b0.001 b0.001

0,04 −0,02 0,0005 p for trend = 0.737 R2 = 0.0002

0,35 0,71 0,99

0,02 −0,04 −0,03 p for trend = 0.26 R2 = 0.0287

0,7 0,29 0,29

0,04 −0,02 0,01 p for trend = 0.91 R2 = 0.0308

0,44 0,63 0,85

CVH stands for cardiovascular health status. ⁎ Beta regression coefficients and p values derived from linear regression. a Model 1 was adjusted for sex, age, level of education and depressive symptoms. b Model 2 = Model 1 + socioeconomic deprivation measured by the EPICES score [23]. c Perceived stress measured by the PSS4 scale [20, 21].

3.3. Cross-sectional and longitudinal associations between baseline CVH scores (exposure) and quartiles of perceived stress (outcome) At baseline, higher global CVH score (exposure) was associated with lower likelihood of being in the higher quartile of perceived stress (outcome) (p for trend b0.01). Specifically, a 1-point increase in CVH score was related to a significantly 4% lower likelihood of being in the third (OR = 0.96; 95% CI: 0.93; 0.99) and fourth quartile of perceived stress (OR = 0.96; 95% CI: 0.93; 0.98) in multivariable analysis (Table 4). This association remained for behavioral CVH score for which there was a 8% (OR = 0.92; 95% CI: 0.88; 0.96) and 9% (OR = 0.91; 95% CI: 0.87; 0.94) decreased likelihood of being in the third and in the fourth quartile of perceived stress respectively. This association was not observed for health CVH score.

At 4 years of follow-up, among the 8584 subjects who were followed-up, a total of 7529 (88%) had complete data for the 7 metrics of CVH, covariates at baseline, and perceived stress at both baseline and 4 years. The mean PSS4 score at 4 years was 3.68 (SD: 2.93) compared to 3.88 (SD: 2.78) at baseline. In linear regression analysis, higher baseline behavioral CVH score (exposure) was significantly associated with lower PSS4 score (outcome) after 4 years of follow-up, which remained significant after adjusting for baseline PSS4 score (p b 0.001) (Supplementary 9). 4. Discussion Subjects with a high level of perceived stress had a 20% decreased likelihood of being in ideal CVH status. This association appeared to be

Table 3 Odds ratios of quartiles of perceived stress (exposure) for CVH status (outcome). Model 1a

Unadjusted model IC [95%]

p value⁎

OR

Second vs. first quartile of perceived stress Poor CVH status (n = 471)d 1 Intermediate CVH status (n = 854) 0,91 Ideal CVH status (n = 72) 1,05

[0.79–1.06] [0.76–1.45]

0.23 0,78

Third vs. first quartile of perceived stressc Poor CVH status (n = 769)d Intermediate CVH status (n = 1277) Ideal CVH status (n = 113)

1 0,84 1,01

[0.74–0.95] [0.75–1.34]

Fourth vs. first quartile of perceived stressc Poor CVH status (n = 1174)d 1 Intermediate CVH status (n = 1842) 0,79 Ideal CVH status (n = 158) 0,92

[0.70–0.89] [0.71–1.20]

OR

Model 2b IC [95%]

p value⁎

OR

IC [95%]

p value⁎

1 0.90 0,98

[0.78–1.04] [0.70–1.36]

0,16 0,89

1 0,89 0.90

[0.76–1.03] [0.64–1.27]

0,12 0,56

b0.01 0,97

1 0,81 0,89

[0.71–0.92] [0.67–1.20]

0,001 0,45

1 0,84 0.94

[0.74–0.96] [0.70–1.27]

0,01 0,69

b0.001 0,54

1 0,77 0.78

[0.68–0.87] [0.59–1.03]

b0.001 0.075

1 0,83 0,82

[0.73–0.94] [0.62–1.1]

b0.01 0.20

c

CVH stands for cardiovascular health status. ⁎ Odds ratios, 95% confidence interval limits and p values derived from polytomous logistic regression using poor CVH status as the reference category. a Model 1 was adjusted for sex, age, level of education and depressive symptoms. b Model 2 = Model 1+ socioeconomic deprivation measured by the EPICES score [23]. c Perceived stress measured by the PSS4 scale [20, 21]. d CVH status: poor: CVH score from 0 to 7 (n = 3112); intermediate: CVH score from 8 to 11 (n = 5357); ideal: CVH score from 12 to 14 (n = 445).

Please cite this article as: L. Poirat, et al., Perceived stress is inversely related to ideal cardiovascular health: The Paris Prospective Study III, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.06.040

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Table 4 Odds ratios per 1 point increase in CVH scores (exposure) for higher quartiles of perceived stress at baseline (outcome). Model 1a

Unadjusted model p value⁎

OR

0,98 [0.95–1.02] 0.96 [0.94–0.99] 0,95 [0.93–0.98] p for trend b0.001

0,33 b0.01 b0.001

0,95 [0.91–0.99] 0,92 [0.89–0.96] 0.90 [0.87–0.93] p for trend b0.001 1,02 [0.98–1.07] 0,99 [0.95–1.03] 1.00 [0.96–1.04] p for trend = 0.76

OR Global CVH score Second vs. first quartile of perceived stressc Third vs. first quartile of perceived stress Fourth vs. first quartile of perceived stress Behavioral CVH score Second vs. first quartile of perceived stressc Third vs. first quartile of perceived stress Fourth vs. first quartile of perceived stress Health CVH score Second vs. first quartile of perceived stressc Third vs. first quartile of perceived stress Fourth vs. first quartile of perceived stress

IC [95%]

Model 2b p value⁎

OR

0,98 [0.94–1.01] 0,95 [0.92–0.98] 0,94 [0.91–0.97] p for trend b0.001

0,161 b0.001 b0.001

0,98 [0.94–1.01] 0,96 [0.93–0.99] 0,96 [0.93–0.98] p for trend b0.01

0,16 0,006 0,002

0.02 b0.001 b0.001

0,95 [0.90–0.99] 0.91 [0.87–0.94] 0,89 [0.85–0.92] p for trend b0.001

0.02 b0.001 b0.001

0,94 [0.89–0.98] 0,92 [0.88–0.96] 0,91 [0.87–0.94] p for trend b0.001

b0.01 b0.001 b0.001

0,35 0,71 0,99

1,01 [0.96–1.06] 0,98 [0.93–1.02] 0,98 [0.94–1.02] p for trend = 0.25

0.70 0.30 0,42

1,02 [0.97–1.07] 0,99 [0.95–1.03] 1.00 [0.96–1.05] p for trend = 0.85

0,45 0,63 0,83

IC [95%]

IC [95%]

p value⁎

⁎ Odds ratio, 95% confidence interval limits and p-values were obtained by multinomial logistic regression using the first quartile of perceived stress as the reference category. a Model 1 was adjusted for sex, age, level of education and depressive symptoms. b Model 2 = Model 1+ socioeconomic deprivation measured by the EPICES score [23]. c Perceived stress measured by the PSS4 scale [20, 21]. CVH stands for cardiovascular health status.

driven by behavioral metrics, and especially diet and physical activity, rather than health CVH metrics. Our study also suggests that those with higher CVH score were less likely to be in the highest quartiles of perceived stress at baseline and at 4 years of follow-up. Again, this association existed for the behavioral, but not the health, CVH metrics. Several studies have reported associations between high level of perceived stress and one specific risk factor such as diabetes, blood pressure or smoking [26–28]. Only a few studies have been able to study the effect of perceived stress on several risk factors considered simultaneously. In the Copenhagen City Heart Study, the largest study so far on perceived stress and individual risk factors (n = 7066), participants with high level of stress were less likely to stop smoking or reduce alcohol consumption, were more likely to be physically inactive and require antihypertensive medication. Further, stressed women were more likely to become overweight while stressed men were twice more likely to develop diabetes during follow-up. No associations with total and HDL cholesterol or with high blood pressure were reported [29]. Some studies have also investigated the association of stress with a combination of risk factors such as the metabolic syndrome. Most of these studies focused on stress at work. For instance, in the Whitehall II study, employees with chronic stress at work had a 2.29 fold increased risk of developing metabolic syndrome over 9 to 14 years of follow up [16]. These results were confirmed in a systematic review of 28 studies showing a longitudinal association between chronic psychosocial distress and development of metabolic syndrome [30]. To our knowledge, the association between perceived stress and the 7-item CVH has only been suggested in two preliminary cross-sectional analyses (published abstracts) conducted in American populations. In the Women's Health Study there was an inverse association between psychological cumulative stress (including negative/traumatic life events as well as stress related to work, financial difficulties, discrimination, familial and marital relationships) and ideal CVH [31]. The second study examined self-perceived psychological factors, including perceived stress, and their association with ideal CVH in subjects of the Baptist South Health Florida Employee study. This study showed that higher perceived stress was related to lower likelihood of optimal CVH in both men and women after adjusting for age and education [32]. We extended the results of these two preliminary studies in a number of ways. Firstly, we provided study results in a European (French) context, which differs from the American setting specifically in regards to the health care system and ethnicity distribution. Secondly, the two previous studies were mostly conducted in women: the first was

conducted exclusively in women, while in the second, 74% were women. In the current study, 40% were women while 60% were men, which allowed us to examine the effect of sex on the association between perceived stress and CVH more accurately. Thirdly, given the frequent coexistence of stress and depressive symptoms, we systematically adjusted our analysis for depressive status, contrary to the second study. Fourth, neither of the previous studies addressed the bidirectional association between stress and CVH although our study results suggest that it might be the case. Finally, we performed both cross-sectional and longitudinal analyses, however, the earlier two studies were limited to cross-sectional analyses. Our analysis by metrics suggests that perceived stress is inversely related to ideal behavioral metrics, which is consistent with the study results of the Copenhagen City Heart Study [29]. The lack of association with ideal smoking status in our study was driven by our adjustment for depressive symptoms. Also, it appeared from our study that the lack of association between perceived stress and ideal BMI was due to the confounding effect of socioeconomic deprivation. Finally, the higher odds of ideal total cholesterol level associated with higher level of perceived stress in our study were unexpected and might be a spurious finding. There are several possible pathways underlying the inverse association between perceived stress and CVH. Acute perceived stress has been shown to activate the hypothalamic-pituitary-adrenocortical axis and the sympatho-adrenomedulary axis, which results in cortisol and catecholamine release, transient suppression of the baroreflex sensitivity and peripheral vasoconstriction [33, 34]. Over time, both catecholamines and cortisol secretion may contribute to elevated blood pressure as well as to reduced insulin sensitivity and consequent glycaemic impairment. Given these abnormalities, one would have expected an association between perceived stress and health CVH in the present study, which was not the case. However, the well-established association between stress and increased risk of CVD suggests that other biological pathways including brain-mediated increase of bone-marrow activity and arterial inflammation may be involved [35]. We found a robust association between perceived stress and behavioral CVH, particularly for diet and physical activity. Studies have shown that poor ability to cope with stress was related to less engagement in regular and intense physical activity and inappropriate food intake (i.e. frequently consuming, albiet in small amounts, fatty and sweet food) [36, 37]. This is consistent with the fact that rumination and worry, which may be correlated with perceived stress, have also been related to poor health behaviors [38].

Please cite this article as: L. Poirat, et al., Perceived stress is inversely related to ideal cardiovascular health: The Paris Prospective Study III, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.06.040

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L. Poirat et al. / International Journal of Cardiology xxx (2017) xxx–xxx

Regarding the reported association between CVH as exposure and perceived stress as outcome, a healthy diet and physical activity could improve emotional state through several pathways, via a reduction in oxidative stress or inflammation, better social integration or increased parasympathetic vagal tone [39, 40]. However, future studies are required to better understand the underlying pathways linking perceived stress with behavioral CVH. We have recently reported that depression and socioeconomic deprivation were inversely related to higher CVH [9, 10]. By additionally showing in the current study that perceived stress was inversely related to higher CVH, independently of depression and socioeconomic deprivation, this has strong public health implications for the prevention of CVD. Our findings suggests that a combined approach including screening of depressive symptoms, deprivation and perceived stress, may help physicians and health care providers to target vulnerable populations who are less likely to attain ideal CVH and in whom appropriate interventions should be conducted. We recognize that this is not an easy task. However, the simplicity and shortness of the questionnaires used to assess perceived stress (and to assess depressive symptoms and individual socioeconomic deprivation) represent important advantages. Psychological interventions, such as cognitive behavior therapy or mindfulness-based stress reduction programs, have been found to reduce perceived stress, systolic blood pressure, anger and cardiac mortality in patients with already known CVD [41–43]. Mindfulness experience has been developped for recent years and is the most studied intervention in treating stress. For example, mindfulness interventions reduced perceived stress in workers such as firefighters or health professionnals and healthy young adults [44–46]. In the primary prevention setting, recent evidence suggests that mindfulness interventions might be useful, although additional evidence is needed [47]. We acknowledge the following limitations. Firstly, the generalizability of our results to subjects aged below 50 and above 75 years, and to non- Caucasians needs to be evaluated. Secondly, being volunteers to take part in the study, the study participants may be more concerned with their health than their counterparts of similar age. This may affect the prevalence of CVH and stress but not the associations reported here. Third, as in many large epidemiological studies, the definition of diet and of physical activity was not optimal. Fourth, the nature and the causes of perceived stress were unknown. Fifth, perceived stress might refer to several coping profiles, which may be differentially associated with CVH [48]. Finally, CVH metrics were only available at baseline so that we could not evaluate the association between changes in CVH and changes in perceived stress. To conclude, in a large French community based cohort, we reported an inverse and possibly bi-directional association between ideal CVH and perceived stress. It was mainly driven by behavioral CVH, especially diet and physical activity, and was independent of depression and socioeconomic deprivation. Screening and collaborative care for stress may help in shifting the community from poor to ideal CVH and to reduce the burden of CVD. Acknowledgements We thank N Estrugo, S Yanes, JF Pruny and J Lacet Machado for performing the study recruitment of PPSIII study participants, Dr. MF Eprinchard, Dr. JM Kirzin and all the medical and technical staff of the IPC Center, the Centre de Ressources Biologiques de l'Hôpital Européen Georges Pompidou staff (C. de Toma, B. Vedie), and the Platform for Biological Resources (PRB) of the Hôpital Européen Georges Pompidou for the management of the biobank. The PPSIII is organized under an agreement between INSERM and the IPC Center, and between INSERM and the Biological Research Center at the Européen Georges Pompidou hospital, Paris, France. We also thank the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés (CNAM-TS, France) and the Caisse Primaire d'Assurance Maladie de Paris (CPAM-P, France) for helping make this study possible.

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