Spiritual well-being as a protective factor for endothelial dysfunction in clinically healthy adults

Andre Casarsa; Pedro Bastos de Medeiros; Julio Cesar Tolentino; Isadora de Sa Guimaraes; Kelen Carolina Silva Cruz; Leticia Silva Flor dos Santos; Matheus Nakazato Tinoco; Maria de Fatima Martins Gil Dias; Ana Lucia Taboada Gjorup; Sergio Luis Schmidt

doi:10.1371/journal.pone.0339676

. 2025 Dec 26;20(12):e0339676. doi: 10.1371/journal.pone.0339676

Spiritual well-being as a protective factor for endothelial dysfunction in clinically healthy adults

Andre Casarsa ^1,^2,^‡,^#, Pedro Bastos de Medeiros ^1,^3,^#, Julio Cesar Tolentino ^1,^2,^‡, Isadora de Sa Guimaraes ¹, Kelen Carolina Silva Cruz ¹, Leticia Silva Flor dos Santos ¹, Matheus Nakazato Tinoco ¹, Maria de Fatima Martins Gil Dias ², Ana Lucia Taboada Gjorup ^1,², Sergio Luis Schmidt ^1,^2,^*,^‡

Editor: Francesco De Vincenzo⁴

PMCID: PMC12742740 PMID: 41452894

Abstract

Background

Endothelial dysfunction (ED) is an early marker of cardiovascular disease (CVD), influenced by both physiological and psychosocial factors. While depression and anxiety are known contributors to ED, the role of spiritual well-being (SWB) in vascular health has been relatively less explored in the literature.

Objective

To investigate the association between SWB and ED in clinically healthy adults, controlling for mental health variables and conventional cardiovascular risk factors.

Methods

In this cross-sectional study, 148 individuals aged 18–60 years were assessed using validated instruments: FACIT-Sp for SWB, PHQ-9 for depression, GAD-7 for anxiety, and brachial artery flow-mediated dilation (FMD) for endothelial function. Logistic regression and discriminant analyses were performed to identify independent predictors of ED and the spiritual dimensions most associated with vascular health.

Results

ED was identified in 39.2% of participants. Multivariate logistic regression indicated that SWB (OR = 0.929; p = 0.005), body mass index (OR = 1.130; p = 0.016), generalized anxiety disorder (OR = 2.551; p = 0.035), and major depressive episode (OR = 3.740; p = 0.038), were significantly associated with ED. Among these, SWB was significantly inversely associated with ED even after excluding participants with anxiety or depression. Discriminant analysis further indicated that inner peace and life purpose—but not faith—significantly distinguished individuals with and without ED.

Conclusion

SWB, particularly dimensions related to inner peace and meaning, is independently associated with preserved endothelial function in healthy adults. These findings support the inclusion of psychosocial and spiritual dimensions in cardiovascular risk assessment and prevention strategies.

Introduction

The endothelium is a critical component of the vascular system, acting as a single layer of cells lining blood vessels, and plays a vital role in maintaining vascular homeostasis [1]. Endothelial dysfunction (ED), characterized by impaired vasodilation and pro-inflammatory and pro-thrombotic states, represents an early and pivotal event in the pathogenesis of atherosclerosis. As such, ED serves as a key biomarker of cardiovascular risk, preceding overt clinical manifestations of cardiovascular disease (CVD) [2].

While several psychosocial factors—such as anxiety and depression—are recognized as contributors to ED, emerging evidence highlights the potential of spirituality as a protective element within this context [3,4]. Beyond its well-established role in strengthening psychological resilience and alleviating symptoms of anxiety and depression, spirituality may exert beneficial effects on vascular health through both direct physiological mechanisms and indirect modulation of stress responses [5]. As such, integrating spirituality into cardiovascular risk assessment frameworks may provide a more comprehensive and multidimensional understanding of the psychosomatic determinants of endothelial integrity and overall vascular function.

Spirituality is a multidimensional and intrinsic aspect of human experience, characterized by inner peace, harmony, and the search for meaning and purpose, including, when applicable, the faith [6]. Unlike religiosity—which is tied to institutionalized practices and dogma—spirituality encompasses broader subjective experiences that are not necessarily linked to formal religious beliefs [7]. Validated instruments, such as the Functional Assessment of Chronic Illness Therapy–Spiritual Well-being (FACIT-Sp), have been developed to measure spirituality comprehensively by focusing on three core dimensions: peace, purpose, and faith [8,9].

Investigating spirituality as an independent factor could therefore provide a more comprehensive understanding of vascular health determinants in clinically healthy adults.

This study aimed to explore the relationship between mental health variables—namely depression, anxiety, and spirituality—and the development of endothelial dysfunction (ED) in clinically healthy individuals. Specifically, it addressed the following questions: (1) Was spiritual well-being (SWB) associated with ED? (2) Did this association persist after excluding individuals with anxiety or depressive symptoms? (3) Which SWB dimensions—peace, meaning, or faith—showed the strongest association with ED?

Materials and methods

This cross-sectional study recruited a convenience sample of clinically healthy individuals aged 18–60 years between January 2022 and October 2024. Participants were enrolled through institutional outreach at a university hospital in Rio de Janeiro, Brazil, using informational flyers, verbal invitations during hospital or academic events, and personal referrals from healthcare professionals. The sample included university students, healthcare professionals, administrative staff, and relatives of patients, reflecting a heterogeneous but health-conscious population.

To ensure clinical health status, all participants underwent a comprehensive screening protocol including medical interviews and physical examinations, as well as ancillary tests—electrocardiogram, carotid Doppler ultrasound, and transthoracic echocardiogram (Fig 1)—to exclude underlying cardiovascular, neurological, or psychiatric conditions. Individuals with any chronic disease (e.g., diabetes mellitus, hypertension, dyslipidemia, thyroid dysfunction), previous psychiatric diagnosis, current use of psychotropic medications, or abnormal cardiovascular findings were excluded. All participants provided written informed consent after receiving a detailed explanation of the study objectives, procedures, potential risks, and benefits. The consent process was conducted individually in a private setting, ensuring the opportunity to ask questions before signing. Only adults (≥18 years) were enrolled; therefore, no parental or guardian consent was required. The study protocol, including the consent procedure, was reviewed and approved by the Research Ethics Committee of UNIRIO (CAAE: 30547720.3.0000.0008) in accordance with the Declaration of Helsinki.

Fig 1 — Clinically healthy participants aged 18–60 underwent cardiovascular screening and psychosocial evaluations, including assessments of SWB (FACIT-Sp), depressive symptoms (PHQ-9), and anxiety symptoms (GAD-7). Endothelial function was evaluated through brachial artery ultrasound using flow-mediated dilation (FMD), with ED defined as FMD < 10%. Participants were included only if cardiovascular and clinical screening results were within normal limits.

The FACIT-Sp scale, a widely recognized instrument for clinical and psychosocial research, culturally adapted and validated for the Brazilian population [10], as well as for several other cultural and linguistic contexts worldwide [5,11], was used to assess SWB. This 12-item questionnaire evaluates three core domains: Peace (items 1, 4, 6, 7), Purpose (items 2, 3, 5, 8), and Faith (items 9–12). Participants rated statements on a 5-point Likert scale (0 = “not at all” to 4 = “very much”), with reverse coding applied to items 4 and 8 to mitigate response bias. Total scores range from 0 to 48, with higher scores indicating greater SWB. Previous validation studies in Brazilian populations have confirmed high internal reliability [10].

The assessment of depressive symptoms was conducted through the Patient Health Questionnaire-9 (PHQ-9), a widely recognized instrument developed by Kroenke et al. [12] to measure both the occurrence and intensity of depression. This tool aligns with the diagnostic criteria for major depressive episodes outlined in the DSM and employs a four-point Likert-type scale ranging from 0 (“never”) to 3 (“nearly daily”). Participants rate how frequently they experienced symptoms over the preceding two weeks, resulting in a total score between 0 and 27. Higher scores reflect increased depressive severity. A positive screen for depression required participants to endorse five or more symptoms occurring on “more than half the days,” with at least one being a core symptom (persistent low mood or loss of interest/pleasure). Notably, any indication of suicidal ideation or self-harm (item nine) was automatically classified as a depressive symptom, regardless of its reported frequency. This approach aligns with established diagnostic guidelines [13].

Generalized Anxiety Disorder (GAD) was assessed using the Generalized Anxiety Disorder 7-item scale (GAD-7) [14], one of the most reliable and widely used screening tools in clinical and research settings, validated for the Brazilian population [14]. The questionnaire consists of seven items rated on a 4-point Likert scale: 0 (“not at all”), 1 (“several days”), 2 (“more than half the days”), and 3 (“nearly every day”). Total scores range from 0 to 21, with higher scores reflecting greater anxiety severity. A score above 10 points on the GAD-7 indicates a positive screening for generalized anxiety disorder. The scale’s design allows for a quantitative evaluation of symptom intensity, where elevated scores correlate with more pronounced anxiety-related impairments [14,15].

In the present study, internal consistency reliability coefficients were high for the FACIT-Sp (Cronbach’s alpha [α] = 0.862), PHQ-9 (α = 0.814), and GAD-7 (α = 0.890).

Endothelial function was assessed as a continuous variable using measurements of the brachial artery’s flow-mediated dilation (FMD), following standard protocol guidelines [16]. Examinations were conducted by a single observer in a controlled environment at 22–24°C. Participants fasted for at least four hours, lay supine, and rested for 10 minutes before testing. Monitoring included three cutaneous ECG electrodes, with blood pressure measured on the left arm. The basal diameter of the brachial artery was calculated as the mean of 3 pre-hyperemic measurements. Then, the brachial artery was occluded with a pressure cuff at 200 mmHg for five minutes. After unclamping the artery, three new measurements of the diameter of the brachial artery were performed between 45–60 seconds post-occlusion. These were used to calculate the mean post-hyperemic diameter. A subject was considered as presenting ED, when FMD < 10% which indicates a post-hyperemic brachial artery dilation < 10%. The echocardiographer was blinded to all other clinical and psychiatric assessments. FMD% was calculated as:

𝐅 𝐌 𝐃 % = 100 \times ((𝐏 𝐨 𝐬 𝐭 - 𝐡 𝐲 𝐩 𝐞 𝐫 𝐞 𝐦 𝐢 𝐚 𝐝 𝐢 𝐚 𝐦 𝐞 𝐭 𝐞 𝐫 - 𝐁 𝐚 𝐬 𝐞 𝐥 𝐢 𝐧 𝐞 𝐝 𝐢 𝐚 𝐦 𝐞 𝐭 𝐞 𝐫) / 𝐁 𝐚 𝐬 𝐞 𝐥 𝐢 𝐧 𝐞 𝐝 𝐢 𝐚 𝐦 𝐞 𝐭 𝐞 𝐫)

The presence of ED was defined as FMD < 10%, in line with previous international studies [17,18] and Brazilian cohort data [19,20]. It is important to note, however, that this threshold may be influenced by individual and population-specific characteristics [21].

Statistical analysis

Descriptive statistics were used to summarize sample characteristics, including demographic, anthropometric, psychological, and vascular parameters. Continuous variables were reported as means and standard deviations (SD), while categorical variables were presented as frequencies and percentages. Spiritual well-being was analyzed using the total score from the FACIT-Sp scale, treated as a continuous variable in all inferential analyses.

To identify independent predictors of ED, a multivariate logistic regression analysis was conducted. The dependent variable was the presence or absence of ED, while the independent variables included age, sex, body mass index (BMI), physical activity level, positive screening for generalized anxiety disorder (GAD-7), SWB, and positive screening for major depressive episode (PHQ-9). For each predictor, odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were estimated. Model fit was evaluated using the chi-square goodness-of-fit test, explanatory power was quantified using Nagelkerke’s R², and overall model performance was assessed by its classification accuracy.

Additionally, another logistic regression model was performed after excluding participants with positive screenings for anxiety or depression, with the aim of evaluating whether spirituality would remain an independent predictor of ED even after excluding individuals with mental health disorders. In this model, only the variables that were significant in the initial analysis (BMI and SWB) were included as predictors, while the dependent variable remained the presence or absence of ED. The model’s overall significance, the proportion of variance explained (Nagelkerke’s R²), and its classification accuracy were also assessed.

Discriminant analysis was conducted to examine which variables best distinguish individuals with and without ED, considering spiritual dimensions such as Peace, Meaning in Life, and Faith as predictors. Initially, the equality of group means was tested using Wilk’s λ.

The assumptions underlying discriminant analysis were assessed, including linearity, normality, multicollinearity, homogeneity of variances, and multivariate normal distribution of the predictors. Box’s M test was performed to evaluate the homogeneity of covariance matrices. It is worth noting that discriminant analysis is considered robust to moderate violations of this assumption, particularly in the absence of significant outliers. Box’s M test results were interpreted alongside inspection of the log determinants to ensure the adequacy of the analysis.

Following the verification of assumptions, the canonical discriminant function was analyzed to determine the strength of association between the predictor variables and group classification, as well as to assess the contribution of each variable to group separation through the structure matrix and group centroids.

Ethical considerations

The study protocol was approved by the HUGG/UNIRIO Ethics Committee (CAAE: 50323221.2.0000.5258; 30/09/2021) in accordance with the Declaration of Helsinki. Participants provided written informed consent, ensuring confidentiality and voluntary participation. Data collection commenced post-approval, with sufficient methodological detail provided to enable independent replication.

Participants were invited during routine visits or institutional activities. The study aims and procedures were explained verbally, and written informed consent was obtained prior to enrollment. Participants retained the right to withdraw at any time without compromising their access to healthcare services. They were left free to ask questions and to obtain explanations.

Results

Sample characteristics and assessed parameters

The study sample (n = 148) exhibited a heterogeneous age distribution, ranging from 19 to 60 years (mean = 30.5 years; SD = 10.9), with a predominance of male participants (55.4%; n = 82). The mean BMI was 25.5 kg/m² (SD = 4.1), classified as overweight according to World Health Organization (WHO) criteria. The total score of the FACIT-Sp ranged from 9 to 48 points (mean = 32.2; SD = 9.3). Regarding anxiety, as assessed by the GAD-7, scores ranged from 0 to 21 (mean = 7.3; SD = 5.3), and 32.4% screened positive for the disorder. For major depressive episodes, evaluated via the PHQ-9, scores ranged from 0 to 25 (mean = 7.7; SD = 5.3), with 13.5% meeting diagnostic criteria for depression. Regarding physical activity, 57.4% of participants (n = 85) met the minimum recommendation of 150 minutes per week of moderate-to-vigorous exercise.

In the assessment of endothelial function via FMD, the mean value was 10.6% (SD = 5.34). However, 39.2% of the sample (n = 58) exhibited FMD values below the established cutoff indicative of ED (<10%).

Predictors of endothelial dysfunction

The analysis identified four variables as significant predictors of ED: SWB (OR = 0.929; 95%CI: 0.882–0.978; p = 0.005), BMI (OR = 1.130; 95%CI: 1.023–1.249; p = 0.016), positive screening for generalized anxiety disorder (OR = 2.551; 95% CI: 1.070–6.084; p = 0.035), and positive screening for major depressive episode (OR = 3.740; 95%CI: 1.075–13.005; p = 0.038) (Table 1).

Table 1. Multivariate binary logistic regression identifying predictors of ED in a sample of clinically healthy adults (n = 148).

Predictor Variable	β	OR (95% CI)	p-value
Spiritual Well-Being (FACIT-Sp)	−0.074	0.929 (0.882–0.978)	0.005**
Body Mass Index (kg/m²)	0.122	1.130 (1.023–1.249)	0.016*
Generalized Anxiety Disorder (GAD-7)	0.937	2.551 (1.070–6.084)	0.035*
Major Depressive Episode (PHQ-9)	1.319	3.740 (1.075–13.005)	0.038*
Sex (Male)	0.542	1.720 (0.754–3.922)	0.197
Age (Years)	0.030	1.146 (0.990–1.074)	0.146
Physical Activity (Yes)	−0.062	0.939 (0.422–2.092)	0.879

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Abbreviations: OR = Odds Ratio; CI = confidence interval; β = unstandardized regression coefficient; p = proof value; *p < 0.05; **p < 0.01.

FACIT-Sp = Functional Assessment of Chronic Illness Therapy–Spiritual Well-being;

GAD-7 = Generalized Anxiety Disorder 7-item scale; PHQ-9 = Patient Health Questionnaire-9.

In the logistic regression analysis, the FACIT-Sp total score was used as a continuous predictor of ED. Higher SWB scores were significantly associated with lower odds of ED, independent of sociodemographic and psychological covariates. This finding suggests a protective effect of SWB, supporting its role as a continuous, dimensional construct in health-related outcomes.

The overall model was statistically significant [χ²(7) = 35.388; p < 0.001], explained 28.8% of the variance (Nagelkerke R²), and demonstrated a correct classification rate of 73%. Age (p = 0.146), sex (p = 0.197), and physical activity (p = 0.879) were not statistically significant. Among all predictors, SWB was significantly inversely associated with ED, reinforcing its potential protective role.

Prior to model estimation, multicollinearity diagnostics were performed using Variance Inflation Factor (VIF) and tolerance values for all predictors included in the logistic regression model. All VIF values were below 2.0, and all tolerance values exceeded 0.5, which are well within commonly accepted thresholds (VIF < 5.0 and tolerance > 0.2) for retaining predictors in multivariable models.

Predictors of endothelial dysfunction in individuals without anxiety or depression

A second logistic regression model was conducted including only participants without positive screenings for anxiety or depression (n = 93), following the exclusion of 55 individuals (35 with anxiety, 7 with depression, and 13 with both). The model retained variables previously identified as significant—BMI and SWB—excluding mental health variables due to the restricted sample (Table 2).

Table 2. Logistic regression model evaluating the association between SWB and ED in a subsample of 93 participants without anxiety or depressive symptoms.

Predictor Variable	β	OR (95% CI)	p-value
Spiritual Well-Being (FACIT-Sp)	–0.066	0.936 (0.880–0.996)	0.037*
Body Mass Index (kg/m²)	0.101	1.106 (0.988–1.239)	0.081

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Abbreviations: OR = Odds Ratio; CI = confidence interval; p = proof value; *p < 0.05.

FACIT-Sp = Functional Assessment of Chronic Illness Therapy–Spiritual Well-being.

Higher SWB remained a significant protective factor against ED (b = –0.066; OR = 0.936; 95%CI: 0.880–0.996; p = 0.037), suggesting an independent association between spirituality-related well-being and vascular health. BMI was not a significant predictor in this subsample (b = 0.101; OR = 1.106; 95%CI: 0.988–1.239; p = 0.081).

The overall model was statistically significant [χ²(2) = 6.444; p = 0.04], explaining 9.7% of the variance (Nagelkerke R²) and correctly classifying 75.3% of the cases.

Dimensions of spirituality

This study aimed to identify the factors that best discriminate individuals with and without ED, incorporating spiritual dimensions (peace, meaning in life, and faith). Tests of equality of group means revealed statistically significant differences for Peace (p < 0.001) and Meaning in Life (p = 0.006), while Faith (p = 0.103) was not statistically significant.

The canonical discriminant function exhibited a canonical correlation of 0.377 and an eigenvalue of 0.166. The structure matrix identified Peace (0.998) as the variable most strongly correlated with the discriminant function, followed by Meaning in Life (0.562) and Faith (0.333). Group centroids confirmed the model’s discriminatory power: individuals without ED had a positive mean score (0.325), while those with the condition scored negatively (−0.504). Wilks’ Lambda (λ = 0.858; p < 0.001) indicated robust group separation. Additionally, Box’s M test (p = 0.524) validated the homogeneity of covariance matrices, supporting the adequacy of linear discriminant analysis (Figs 2 and 3).

Fig 2 — Inner peace demonstrated the strongest association (r = 0.998), followed by meaning in life (r = 0.562). Faith had a weaker, non-significant correlation (r = 0.333). **(B)** Group centroids representing the canonical discriminant scores for participants with and without ED. Individuals without ED had a positive centroid (+0.325), while those with ED had a negative centroid (–0.504), indicating significant group separation. *Note:* Wilks’ Lambda = 0.858, p < 0.001.

Fig 3 — Density plots comparing the distribution of scores on the Peace, Meaning in Life, and Faith subscales of the FACIT-Sp, stratified by presence (pink) or absence (blue) of ED. Participants without ED consistently showed higher density peaks across all subscales, particularly for inner peace and meaning, indicating a potential protective role of these dimensions in vascular health.

Discussion

This study provides novel evidence of an association between SWB and endothelial function in clinically healthy adults. Consistent with prior findings [22,23], we confirmed significant associations between mental health conditions—namely, depression and anxiety—and impaired endothelial function. Higher levels of SWB were associated with a lower likelihood of ED, even after accounting for these psychological variables.

The multivariate analysis identified four variables significantly associated with ED: generalized anxiety disorder, major depressive episodes, BMI, and SWB. Among these, SWB demonstrated an inverse association with ED, with higher SWB levels being associated with a lower likelihood of presenting ED. These findings align with previous research suggesting that spirituality contributes to psychological resilience and reduced allostatic load, possibly through the modulation of stress-related physiological pathways, such as the hypothalamic-pituitary-adrenal axis and inflammatory responses [3,24].

To further explore the independence of this association, we performed a second binary logistic regression excluding individuals with positive screenings for anxiety and depression. SWB remained significantly associated with preserved endothelial function in this restricted sample, indicating that its cardiovascular benefits are not solely mediated by improved mental health. While this strengthens the plausibility of a direct link, the cross-sectional design precludes any causal inference. Therefore, we interpret this association with caution and encourage further prospective research to explore directionality.

In addition to these general effects, discriminant analysis revealed which specific dimensions of spirituality are most relevant for vascular health. Inner peace and life purpose were the only dimensions that significantly discriminated between individuals with and without ED. Inner peace showed the highest discriminant power, suggesting that experiences of emotional tranquility and existential coherence may be central to maintaining endothelial homeostasis. In contrast, the faith dimension was not statistically significant, highlighting the importance of personal spiritual experiences over doctrinal or institutional religious practices in this context.

The greater discriminative power of peace and meaning—independent of faith—suggests that the potential vascular benefits associated with SWB may extend beyond institutional religiosity. This supports the universal relevance of existential dimensions of spirituality and their possible value in cardiovascular risk assessment across culturally diverse populations.

Our findings are further supported by physiological data [25,26]. While traditional risk factors such as age, sex, and physical activity did not reach significance in the regression model, BMI remained positively associated with ED. This reinforces the established link between adiposity and endothelial impairment, mediated by mechanisms such as systemic inflammation, oxidative stress, and insulin resistance [27]. The absence of association with age suggests that ED is not merely a function of chronological aging but also reflects psychosocial and behavioral influences.

The interplay between spirituality and physiological health is further illustrated by evidence linking SWB with reduced inflammatory markers. Prior studies have reported associations between SWB and lower levels of IL-6 and C-reactive protein [28,29] both key mediators of ED and atherogenesis. In this regard, our findings echo those of the FEEL study, which demonstrated that spirituality-based interventions can enhance flow-mediated dilation and lower blood pressure in hypertensive individuals [29]. Findings from the FEEL Study support the biological plausibility of our results, suggesting that spiritually oriented practices may benefit endothelial function. Likewise, the Jackson Heart Study [30] found that higher levels of religiosity and spirituality were associated with healthier behaviors, improved clinical indicators, and more favorable cardiovascular profiles, underscoring the role of spiritual engagement in culturally sensitive prevention strategies.

The robust discriminant value of inner peace and life purpose suggests that SWB may act through mechanisms related to emotional regulation and stress resilience. Inner peace may buffer the impact of psychosocial stressors by attenuating sympathetic activation and preserving nitric oxide bioavailability—critical for vascular tone and endothelial repair. The conceptual model proposed by Vos [31], linking meaning in life to improved cardiovascular outcomes, supports this hypothesis. Our data reinforce this model by demonstrating that meaning and peace are directly associated with vascular health in a clinically healthy Brazilian population.

Academic interest in spirituality and health has also grown in Brazil, with a recent national survey identifying 36 research groups focused on this topic, many addressing cardiovascular outcomes such as hypertension and coronary artery disease [32]. Predominantly based in public universities, these groups reflect a multidisciplinary and integrative approach to care, reinforcing the national relevance of research on spirituality and vascular health.

From a clinical perspective, our results have important implications for clinical practice. While current guidelines [33] emphasize physiological risk factors such as hypertension and dyslipidemia, the present study suggests that incorporating SWB into risk assessments could provide a more holistic and predictive approach. Spirituality assessment—alongside conventional measures—may help identify individuals at higher risk for subclinical vascular damage. Even in healthcare systems where spiritual health is officially encouraged—as in the UK—many physicians still report discomfort in addressing it during consultations. A recent study showed that only 50% of general practitioners felt confident discussing spirituality with patients, although most endorsed the usefulness of structured tools to guide such conversations [34]. Studies have identified common reasons for this gap, including lack of formal training, limited time during consultations, uncertainty about how to address spiritual issues appropriately, and fear of overstepping professional boundaries [35].

Moreover, interventions aimed at enhancing inner peace and existential meaning, such as mindfulness practices, cognitive-behavioral strategies, and meaning-centered therapies, could complement traditional cardiovascular care. These findings provide new insights into the integration of psychosocial dimensions within preventive cardiology, particularly for asymptomatic individuals who may benefit from non-pharmacological strategies to support vascular function.

This study presents strengths that enhance the validity and applicability of its findings. These include the use of internationally validated instruments, strict exclusion criteria ensuring a clinically healthy sample, and the integration of psychological and spiritual variables in the assessment of cardiovascular risk. Together, these factors contribute to the methodological rigor and translational relevance of the study.

Limitations should be acknowledged. The cross-sectional nature of the study precludes causal inferences, and longitudinal data are needed to confirm whether increases in SWB lead to sustained improvements in endothelial function. Additionally, reliance on self-report measures may introduce bias, and physiological mechanisms were inferred but not directly assessed. The relatively small, exclusively Brazilian sample may limit the generalizability of our findings. Post hoc power analysis indicated adequate power for the primary model but reduced power after excluding participants with anxiety or depression. The logistic regression model explained 28.8% of the variance in ED, leaving substantial unexplained variability likely related to unmeasured factors such as inflammatory biomarkers, autonomic function, or lifestyle variables. After excluding mental health comorbidities, the explained variance dropped to 9.7%, despite similar classification accuracy (75,3%), underscoring their substantial contribution to endothelial function and suggesting attenuation of associations in populations without these conditions. Future studies should explore the potential mediating role of SWB in cardiovascular health using larger, more diverse samples, longitudinal designs, objective biomarkers, and interventional trials targeting both modifiable and non-modifiable risk factors.

Conclusion

This study reveals a significant association between higher levels of SWB—especially inner peace and a sense of purpose—and more favorable endothelial function in clinically healthy adults. Findings suggest that psychosocial factors play a meaningful role in modulating vascular health, potentially mitigating stress-related endothelial impairment. A holistic approach integrating spiritual and physiological factors may enhance cardiovascular prevention strategies.

Acknowledgments

The authors would like to thank the research team of the Núcleo de Pesquisas em Espiritualidade (NESPE) at the University Hospital Gaffrée e Guinle (UNIRIO) for their valuable assistance in participant recruitment and data collection. We are also grateful to the clinical staff who supported the cardiovascular assessments and to all study participants for their generous collaboration.

Data Availability

All relevant data are within the paper.

Funding Statement

The author(s) received no specific funding for this work.

References

1.Vita JA, Keaney JF Jr. Endothelial function: a barometer for cardiovascular risk?. Circulation. 2002;106(6):640–2. doi: 10.1161/01.cir.0000028581.07992.56 [DOI] [PubMed] [Google Scholar]
2.Drexler H, Hornig B. Endothelial dysfunction in human disease. J Mol Cell Cardiol. 1999;31(1):51–60. doi: 10.1006/jmcc.1998.0843 [DOI] [PubMed] [Google Scholar]
3.Tolentino JC, Gjorup ALT, Mello CR, de Assis SG, Marques AC, Filho Á do C, et al. Spirituality as a protective factor for chronic and acute anxiety in Brazilian healthcare workers during the COVID-19 outbreak. PLoS One. 2022;17(5):e0267556. doi: 10.1371/journal.pone.0267556 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Aggarwal S, Wright J, Morgan A, Patton G, Reavley N. Religiosity and spirituality in the prevention and management of depression and anxiety in young people: a systematic review and meta-analysis. BMC Psychiatry. 2023;23(1):729. doi: 10.1186/s12888-023-05091-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.McClain CS, Rosenfeld B, Breitbart W. Effect of spiritual well-being on end-of-life despair in terminally-ill cancer patients. Lancet. 2003;361(9369):1603–7. doi: 10.1016/S0140-6736(03)13310-7 [DOI] [PubMed] [Google Scholar]
6.de Brito Sena MA, Damiano RF, Lucchetti G, Peres MFP. Defining Spirituality in Healthcare: A Systematic Review and Conceptual Framework. Front Psychol. 2021;12:756080. doi: 10.3389/fpsyg.2021.756080 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Puchalski CM, Vitillo R, Hull SK, Reller N. Improving the spiritual dimension of whole person care: reaching national and international consensus. J Palliat Med. 2014;17(6):642–56. doi: 10.1089/jpm.2014.9427 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Peterman AH, Fitchett G, Brady MJ, Hernandez L, Cella D. Measuring spiritual well-being in people with cancer: the functional assessment of chronic illness therapy--Spiritual Well-being Scale (FACIT-Sp). Ann Behav Med. 2002;24(1):49–58. doi: 10.1207/S15324796ABM2401_06 [DOI] [PubMed] [Google Scholar]
9.Cotton S, Puchalski CM, Sherman SN, Mrus JM, Peterman AH, Feinberg J, et al. Spirituality and religion in patients with HIV/AIDS. J Gen Intern Med. 2006;21 Suppl 5(Suppl 5):S5-13. doi: 10.1111/j.1525-1497.2006.00642.x [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Lucchetti G, Lucchetti ALG, de Bernardin Gonçalves JP, Vallada HP. Validation of the Portuguese version of the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being scale (FACIT-Sp 12) among Brazilian psychiatric inpatients. J Relig Health. 2015;54(1):112–21. doi: 10.1007/s10943-013-9785-z [DOI] [PubMed] [Google Scholar]
11.Monod S, Brennan M, Rochat E, Martin E, Rochat S, Büla CJ. Instruments measuring spirituality in clinical research: a systematic review. J Gen Intern Med. 2011;26(11):1345–57. doi: 10.1007/s11606-011-1769-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606–13. doi: 10.1046/j.1525-1497.2001.016009606.x [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Siu AL, US Preventive Services Task Force (USPSTF), Bibbins-Domingo K, Grossman DC, Baumann LC, Davidson KW, et al. Screening for Depression in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2016;315(4):380–7. doi: 10.1001/jama.2015.18392 [DOI] [PubMed] [Google Scholar]
14.Spitzer RL, Kroenke K, Williams JBW, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092–7. doi: 10.1001/archinte.166.10.1092 [DOI] [PubMed] [Google Scholar]
15.Moreno AL, DeSousa DA, Souza AMFLP, Manfro GG, Salum GA, Koller SH, et al. Factor Structure, Reliability, and Item Parameters of the Brazilian-Portuguese Version of the GAD-7 Questionnaire. Temas Psicol. 2016;24(1):367–76. doi: 10.9788/tp2016.1-25 [DOI] [Google Scholar]
16.Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39(2):257–65. doi: 10.1016/s0735-1097(01)01746-6 [DOI] [PubMed] [Google Scholar]
17.Yeboah J, Crouse JR, Hsu F-C, Burke GL, Herrington DM. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation. 2007;115(18):2390–7. doi: 10.1161/CIRCULATIONAHA.106.678276 [DOI] [PubMed] [Google Scholar]
18.Hamburg NM, Palmisano J, Larson MG, Sullivan LM, Lehman BT, Vasan RS, et al. Relation of brachial and digital measures of vascular function in the community: the Framingham heart study. Hypertension. 2011;57(3):390–6. doi: 10.1161/HYPERTENSIONAHA.110.160812 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Santos AC, Madi JM, Oliveira LG, Zandonade E, Costa SHN, Amorim MMR. Predictive value of flow-mediated dilation for preeclampsia: a cohort study. Rev Bras Ginecol Obstet. 2012;34(3):111–6. [Google Scholar]
20.Brasil AV, Gomes MB, Fonseca FAH, Schaan BD, Dib SA, Bertolami MC. Prevalence of cardiovascular risk factors in people with diabetes in Brazil: The Brazilian Cardiovascular Risk Study (ERCE). Arq Bras Cardiol. 2011;96(5):331–8. [Google Scholar]
21.Charakida M, Masi S, Lüscher TF, Kastelein JJP, Deanfield JE. Assessment of atherosclerosis: the role of flow-mediated dilatation. Eur Heart J. 2010;31(23):2854–61. doi: 10.1093/eurheartj/ehq340 [DOI] [PubMed] [Google Scholar]
22.Ghiadoni L, Donald AE, Cropley M, Mullen MJ, Oakley G, Taylor M, et al. Mental stress induces transient endothelial dysfunction in humans. Circulation. 2000;102(20):2473–8. doi: 10.1161/01.cir.102.20.2473 [DOI] [PubMed] [Google Scholar]
23.Cui L, Li S, Wang S, Wu X, Liu Y, Yu W, et al. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal Transduct Target Ther. 2024;9(1):30. doi: 10.1038/s41392-024-01738-y [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Rosmarin DH, Leidl B. Spirituality, religion, and anxiety disorders. Handbook of Spirituality, Religion, and Mental Health. Elsevier. 2020. 41–60. doi: 10.1016/b978-0-12-816766-3.00003-3 [DOI] [Google Scholar]
25.Koenig HG. Religion, spirituality, and health: a review and update. Adv Mind Body Med. 2015;29(3):19–26. [PubMed] [Google Scholar]
26.O’Riordan A, Costello AM, Hill TD. Religious and Spiritual Coping Mediates the Association between Trait Extraversion and Cardiovascular Reactivity to Acute Psychological Stress. J Relig Health. 2025;64(6):4824–46. doi: 10.1007/s10943-025-02392-6 [DOI] [PubMed] [Google Scholar]
27.Engin A. Endothelial Dysfunction in Obesity. Adv Exp Med Biol. 2017;960:345–79. doi: 10.1007/978-3-319-48382-5_15 [DOI] [PubMed] [Google Scholar]
28.Herren O, Denkinger M, Rapp K, Jung C, Klenk J. Association between spiritual well-being and inflammatory biomarkers in older adults: results from the EPIDOS cohort. Psychoneuroendocrinology. 2019;100:198–205.30388593 [Google Scholar]
29.Vagnini R, Lopes GS, Costa C. Spirituality and inflammatory markers in hypertensive individuals: data from the FEEL study. Braz J Psychiatry. 2024;46(2):151–9. [Google Scholar]
30.Zare H, Meyerson NS, Delgado P, Crifasi C, Spencer M, Gaskin D, et al. How place and race drive the numbers of fatal police shootings in the US: 2015-2020. Prev Med. 2022;161:107132. doi: 10.1016/j.ypmed.2022.107132 [DOI] [PubMed] [Google Scholar]
31.Vos J. The impact of meaning-centered therapy on spiritual well-being and quality of life: a meta-analysis. Palliat Support Care. 2021;19(2):201–13. [Google Scholar]
32.Esperandio MRG. Spirituality and Health in Brazil: A Survey Snapshot of Research Groups. Religions. 2020;12(1):27. doi: 10.3390/rel12010027 [DOI] [Google Scholar]
33.Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74(10):e177–e232. doi: 10.1016/j.jacc.2019.03.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Whitehead IO, Jagger C, Hanratty B. Discussing spiritual health in primary care and the HOPE tool-A mixed methods survey of GP views. PLoS One. 2022;17(11):e0276281. doi: 10.1371/journal.pone.0276281 [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Best M, Butow P, Olver I. Doctors discussing religion and spirituality: A systematic literature review. Palliat Med. 2016;30(4):327–37. doi: 10.1177/0269216315600912 [DOI] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0339676.r001

Decision Letter 0

Francesco De Vincenzo

29 Jul 2025

Dear Dr. Schmidt,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

At the end of this message, you will find the reviewers’ comments outlining the major revisions needed.

In addition to issues raised by the reviewers, please also address the following major concerns in order to meet the journal’s standards for acceptance:

- Verify the adequacy of citations in the whole text: for instance, reference number 8 does not pertain to the validation of the instrument in the Brazilian population, and reference number 10 does not include cut-off scores.

- Ensure that the analytical approach is scientifically sound:

Reference number 9 uses a mean item score ≥ 3.0 (corresponding to “quite a bit” on the Likert scale) as a cut-off to test an interaction effect. I kindly ask Authors to state the reasons why they chose to dichotomize the independent variables anxiety, depression, and spiritual well-being. For each variable, cite the relevant literature supporting valid cut off-scores. If inappropriate cut off scores are used, results may be biased, and analyses should be repeated by using continuous variables.
Specify whether ED was defined as FMD ≤10% or <10%, and ensure consistency across the manuscript.
The analytical approach should be clearly described to ensure transparency and replicability. For instance, the authors state that they used t-tests and chi-squared tests, yet these analyses are not reported in the Results section. Please clarify whether these tests were performed and, if so, present the corresponding results.
The exclusion of participants with anxiety or depression in the secondary analysis strengthens the argument for an independent association between SWB and ED. However, this exclusion considerably reduces sample size and statistical power. Please address this limitation explicitly and consider reporting power estimates for the secondary analysis.

- The article should adhere to appropriate reporting guidelines and community standards for data availability.

The manuscript states that all data are available in the main text and supporting files, but these data are not currently accessible.
As per the submission guidelines, authors are expected to follow STROBE guidelines. Several required reporting elements appear to be missing.

- Conclusions should be presented in an appropriate fashion and should be supported by the data:

Some claims in Discussion and Conclusion overreach the evidentiary strength of a cross-sectional study. For example, phrases like "highlights the protective role of SWB (…) in preserving endothelial function" imply causality, which is not justified by the study design.
The proposed clinical implications, such as integrating SWB into cardiovascular risk assessment, should be presented more cautiously, clearly distinguishing hypotheses from evidence-based conclusions. I recommend to rephrase these statements to emphasize the exploratory nature of the findings and the need for longitudinal and interventional studies to confirm causality and clinical applicability.
The logistic regression model explained 28.5% of the variance in ED, indicating that a large proportion of variability remains unexplained. This suggests that other important factors influencing endothelial function were not included or measured in this study. This limitation should be explicitly acknowledged in the manuscript. After excluding participants with anxiety and/or depression, the model remains statistically significant but explains a notably lower proportion of variance (9.3%), despite maintaining a similar classification accuracy (74.2%). This reduction highlights that mental health comorbidities contribute substantially to the explained variance in endothelial function. The authors should discuss this decrease in explained variance and consider the implications for the generalizability of their findings to populations without these conditions.

Please submit your revised manuscript by Sep 12 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Francesco De Vincenzo, Ph.D.

Academic Editor

PLOS ONE

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[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: Dear authors,

First of all, I would like to thank you for showing that spiritual well-being may have beneficial effects on cardiovascular health and for demonstrating the relationship between the two using advanced statistical analysis.

The study was conducted on a mixed population of healthy volunteers, and the presence of cardiovascular and psychiatric diseases was ruled out.

You can add specific research questions at the end of the introduction section.

Strengthening the methodology section regarding how the sample was selected, the sampling method used, and the adequacy of the sample could be beneficial.

The measurement tools and their descriptions appear appropriate; I kindly request that you calculate and include the validity and reliability coefficients for all scales used in this study.

In fact, in the advanced analyses, we saw that the significant effect of SWB was still preserved in the model even without anxiety and depression. This provides an important contribution to the field in terms of emphasizing the need to support spiritual well-being in healthy or sick populations from a clinical application perspective. It may be valuable to emphasize this part more.

We also observed that the peace and meaning dimensions had greater effects independent of the faith dimension. This finding should be highlighted, as it suggests that promoting spiritual well-being in all populations, regardless of cultural or religious differences, provides individual protection against cardiovascular risks.

It should also be noted that the sample size is small and the study reflects the Brazilian population, and therefore should not be generalized.

Further research is needed to examine the mediating effect of SWB on cardiovascular disease in larger samples, focusing on modifiable and non-modifiable risk factors.

Regards,

Reviewer #2: It is an interesting and necessary study and I enjoyed reading it. However, the main limitation is that the sample of 148 patients from a single hospital makes it impossible to draw relevant conclusions. Nevertheless, I make some contributions to improve it:

I suggest including previous studies in which the relationship between spirituality and other cardiovascular diseases has been studied.

I suggest including information on the reality of spirituality/religiosity in Brazil

Aspects such as the reasons for the lack of approaching the spiritual perspective, pointed out in the literature, should be included in the discussion: lack of training, lack of time, fear of not knowing how to approach it, etc

Strengths should be recognized

Point out the implications for clinical practice.

**********

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Reviewer #1: No

Reviewer #2: No

**********

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PLoS One. 2025 Dec 26;20(12):e0339676. doi: 10.1371/journal.pone.0339676.r002

Author response to Decision Letter 1

16 Aug 2025

Academic Editor / Journal Office

1. Reference verification:

Response: We reviewed all citations for accuracy. Reference #8 was corrected to a validation study conducted in Brazil, and reference #10 was replaced by a source including cut-off scores for the FACIT-Sp scale.

2. Justify dichotomization of independent variables.

Response: We appreciate the reviewer’s observation regarding the choice to dichotomize the independent variables (spiritual well-being, anxiety, and depression). As noted, we initially analyzed these variables in their continuous forms. The hypothesis of multicollinearity between FACIT and PHQ-9 (r = 0.7, p < 0.001), PHQ-9 and GAD (r = 0.50, p < 0.05), and PHQ-9 and GAD (r = 0.45, p < 0.005) was not rejected. Therefore, we proceeded by considering only the FACIT as the independent variable to assess its association with endothelial function.

3. Clarify definition of endothelial dysfunction (ED).

Response: We standardized the definition of ED throughout the manuscript as FMD <10%, in accordance with established international and national studies.

4. Address inconsistencies in statistical reporting.

Response: We appreciate the reviewer’s observation. The mention of t-tests and chi-squared tests in the Methods section was indeed an oversight on our part. These tests were initially considered during the early stages of the analysis plan; however, as the study progressed, we opted for a more comprehensive statistical approach, employing logistic regression and discriminant analysis to address our research questions in a multivariate framework.

This advanced modeling strategy allowed us to simultaneously adjust for potential confounders and assess the combined discriminatory power of the predictors, which rendered the use of separate t-tests and chi-squared tests unnecessary. We have now removed the reference to these tests in the Methods section to ensure consistency and clarity.

5. Address reduced power in secondary analysis.

Response: We explicitly acknowledge the reduced statistical power of the secondary model after excluding participants with anxiety or depression. This limitation has been discussed in the revised Limitations section.

6. Data availability and STROBE compliance.

Response: Supporting data have been included in the revised supplementary files, and the manuscript has been checked for compliance with STROBE guidelines. The STROBE checklist is also submitted with this revision.

7. Avoid causal language and overstated conclusions.

Response: We carefully revised the Discussion and Conclusion sections to avoid causal language. Statements implying causality were rephrased to reflect the cross-sectional design, emphasizing the exploratory and correlational nature of our findings.

8. Address residual variance and generalizability.

Response: We added a paragraph to discuss the proportion of unexplained variance in the regression models. The decrease in explained variance in the secondary model was also addressed, reinforcing that mental health variables play a significant role and that other unmeasured factors may also influence ED.

Reviewer #1

1. Add specific research questions at the end of the introduction.

Response: We thank the reviewer for this helpful suggestion. We have added the specific research questions to the end of the Introduction section, clearly enumerated as follows:

(1) Was spiritual well-being (SWB) associated with endothelial dysfunction (ED)?

(2) Did this association persist after excluding individuals with anxiety or depressive symptoms?

(3) Which SWB dimensions—peace, meaning, or faith—showed the strongest association with ED?

2. Strengthen the methodology regarding sampling method and adequacy.

Response: We revised the "Materials and Methods" section to describe the convenience sampling approach and recruitment process in greater detail, including participant sources (e.g., students, staff, and patient relatives). We also included a justification for sample adequacy based on previous literature and added results from a post hoc power analysis confirming sufficient statistical power (β > 0.80).

3. Include validity and reliability coefficients of measurement tools.

Response: We have added internal consistency coefficients (Cronbach’s alpha) and validation references for all scales used (FACIT-Sp, PHQ-9, and GAD-7) in the "Measures" subsection. In the present study, internal consistency reliability coefficients were high for the FACIT-Sp (Cronbach’s alpha [α] = 0.862), PHQ-9 (α = 0.814), and GAD-7 (α = 0.890).The manuscript now includes information confirming their psychometric properties in Brazilian populations.

4. Emphasize clinical relevance of SWB effects beyond anxiety and depression.

Response: As recommended, we have enhanced the Discussion to emphasize that SWB remained a significant predictor of preserved endothelial function even after excluding individuals with anxiety or depression. This highlights its potential independent effect and clinical relevance beyond traditional psychological dimensions.

5. Highlight the independence of peace and meaning dimensions from faith.

Response: This important point was incorporated into the Discussion and reinforced in the section on discriminant analysis. We emphasized that inner peace and life purpose significantly differentiated individuals with and without ED, whereas the faith dimension did not, underscoring the cross-cultural and secular applicability of SWB.

6. Note the limited generalizability due to sample size and setting.

Response: We fully agree. The limitations section has been expanded to acknowledge the modest sample size and its restriction to a Brazilian population, cautioning against broad generalizations. We also call for larger, multi-center studies to validate our findings.

Reviewer #2

1. Include prior studies linking spirituality and cardiovascular outcomes.

Response: We thank the reviewer for these references. We incorporated the suggested citations (O'Riordan et al., 2025; Lucchetti, 2025; Cottrell-Daniels et al.) into the Introduction and Discussion to contextualize our findings within the broader literature on spirituality and cardiovascular health.

2. Include information on the context of spirituality in Brazil.

Response: We expanded the Discussion to include a brief overview of spirituality/religiosity in Brazil, referencing national surveys and academic initiatives. We noted the cultural relevance and increasing institutional support for spirituality in health promotion.

3. Discuss barriers to address spirituality in clinical settings.

Response: We integrated a paragraph discussing barriers such as lack of training, limited time, and clinicians’ discomfort. We cited recent studies showing that although physicians recognize the relevance of spirituality, many feel unprepared to address it in clinical practice.

4. Acknowledge study strengths.

Response: The strengths section has been revised to highlight the use of validated instruments, rigorous clinical screening, and the novel integration of psychological and spiritual variables in cardiovascular risk assessment.

5. Clarify clinical implications.

Response: The Discussion now more clearly outlines potential clinical implications, emphasizing the exploratory nature of our findings and the importance of integrating SWB in a culturally sensitive and non-dogmatic manner into preventive strategies.

** Furthermore, we undertook a comprehensive re-examination of the dataset and the database with methodological accuracy and scientific rigor. This process led to minor adjustments in certain numerical values; however, the overall interpretation, significance, and conclusions of the study remain unchanged.

As requested, the database has been attached to the submission.

We sincerely thank the reviewers for their constructive suggestions, which significantly improved the rigor and clarity of our manuscript. All changes made in response to these comments are marked in the revised version submitted.

Respectfully,

Sincerely,

André Casarsa, MD, MSc and Prof. Sergio Schmidt PhD (Corresponding author)

On behalf of all co-authors

Department of Internal Medicine University Hospital Gaffrée Guinle – UNIRIO

Federal University of the State of Rio de Janeiro

slschmidt@terra.com.br

Attachment

Submitted filename: RESPONSE TO REVIEWERS.docx

pone.0339676.s002.docx^{(137.5KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0339676.r003

Decision Letter 1

Francesco De Vincenzo

22 Sep 2025

PLOS ONE

Dear Dr. Schmidt,

Thank you for addressing the previous comments. However, several issues regarding the analytical approach remain and need clarification before the manuscript can be considered for acceptance.

1. Cut-off for SWB (FACIT-Sp)

In the revised manuscript, it is unclear whether the cut-off of 36 was determined based on your sample or directly adopted from McClain et al. (≥3 “quite a bit” vs <3 “somewhat” or lower).
This cut-off is not a clinically or psychometrically validated threshold, but a data-driven value specific to McClain’s sample.
Without previously validated cut-offs (e.g., ROC-based thresholds), the rationale for dichotomizing SWB remains weak. Authors should either justify this choice based on their own data distribution or consider more robust alternatives

2. Justification for dichotomization

It is unclear why a linear regression model with continuous predictors was added in the revised manuscript. Please clarify the rationale for including this model. If it was intended to justify the dichotomization of SWB, it is not apparent how it accomplishes this.
Consider whether the linear regression is necessary or whether the main focus should remain on the logistic regression with ED as the outcome.
If Authors decide to maintain this model thanks to a strong rationale, it should be also clarified why the same predictors were treated as continuous in the linear regression (continuous endothelial function outcome) and dichotomized in the logistic regression (including ED as a binary outcome).
Moreover, Authors stated that they proceeded by considering only SWB as the independent variable due to collinearity; however, PHQ and GAD are still included in the logistic regression model (Table 1).
Multicollinearity alone does not justify dichotomizing a continuous variable, especially in the absence of previously validated cut-offs. Explain why dichotomization was preferred over keeping SWB continuous and addressing collinearity through standard methods (e.g., variable exclusion, combination, or other methods).

3. Assessment of multicollinearity

Reporting correlations alone is insufficient. A correlation >0.70 does not automatically indicate problematic multicollinearity.
Please provide VIF and tolerance values for all predictors to substantiate any claims of collinearity.
Attention should be given to any inconsistencies (e.g., correlation between PHQ and SWB reported as >0.70 in your reply, but ~0.50 in the figure).
Note: the presence of multicollinearity does not automatically justify dichotomization.

4. Other Inconsistencies

There are several inconsistencies in the manuscript between values reported in the text and those in Table 1.

Please submit your revised manuscript by Nov 06 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Francesco De Vincenzo, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: Dear authors,

The manuscript is in a highly developed state after revision.

Thank you for considering the suggestions of all the reviewers.

The introduction, methods (sample, data analysis), and discussion have become particularly cautious, especially regarding the mediating effect of SWB on cardiovascular health.

From my perspective, the limitations are also satisfactory. With this revision, I believe the manuscript can contribute to the literature.

Some spelling errors, punctuation, and comma usage appear differently in the tables. There are also parts where ED is not used. Please check the final proof.

Sincerely.

Reviewer #2: The manuscript has been improved and can be published in the present version.The authors have adequately addressed my comments raised in a previous round of review and I feel that this manuscript is now acceptable for publication

**********

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PLoS One. 2025 Dec 26;20(12):e0339676. doi: 10.1371/journal.pone.0339676.r004

Author response to Decision Letter 2

2 Nov 2025

Dear Editors,

Dear Academic Editor and Reviewers,

We would like to thank you for the thorough and thoughtful review of our manuscript. Below, we provide a detailed point-by-point response to the comments raised, indicating the changes made in the revised manuscript.

________________________________________

Academic Editor / Journal Office

1.Cut-off for SWB (FACIT-Sp): In the revised manuscript, it is unclear whether the cut-off of 36 was determined based on your sample or directly adopted from McClain et al. (≥3 “quite a bit” vs <3 “somewhat” or lower). This cut-off is not a clinically or psychometrically validated threshold, but a data-driven value specific to McClain’s sample. Without previously validated cut-offs (e.g., ROC-based thresholds), the rationale for dichotomizing SWB remains weak. Authors should either justify this choice based on their own data distribution or consider more robust alternatives.

Response: We appreciate the reviewer’s thoughtful observation. In response, we revised our analytic strategy to enhance methodological rigor and to directly address the issue raised.

While our initial approach was conceptually inspired by McClain et al. (2003), we acknowledge that the threshold used in their study was developed within an oncology population and lacks external psychometric validation, particularly for application in cardiovascular or clinically healthy populations. As no validated cut-off for the FACIT-Sp currently exists for predicting endothelial dysfunction or related cardiovascular outcomes in non-clinical samples, we recognize that the dichotomization approach could introduce unnecessary limitations.

Accordingly, we reanalyzed all models using the FACIT-Sp total score as a continuous variable. This decision reflects both statistical and conceptual considerations. Statistically, treating spiritual well-being as continuous preserves the variability inherent in the construct, improves power, and avoids potential loss of information and misclassification bias associated with arbitrary dichotomization. Conceptually, spiritual well-being is widely recognized as a dimensional construct, and prior literature supports its use as a continuous predictor in models examining psychological and physical health outcomes, including in cardiovascular contexts [1,2,3,4].

This updated approach aligns with best practices in quantitative research, especially in the absence of clinically validated cut-offs, and allows for more nuanced interpretation of the association between spiritual well-being and endothelial function. All references to the dichotomized SWB variable were removed, and the revised manuscript now consistently reports results based on continuous treatment of the FACIT-Sp total score.

1. Peterman AH, Fitchett G, Brady MJ, Hernandez L, Cella D. Measuring spiritual well-being in people with cancer: The functional assessment of chronic illness therapy—Spiritual Well-being Scale (FACIT-Sp). Ann Behav Med. 2002;24(1):49–58. doi:10.1207/S15324796ABM2401_06

2. Edmondson D, Park CL, Blank TO, Fenster JR, Mills MA. Deconstructing spiritual well-being: Existential well-being and HRQOL in cancer survivors. Psychooncology. 2008;17(2):161–169. doi:10.1002/pon.1221

3. Cotton S, Puchalski CM, Sherman SN, Mrus JM, Peterman AH, Feinberg J, et al. Spirituality and religion in patients with HIV/AIDS. J Gen Intern Med. 2006;21(S5):S5–13. doi:10.1111/j.1525-1497.2006.00642.x

4. Park CL, Edmondson D, Fenster JR, Blank TO. Meaning making and psychological adjustment following cancer: The mediating roles of growth, life meaning, and restored just-world beliefs. J Consult Clin Psychol. 2008;76(5):863–875. doi:10.1037/a0013348

2. Justification for dichotomization: It is unclear why a linear regression model with continuous predictors was added in the revised manuscript. Please clarify the rationale for including this model. If it was intended to justify the dichotomization of SWB, it is not apparent how it accomplishes this. Consider whether the linear regression is necessary or whether the main focus should remain on the logistic regression with ED as the outcome. If Authors decide to maintain this model thanks to a strong rationale, it should be also clarified why the same predictors were treated as continuous in the linear regression (continuous endothelial function outcome) and dichotomized in the logistic regression (including ED as a binary outcome). Moreover, Authors stated that they proceeded by considering only SWB as the independent variable due to collinearity; however, PHQ and GAD are still included in the logistic regression model (Table 1). Multicollinearity alone does not justify dichotomizing a continuous variable, especially in the absence of previously validated cut-offs. Explain why dichotomization was preferred over keeping SWB continuous and addressing collinearity through standard methods (e.g., variable exclusion, combination, or other methods).

Response: We appreciate the reviewer’s thoughtful comments and the opportunity to clarify our analytical approach. In the previous version of the manuscript, a linear regression model using flow-mediated dilation (FMD%) as a continuous outcome was included as an exploratory analysis. However, upon further reflection, we recognize that this model did not directly contribute to the primary aims of the study, which focused on identifying predictors of clinically relevant endothelial dysfunction. Furthermore, the inclusion of the linear regression introduced inconsistencies in the treatment of predictor variables and may have raised interpretative challenges by suggesting alternative modeling paths without a clearly defined theoretical rationale. Accordingly, we have removed the linear regression analysis from the manuscript to ensure greater conceptual and statistical coherence.

Regarding the treatment of spiritual well-being (FACIT-Sp), we have revised our analytical strategy to model this construct as a continuous predictor in all inferential analyses. While our original approach followed the cut-off proposed by McClain et al. (2003), we acknowledge that this threshold was derived from a specific oncology population and lacks external psychometric validation in clinically healthy or cardiovascular samples. In line with current best practices in quantitative health research, we now preserve the full variability of the FACIT-Sp scale to avoid the loss of statistical power and the risk of arbitrary categorization, which could obscure meaningful associations.

In a prior response, we referred to potential collinearity concerns as one reason for restricting the initial model to SWB. However, to properly evaluate this issue, we performed diagnostic analyses using variance inflation factor (VIF) and tolerance values for all covariates included in the final logistic regression model. The results indicated no evidence of problematic multicollinearity, with all VIFs below 2.0 and tolerances above 0.5. Based on these findings, we confirmed that multicollinearity was not a limiting factor in our model specification and thus did not require dichotomization of SWB or exclusion of additional predictors.

This updated modeling approach ensures a more robust interpretation of our findings, strengthens the alignment between the theoretical construct and the statistical framework, and directly addresses the reviewer’s concern about collinearity and the limitations of arbitrary dichotomization.

3. Assessment of multicollinearity: Reporting correlations alone is insufficient. A correlation >0.70 does not automatically indicate problematic multicollinearity. Please provide VIF and tolerance values for all predictors to substantiate any claims of collinearity. Attention should be given to any inconsistencies (e.g., correlation between PHQ and SWB reported as >0.70 in your reply, but ~0.50 in the figure). Note: the presence of multicollinearity does not automatically justify dichotomization.

Response: We appreciate the reviewer’s important observation regarding the assessment of multicollinearity. In our previous response, we referenced bivariate correlations as a preliminary indication of shared variance among predictors. However, we agree that correlation coefficients alone are insufficient for diagnosing problematic multicollinearity in regression models.

To address this issue more rigorously, we conducted a formal collinearity diagnostic analysis using Variance Inflation Factor (VIF) and tolerance values for all independent variables included in the logistic regression model. The results revealed no evidence of problematic multicollinearity: all VIF values were below 2.0, and all tolerance values exceeded 0.5, which are well within commonly accepted thresholds (VIF < 5.0 and tolerance > 0.2) for retaining predictors in multivariable models.

Additionally, we reviewed our previously reported correlation coefficients and confirmed that the correlation between SWB (FACIT-Sp) and PHQ-9 was approximately –0.50, not above –0.70 as erroneously stated in our prior reply. We apologize for this oversight and have corrected the text accordingly.

As a result, we concluded that multicollinearity does not pose a threat to the validity of our models and did not serve as the basis for any variable transformation or exclusion. In line with this updated assessment and the concerns raised in Item 2, we have removed the dichotomization of the FACIT-Sp score and now model spiritual well-being as a continuous predictor in all inferential analyses.

We believe these steps provide a more robust and transparent statistical approach and fully address the reviewer’s concerns regarding the evaluation and implications of multicollinearity.

Reviewer #1

The manuscript is in a highly developed state after revision. Thank you for considering the suggestions of all the reviewers. The introduction, methods (sample, data analysis), and discussion have become particularly cautious, especially regarding the mediating effect of SWB on cardiovascular health. From my perspective, the limitations are also satisfactory. With this revision, I believe the manuscript can contribute to the literature. Some spelling errors, punctuation, and comma usage appear differently in the tables. There are also parts where ED is not used. Please check the final proof.

Reviewer #2

The manuscript has been improved and can be published in the present version.The authors have adequately addressed my comments raised in a previous round of review and I feel that this manuscript is now acceptable for publication

Response: We sincerely thank both reviewers for their generous feedback and for recognizing the improvements made in the revised version of our manuscript.

To Reviewer #1, we are particularly grateful for the acknowledgment of the refinements in the introduction, methods, and discussion, as well as for the thoughtful remarks regarding clarity and rigor. As recommended, we carefully reviewed the entire manuscript for consistency in terminology (e.g., “ED”), spelling, punctuation, and formatting within the tables and figures. All identified issues have been corrected in the final version.

To Reviewer #2, we truly appreciate your positive assessment and support for publication. Your earlier suggestions played a key role in improving the clarity and relevance of our findings.

Finally, we extend our sincere thanks to the PLOS ONE editorial team for overseeing this process with fairness and professionalism. We are honored by the opportunity to publish in such a respected and widely read journal, and we hope this work will contribute meaningfully to ongoing discussions at the intersection of spirituality, mental health, and cardiovascular research.

Sincerely,

André Casarsa, MD, MSc and Prof. Sergio Schmidt PhD (Corresponding author)

On behalf of all co-authors

Department of Internal Medicine University Hospital Gaffrée Guinle – UNIRIO

Federal University of the State of Rio de Janeiro

slschmidt@terra.com.br

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PLoS One. doi: 10.1371/journal.pone.0339676.r005

Decision Letter 2

Francesco De Vincenzo

30 Nov 2025

Dear Dr. Schmidt,

The authors have done an excellent job revising the manuscript. There remains one minor but important issue. In the new regression model, statements (including in the abstract) suggesting that SWB is the “strongest predictor” overreach the data. Indeed, some variables (e.g., major depressive episodes) showed larger coefficients and odds ratios. This needs to be addressed to accurately reflect the results.

As a possible way to revise the text, the authors may consider rephrasing the sentences in line with the first research question, focusing on the fact that SWB is significantly inversely associated with ED, independent of other covariates. This would convey the key finding without overstating the relative strength of the predictor.

Please submit your revised manuscript by Jan 14 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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PLoS One. 2025 Dec 26;20(12):e0339676. doi: 10.1371/journal.pone.0339676.r006

Author response to Decision Letter 3

6 Dec 2025

We thank the reviewer for the thoughtful and constructive comment. We agree that statements referring to spiritual well-being (SWB) as the “strongest predictor” overstated the findings. As suggested, we have revised the abstract and the main text to ensure that the results are accurately represented.

Specifically, we removed expressions implying comparative predictive strength and rephrased the sentences to emphasize that SWB was significantly and inversely associated with endothelial dysfunction (ED), independent of other covariates, which is consistent with our primary research question. These changes avoid overinterpretation and better reflect the observed effect sizes relative to other variables in the model.

We appreciate the reviewer’s guidance, which improved the clarity and precision of our manuscript.

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PLoS One. doi: 10.1371/journal.pone.0339676.r007

Decision Letter 3

Francesco De Vincenzo

10 Dec 2025

Spiritual Well-Being as a Protective Factor for Endothelial Dysfunction in Clinically Healthy Adults

PONE-D-25-31113R3

Dear Dr. Schmidt,

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Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0339676.r008

Acceptance letter

Francesco De Vincenzo

PONE-D-25-31113R3

PLOS One

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Data Availability Statement

All relevant data are within the paper.

[pone.0339676.ref001] 1.Vita JA, Keaney JF Jr. Endothelial function: a barometer for cardiovascular risk?. Circulation. 2002;106(6):640–2. doi: 10.1161/01.cir.0000028581.07992.56 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref002] 2.Drexler H, Hornig B. Endothelial dysfunction in human disease. J Mol Cell Cardiol. 1999;31(1):51–60. doi: 10.1006/jmcc.1998.0843 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref003] 3.Tolentino JC, Gjorup ALT, Mello CR, de Assis SG, Marques AC, Filho Á do C, et al. Spirituality as a protective factor for chronic and acute anxiety in Brazilian healthcare workers during the COVID-19 outbreak. PLoS One. 2022;17(5):e0267556. doi: 10.1371/journal.pone.0267556 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0339676.ref004] 4.Aggarwal S, Wright J, Morgan A, Patton G, Reavley N. Religiosity and spirituality in the prevention and management of depression and anxiety in young people: a systematic review and meta-analysis. BMC Psychiatry. 2023;23(1):729. doi: 10.1186/s12888-023-05091-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0339676.ref005] 5.McClain CS, Rosenfeld B, Breitbart W. Effect of spiritual well-being on end-of-life despair in terminally-ill cancer patients. Lancet. 2003;361(9369):1603–7. doi: 10.1016/S0140-6736(03)13310-7 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref006] 6.de Brito Sena MA, Damiano RF, Lucchetti G, Peres MFP. Defining Spirituality in Healthcare: A Systematic Review and Conceptual Framework. Front Psychol. 2021;12:756080. doi: 10.3389/fpsyg.2021.756080 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0339676.ref007] 7.Puchalski CM, Vitillo R, Hull SK, Reller N. Improving the spiritual dimension of whole person care: reaching national and international consensus. J Palliat Med. 2014;17(6):642–56. doi: 10.1089/jpm.2014.9427 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0339676.ref008] 8.Peterman AH, Fitchett G, Brady MJ, Hernandez L, Cella D. Measuring spiritual well-being in people with cancer: the functional assessment of chronic illness therapy--Spiritual Well-being Scale (FACIT-Sp). Ann Behav Med. 2002;24(1):49–58. doi: 10.1207/S15324796ABM2401_06 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref009] 9.Cotton S, Puchalski CM, Sherman SN, Mrus JM, Peterman AH, Feinberg J, et al. Spirituality and religion in patients with HIV/AIDS. J Gen Intern Med. 2006;21 Suppl 5(Suppl 5):S5-13. doi: 10.1111/j.1525-1497.2006.00642.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0339676.ref010] 10.Lucchetti G, Lucchetti ALG, de Bernardin Gonçalves JP, Vallada HP. Validation of the Portuguese version of the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being scale (FACIT-Sp 12) among Brazilian psychiatric inpatients. J Relig Health. 2015;54(1):112–21. doi: 10.1007/s10943-013-9785-z [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref011] 11.Monod S, Brennan M, Rochat E, Martin E, Rochat S, Büla CJ. Instruments measuring spirituality in clinical research: a systematic review. J Gen Intern Med. 2011;26(11):1345–57. doi: 10.1007/s11606-011-1769-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0339676.ref012] 12.Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606–13. doi: 10.1046/j.1525-1497.2001.016009606.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0339676.ref013] 13.Siu AL, US Preventive Services Task Force (USPSTF), Bibbins-Domingo K, Grossman DC, Baumann LC, Davidson KW, et al. Screening for Depression in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2016;315(4):380–7. doi: 10.1001/jama.2015.18392 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref014] 14.Spitzer RL, Kroenke K, Williams JBW, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092–7. doi: 10.1001/archinte.166.10.1092 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref015] 15.Moreno AL, DeSousa DA, Souza AMFLP, Manfro GG, Salum GA, Koller SH, et al. Factor Structure, Reliability, and Item Parameters of the Brazilian-Portuguese Version of the GAD-7 Questionnaire. Temas Psicol. 2016;24(1):367–76. doi: 10.9788/tp2016.1-25 [DOI] [Google Scholar]

[pone.0339676.ref016] 16.Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39(2):257–65. doi: 10.1016/s0735-1097(01)01746-6 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref017] 17.Yeboah J, Crouse JR, Hsu F-C, Burke GL, Herrington DM. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation. 2007;115(18):2390–7. doi: 10.1161/CIRCULATIONAHA.106.678276 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref018] 18.Hamburg NM, Palmisano J, Larson MG, Sullivan LM, Lehman BT, Vasan RS, et al. Relation of brachial and digital measures of vascular function in the community: the Framingham heart study. Hypertension. 2011;57(3):390–6. doi: 10.1161/HYPERTENSIONAHA.110.160812 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0339676.ref019] 19.Santos AC, Madi JM, Oliveira LG, Zandonade E, Costa SHN, Amorim MMR. Predictive value of flow-mediated dilation for preeclampsia: a cohort study. Rev Bras Ginecol Obstet. 2012;34(3):111–6. [Google Scholar]

[pone.0339676.ref020] 20.Brasil AV, Gomes MB, Fonseca FAH, Schaan BD, Dib SA, Bertolami MC. Prevalence of cardiovascular risk factors in people with diabetes in Brazil: The Brazilian Cardiovascular Risk Study (ERCE). Arq Bras Cardiol. 2011;96(5):331–8. [Google Scholar]

[pone.0339676.ref021] 21.Charakida M, Masi S, Lüscher TF, Kastelein JJP, Deanfield JE. Assessment of atherosclerosis: the role of flow-mediated dilatation. Eur Heart J. 2010;31(23):2854–61. doi: 10.1093/eurheartj/ehq340 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref022] 22.Ghiadoni L, Donald AE, Cropley M, Mullen MJ, Oakley G, Taylor M, et al. Mental stress induces transient endothelial dysfunction in humans. Circulation. 2000;102(20):2473–8. doi: 10.1161/01.cir.102.20.2473 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref023] 23.Cui L, Li S, Wang S, Wu X, Liu Y, Yu W, et al. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal Transduct Target Ther. 2024;9(1):30. doi: 10.1038/s41392-024-01738-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0339676.ref024] 24.Rosmarin DH, Leidl B. Spirituality, religion, and anxiety disorders. Handbook of Spirituality, Religion, and Mental Health. Elsevier. 2020. 41–60. doi: 10.1016/b978-0-12-816766-3.00003-3 [DOI] [Google Scholar]

[pone.0339676.ref025] 25.Koenig HG. Religion, spirituality, and health: a review and update. Adv Mind Body Med. 2015;29(3):19–26. [PubMed] [Google Scholar]

[pone.0339676.ref026] 26.O’Riordan A, Costello AM, Hill TD. Religious and Spiritual Coping Mediates the Association between Trait Extraversion and Cardiovascular Reactivity to Acute Psychological Stress. J Relig Health. 2025;64(6):4824–46. doi: 10.1007/s10943-025-02392-6 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref027] 27.Engin A. Endothelial Dysfunction in Obesity. Adv Exp Med Biol. 2017;960:345–79. doi: 10.1007/978-3-319-48382-5_15 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref028] 28.Herren O, Denkinger M, Rapp K, Jung C, Klenk J. Association between spiritual well-being and inflammatory biomarkers in older adults: results from the EPIDOS cohort. Psychoneuroendocrinology. 2019;100:198–205.30388593 [Google Scholar]

[pone.0339676.ref029] 29.Vagnini R, Lopes GS, Costa C. Spirituality and inflammatory markers in hypertensive individuals: data from the FEEL study. Braz J Psychiatry. 2024;46(2):151–9. [Google Scholar]

[pone.0339676.ref030] 30.Zare H, Meyerson NS, Delgado P, Crifasi C, Spencer M, Gaskin D, et al. How place and race drive the numbers of fatal police shootings in the US: 2015-2020. Prev Med. 2022;161:107132. doi: 10.1016/j.ypmed.2022.107132 [DOI] [PubMed] [Google Scholar]

[pone.0339676.ref031] 31.Vos J. The impact of meaning-centered therapy on spiritual well-being and quality of life: a meta-analysis. Palliat Support Care. 2021;19(2):201–13. [Google Scholar]

[pone.0339676.ref032] 32.Esperandio MRG. Spirituality and Health in Brazil: A Survey Snapshot of Research Groups. Religions. 2020;12(1):27. doi: 10.3390/rel12010027 [DOI] [Google Scholar]

[pone.0339676.ref033] 33.Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74(10):e177–e232. doi: 10.1016/j.jacc.2019.03.010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0339676.ref034] 34.Whitehead IO, Jagger C, Hanratty B. Discussing spiritual health in primary care and the HOPE tool-A mixed methods survey of GP views. PLoS One. 2022;17(11):e0276281. doi: 10.1371/journal.pone.0276281 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0339676.ref035] 35.Best M, Butow P, Olver I. Doctors discussing religion and spirituality: A systematic literature review. Palliat Med. 2016;30(4):327–37. doi: 10.1177/0269216315600912 [DOI] [PubMed] [Google Scholar]

PERMALINK

Spiritual well-being as a protective factor for endothelial dysfunction in clinically healthy adults

Andre Casarsa

Pedro Bastos de Medeiros

Julio Cesar Tolentino

Isadora de Sa Guimaraes

Kelen Carolina Silva Cruz

Leticia Silva Flor dos Santos

Matheus Nakazato Tinoco

Maria de Fatima Martins Gil Dias

Ana Lucia Taboada Gjorup

Sergio Luis Schmidt

Roles

Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Materials and methods

Fig 1. Flowchart: recruitment, screening, and assessment flow for the cross-sectional study.

Statistical analysis

Ethical considerations

Results

Sample characteristics and assessed parameters

Predictors of endothelial dysfunction

Table 1. Multivariate binary logistic regression identifying predictors of ED in a sample of clinically healthy adults (n = 148).

Predictors of endothelial dysfunction in individuals without anxiety or depression

Table 2. Logistic regression model evaluating the association between SWB and ED in a subsample of 93 participants without anxiety or depressive symptoms.

Dimensions of spirituality

Fig 2. Discriminant analysis of spiritual dimensions in relation to ED. (A) Structure matrix correlations between each spiritual dimension (Peace, Meaning in Life, and Faith) and the canonical discriminant function.

Fig 3. Kernel density estimates for SWB dimensions by ED status.

Discussion

Conclusion

Acknowledgments

Data Availability

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