June 2009 | Vol 6 | N.º 6 | CNIC-9 [PDF (318K)]

Clinical and Epidemiological Research at CNIC: Psychosocial Factors and Cardiovascular Disease

Manuel Franco, Ginés Sanz, and Eliseo Guallar

Summary
The study of the possible association between psychosocial factors such as job strain, depression, social support and stress and the development, treatment and prognosis of cardiovascular disease (CVD) is a promising field of research. Job strain and depression are highly prevalent conditions, and CVD remains the leading cause of death in most countries. Nevertheless, only a few cardiovascular studies have focused on Spain.

The rich variety of cardiovascular studies currently being performed at the National Centre for Cardiovascular Research (CNIC) offers a unique opportunity for the development of this field. We will be able to investigate the relationship of psychosocial factors to CVD outcomes in two large cohort studies of different populations of workers: a case-control study of young women with myocardial infarction and a large sample of participants in a secondary CVD prevention trial. In these studies, we will use several well-established and already validated questionnaires to measure job strain, depression, social support and stress.

Findings related to the possible association between extremely common psychosocial factors such as job strain and depression and the development, treatment and prognosis of CVD will offer excellent opportunities for the development of preventive cardiovascular interventions.

I. Introduction
The study of psychosocial factors—that is, factors connecting individual psychological phenomena to the social environment—has received considerable attention in recent decades. In particular, their possible association with cardiovascular disease (CVD) has been of great interest.¹ CVD research has explored how psychosocial factors, including depression, stress at work and at home, and lack of social support, may contribute to the etiology of CVD, its progression, and patients’ survival.² Part of this effort developed as a possible explanation of the persistent social gradient in CVD morbidity and mortality.³,⁴ Social gradient is determined in cardiovascular epidemiology via examination of the effect of variables such as income, education and occupation.⁵ The Whitehall II study, an ongoing cohort study with 22 years of follow-up, was originally designed to determine the extent to which psychosocial factors both in and outside the work environment explain the social gradient in CVD morbidity and mortality.⁶
Researchers in this field have greatly advanced the theories and specific methods for measuring the hypothesised psychosocial factors. Psychosocial factors are either aspects of the social environment where individuals live or individual characteristics, as seen in Figure 1.

Psychosocial factors may relate directly to the social environment in which an individual lives and works, for example, the level of stress at work⁷-¹⁷ and at home¹⁸-²⁰ and the available social support.¹⁹,²¹-²⁴ During the last decades, large changes in immigration patterns in countries like Spain, the degree of acculturation (i.e. the adoption of the traditions, values, and cultural practices of a host country) among immigrants has shown a positive relation with CVD.²⁵-²⁷ Stress levels at work, or job strain, has been the focus of a large number of CVD studies. Sleeping patterns, which might be altered due to night shift jobs, is also an interesting CVD research topic. Unfortunately we will not have access to night shift workers in our studies and therefore we decided not to include the measurement of sleep patterns.

Psychosocial factors also relate to individual characteristics, including emotions (depression),²⁵ personality traits,² and behaviors.²¹ The psychosocial factor most relevant to CVD outcome is the presence of depression.²⁰,²⁴,²⁶-³¹
The question of how psychosocial factors relate to subclinical and clinical CVD, and through which mechanisms, is of great scientific relevance.² Knowledge of the biological processes involved in the establishment and progression of CVD when a person is under high levels of job strain and depression, which are highly prevalent conditions, reveals excellent opportunities for the introduction of preventive interventions.

As shown in Figure 1, two broad mechanisms link psychosocial factors to CVD outcomes. First, psychosocial factors may be directly associated with established risk factors, such as smoking, diet, and physical activity.³²,³³ Second, psychosocial factors may also directly influence biological processes through their effects on the hypothalamic–pituitary–adrenal axis and the sympathetic and parasympathetic nervous systems.³⁴-³⁶ A third mechanism, not discussed in depth here, once CVD is clinically diagnosed and an individual treatment plan has been assigned, psychosocial factors such as the presence of depression³⁷,³⁸ and social support may influence the degree of adherence to the treatment.

A well-designed systematic review found sufficient evidence of a causal association between depression, social support and psychosocial work characteristics and CVD etiology and prognosis.²
In Spain, very few studies have explored the relationship between psychosocial factors and CVD. A PubMed search for studies conducted in Spain on CVD and psychosocial factors such as depression, social support, job strain and stress (see appendix for the PubMed search terms) yielded only two studies.³⁹,⁴⁰ The first study found that depression was present in as much as 48% of elderly patients with heart failure.³⁹ The second study found that living together and having close friends was associated with lower prevalence and higher awareness of hypertension.⁴⁰

II. Clinical and Epidemiological Research at CNIC
At the National Centre for Cardiovascular Research (CNIC), along with other national and international institutions, we are currently planning and conducting several cardiovascular clinical and epidemiological studies. Two of these studies are based on populations of workers. One is a population of administrative employees at a large company in Spain. The second is a population of white-collar workers at a Spanish automotive factory. A third study will recruit young women and men who experienced myocardial infarction. Finally, a fourth study will study patient adherence to secondary prevention treatments after myocardial infarction.

The diversity of these populations in terms of geographical location, sex distribution, age range, and occupation offers a great opportunity to study well-defined psychosocial factors and their role in CVD etiology, treatment and prognosis. Sadly, none of the populations to be studied currently at CNIC will include a sufficient number of immigrants, and therefore degree of acculturation will not be included among the psychosocial measures.

One of the challenges in researching the relationship between psychosocial factors and CVD is the absence of information about the designs and objectives of published studies, few of which detail the measurement of psychosocial factors and CVD outcomes prior to reporting results². To avoid this limitation, we include in the following description of the clinical and epidemiological cardiovascular studies currently planned at CNIC the specific measures of psychosocial factors to be measured in these studies using already validated questionnaires.

Study on the early detection and progression of subclinical atherosclerosis.
The proposed study aims to assess the distribution of subclinical atherosclerosis by means of advanced imaging techniques in a population of 5,000 administrative employees (65% men and 35% women) 40 to 55 years of age. These employees will be followed for a period of 6 years with the objective of understanding the progression of subclinical atherosclerosis in relation to several risk factors, including psychosocial factors.

Aragón Workers Health Study.
This ongoing study includes 8000 workers at the General Motors–Spain factory in Figueruelas (Zarazoga, Spain). The study is the result of a collaborative effort between CNIC and the Aragón Institute of Health Sciences (IACS). Its overarching goal is to identify genetic, psychosocial, and established risk factors that determine: a) the trajectories of metabolic and cardiovascular risk factors over time (overweight and obesity, blood pressure, lipid profile, glucose abnormalities and diabetes, smoking habits, and non-traditional risk factors); b) the presence and development of subclinical atherosclerosis; and c) the development of clinical cardiovascular and other disease endpoints.

Study of young women with acute myocardial infarction (IMJOVEN)
This study is part of the VIRGO study, a multicenter case-control study conducted in collaboration with the Cardiology Clinic at Yale University. We will characterise sex disparities across a broad range of CVD outcomes. We will determine the relative importance of traditional and novel demographic, clinical, metabolic, psychosocial, and biological factors to CVD outcomes in young women and their excess risk compared with men. Several psychosocial domains will be examined in this study, including depression, perceived stress and social support.

Study of a Fixed Dose Combination Drug for Secondary Cardiovascular Prevention (FOCUS)
The aim of the FOCUS study is to prove the efficacy and safety of the fixed-dose combination polypill concept in secondary cardiovascular prevention in a variety of social and economic settings.⁴¹,⁴² This study will be conducted in several clinical sites in Spain, Italy, Argentina, Brazil and Paraguay. Fourteen hundred patients with a diagnosis of acute myocardial infarction attending any of the selected sites will be recruited. In this study, we will address the association between psychosocial factors, such as depression and social support, and adherence to treatment for secondary cardiovascular prevention.

III. Description of psychosocial factors of interest in the CNIC studies
The rationale for the inclusion of psychosocial factors in the cardiovascular epidemiological studies to be conducted at CNIC was based partly on a review of the most relevant literature in the field. In collaboration with the Multiethnic Study of Atherosclerosis (MESA)43, which included in its design the measurement of psychosocial factors²⁵, and with the aim of being able to compare our findings, we decided to include measurements of: depression, job strain, social support and perceived stress. Because the MESA study included a Spanish-speaking population, all questionnaires were translated into Spanish (i.e., the Spanish spoken in Spain),and the translations were validated.All questionnaires used in the MESA study have been checked again for their adequacy to Spanish spoken in Spain and compared to questionnaires already translated and validated in Spain, when available.⁴⁷ The Spanish versions of the MESA questionnaires were perfectly understandable in Spain.

Table 1 shows a summary of the most cited studies addressing the association of these particular psychosocial factors with CVD outcomes.

1. Depression
Rationale:
A growing body of literature shows that depression increases the risk of myocardial infarction in healthy community samples.²⁶,²⁹-³¹ Among the most convincing mechanisms are excess secretion of cortisol and catecholamines and increased heart rate,35 lack of adherence to treatment, ³⁷,³⁸ and high-risk-factor profiles.
As shown in Table 1, several cohort²⁷ and case-control²⁰ studies found possible associations of depression with CVD outcomes. Finally, the ENRICHD trial was designed to test a psychosocial intervention aiming to treat depression in order to improve prognosis in patients who experienced myocardial infarction.²⁴ No improvement in survival was shown in this trial. The case-control design of the INTERHEART study²⁰ makes it very difficult to interpret the results given the possibility of reverse causation and recall bias.⁴⁴ This is an important epidemiological issue for the interpretation of the IMJOVEN study results, which is also a case-control design.

The depression measure to be used in future CNIC studies
Depressive symptoms will be assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) scale,45 a 20-item questionnaire developed to assess depressive symptoms in community populations.⁴⁵ The CES-D items represent the major components of depression, including depressed mood, feelings of worthlessness, feelings of hopelessness, loss of appetite, poor concentration, and sleep disturbance. The Cronbach a measure of reliability ranges from 0.84 to 0.93.45 Participants are asked to rate each item on a scale from 0 to 3 according to “how often you have felt this way during the past week.” Total scores range from 0 to 60, with higher scores indicating more severe depressive symptoms. The CES-D assesses self-reported depressive symptoms but not clinical depression. Elevated depressive symptoms are defined by a CES-D score of 16 or higher, which is consistent with mild to moderate depression or dysthymia.⁴⁶

2. Job Strain
Rationale:
Numerous studies have linked characteristics of the work environment (such as demands at work and control over the work process) to risk of cardiovascular disease.16 Characteristics of the work environment have also been connected to subclinical disease¹⁴ (carotid IMT and plaque height) and its progression.¹⁵ The inclusion of validated measures of the work environment in the employee cohort studies conducted in Spain will allow examination of how these factors contribute to the progression and clinical expression of subclinical disease across employee groups. The job strain model (which consists of several components: job demands, job control, job insecurity and social support at work) is the model most commonly used in research relating work environment to CVD.

As shown in Table 1, several studies in the past few decades have addressed the association between work environment characteristics and CVD. Karasek was one of the first researchers to develop a valid measure of the work environment, establishing a model of job strain and testing its association with the incidence of coronary heart disease (CHD).¹³ Lynch et al. examined the level of job demands and economic reward in relation to the progression of carotid atherosclerosis in a large sample of Finnish men in the Kuopio Ischemic Heart Disease Risk Factor Study and found a positive association.¹⁵ The Whitehall II study, which used two measures of stress in the work environment—the job strain model and the effort-reward imbalance model—also found positive associations with the incidence of CHD.11,16 Finally, again in the Whitehall II study, Brunner et al.¹⁷ found a positive association between high job strain and two health measures, obesity and waist circumference.

The job strain measure to be used in future CNIC studies
The Job Content Questionnaire (JCQ) developed by Karasek is one of the most commonly used instruments in studies of workers’ stress¹³,⁴⁷. It has subscales corresponding to psychological demands, decision latitude, social support at work, physical demands, and job insecurity. Its reliability has been well documented and most of the subscales have been found it to be reliable for several different populations⁴⁷.

3. Social Support
Rationale:
Low social support, or social isolation, has been variously defined as having few social ties, not having access to practical assistance, or not having a confidant or other source of emotional support. Social isolation has consistently been linked to cardiovascular disease risk and events in large-scale, prospective studies of healthy persons and in studies of individuals with existing heart disease. Social support is a multidimensional construct. Aspects of social support which have been related to CVD outcomes include presence and size of social networks, emotional support (whether participants have someone in their network to provide emotional support when needed), and tangible support (the extent to which the person has someone in his or her life to help with practical, financial or other tangible assistance when needed).

As shown in Table 1, social support, measured as social connection, was found to be related to CVD mortality in a large cohort study of 13,000 men and women from eastern Finland.²²

The social support measure to be used in future CNIC studies:
The Emotional Social Support Inventory (ESSI)24 was developed for the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study and is composed of five items derived from well-validated social support scales found in previous studies to be individually predictive of death in cardiac patients⁴⁸. The ESSI has been proved to be both reliable and valid⁴⁹.

4. Perceived Stress
Rationale:
Experience of chronic stress in diverse domains of life may be important in understanding the progression of subclinical disease as well as its clinical expression. Chronic stress may be related to disease progression through a variety of biological mechanisms and may interact with traditional biological factors. Chronic problems are common among middle-aged men and women. Acute life events have been correlated with social class and may therefore be important in explaining the socioeconomic status differences in disease progression that we can observe in the employees cohort studies conducted in Spain.

As shown in Table 1, studies addressing the association between perceived stress and CVD began as early as in the 1980’s, when stress became a major topic in psychology. Ruberman et al.¹⁹ looked at the association of life stress with fatal myocardial infarction. This was one of the first studies in the field, and after its publication in the New England Journal of Medicine it was considered to be of great relevance. More recently, the INTERHEART study, in an an enormous effort, measured several psychosocial factors including depression and general stress (at home and at work) and assessed their relationship to cases of myocardial infarction.²⁰

The stress measure to be used in future CNIC studies
To assess this area in a simple and brief manner, we will include the 14-item Cohen's Perceived Stress Scale, which assesses the extent to which an individual feels overwhelmed by perceived difficulties⁵⁰, in its validated European Spanish translation⁵¹. The Perceived Stress Scale is a state-of-the-art measure of stress.

IV. Conclusions
The study of the possible associations between psychosocial factors and the development, treatment and prognosis of CVD is a promising field within cardiovascular research.

The rich variety of study designs and the different populations to be studied in Spain at CNIC offer a unique opportunity for the development of this field. For this reason we propose to study several elements of psychosocial factors that will facilitate an understanding of the association between psychosocial factors and cardiovascular disease and may contribute to prevention of this important disease.