These findings lend further support for the biological strain of social isolation and extend the literature in important ways. Among individuals without a prior myocardial infarction, the least socially integrated had more than twice the odds of elevated CRP levels. Whereas low social isolation was previously shown to relate to elevated CRP in older adults aged 70 to 79 years (
Loucks, Berkman et al., 2006), and only among men 60 years of age and older (average age around 70 years; (
Ford et al., 2006)), the current findings suggest this association may emerge in middle-adulthood, as our sample was on average 55 years old. As in prior studies (
Eng et al., 2002;
House et al., 1982;
Kaplan et al., 1988;
Kawachi et al., 1996;
Orth-Gomer et al., 1993), the least socially integrated were also more likely to die from CHD over a 15-year period than individuals at the highest levels of social integration. We extended these studies of initially CHD-free adults by evaluating CRP as a potential mediator of integration and CHD mortality links. Elevated CRP, however, did not explain the association between social isolation and CHD mortality risk in our sample of adults without prior myocardial infarction. Notably, social isolation carried an independent risk comparable to elevated CRP, and increased the risk of CHD death even after controlling for traditional cardiovascular risk factors. These findings support recent recommendations for screening and intervening for social isolation in post-myocardial infarction patients (
Mookadam & Arthur, 2004), and further suggest a similar course for the prevention of CHD and myocardial infarction. As others have noted (
House, 2001), prospective associations between social ties and mortality are consistently shown to be nonlinear, and our findings support the same conclusion. While the least socially integrated carried greater risk for both elevated CRP and CHD mortality, we did not find variation across the higher levels of integration. Such nonlinearity suggests that interventions may benefit those who are indeed socially isolated, but that enhancing the social network of non-isolated individuals may not produce great benefit (
House, 2001). As others have shown (e.g.,
Ford, Loucks, & Berkman, 2006), no specific types of social connections appeared to have a substantially greater contribution to associations between the overall index and outcomes. These findings can further inform interventions, suggesting that the specific type of relationship may be less important than having meaningful social ties, whatever form they take (
House, 2001).
As observed in prior research (
Eng et al., 2002;
Kawachi et al., 1996;
Orth-Gomer et al., 1993), social isolation did not relate strongly to more traditional risk factors in our sample, including diabetes mellitus (χ
2 = .72,
p = .70) or Framingham risk category (χ
2 = 2.30,
p = .17), but was associated with elevated CRP levels (
Ford et al., 2006;
Loucks, Berkman et al., 2006). Low social integration might affect CRP levels through poor health behaviors, though health behaviors did not confound the association between social isolation and elevated CRP or CHD death in this study. Chronic stress is associated with higher levels of circulating inflammatory markers, including IL-6 (
Kiecolt-Glaser et al., 2003;
von Kanel et al., 2006), a stimulator of CRP production, as well as CRP (
Marin, Martin, Blackwell, Stetler, & Miller, 2007). Social ties are posited to influence health by providing resources to buffer the physiological effects of stress (
Berkman et al., 2000;
Cohen, 1988;
Cohen, Doyle, Skoner, Rabin, & Gwaltney, 1997), and possibly stress-related CRP increases.
Although elevated CRP could not explain social isolation’s relationship to increased risk for CHD death, we cannot rule out the possibility that CRP remains an important causal mechanism. In our sample, social isolation and elevated CRP were associated cross-sectionally, and were both independent predictors of CHD death. Prospective studies are necessary to determine if social isolation is predictive of increases in CRP to elevated levels and, in turn, subsequent CHD death. Unknown, too, are how changes in social integration might co-vary with CRP changes and other markers of inflammation that contribute to cardiovascular disease morbidity and mortality and underscore again the necessity of prospective study.
There remain important questions about the role of CRP in CHD development and progression. Atheromatous plaques that develop decades before a clinical event are a target for inflammation, which, in turn, is marked by elevated CRP (
Hingorani, Shah, Casas, Humphries, & Talmud, 2009). In clinical observational research, CRP levels may reflect subclinical disease and associated inflammation, rather than contributing to the development of CHD (
Hingorani et al., 2009). The association between social isolation and CRP levels has been found to be stronger for adults older than 60 years of age, especially men (
Ford et al., 2006;
Loucks, Berkman et al., 2006), raising the possibility that CRP levels reflect subclinical CVD and may not provide additional information about CRP’s causal role in pathways linking social isolation to CHD. Alternatively, a lack of social integration might lead to increased inflammation that then speeds up the progression of underlying subclinical CHD to clinically-manifest CHD. Indeed,
Ford and colleagues (2006) found that low social integration was also associated with increased hypertension prevalence and higher cholesterol levels relative to those more socially integrated. Although our sample characteristics and smaller sample size precluded any age-stratified analyses (over 65% of the sample was below 60 years of age), we did find overall associations between social isolation and higher CRP levels, and CHD death, among primarily middle-aged adults without prior CHD events. These findings extend the limited literature on social integration and CRP by providing evidence of their association in a pre-clinical disease context. Further prospective study of initially cardiovascular disease-free individuals is necessary to clarify whether inflammatory pathways play a mechanistic role in social isolation’s links to CHD mortality.
Limitations of the current study include a substantially Caucasian sample and smaller sample size that precluded examination of potential race and ethnicity or gender differences. Relatively little is known about the moderating role of ethnicity on associations between social isolation and CHD (
Lett et al., 2005). Loucks and colleagues found social isolation and elevated CRP concentration associations to be strongest for older men relative to women (
Ford et al., 2006;
Loucks, Berkman et al., 2006). Our sample was predominantly female, reflecting the higher proportion of females in the parent cohort from which the random sub-cohort was drawn (
Carleton et al., 1995). Given the age-related increase in proportion of females in the population, it is also likely that the age range (40–75 years) and distribution in the case-cohort sample (27.6% were 65 years of age or older) contributed to the higher proportion of females. It is unclear whether the association between social isolation and CHD is stronger for men versus women (
Lett et al., 2005). Larger studies assessing degree of social integration, CRP, and CHD death are needed to clarify the potential moderating effects of race and ethnicity, gender and other sociodemographic characteristics. Though our sample included fewer participants and cases than prior epidemiological studies reporting associations between social isolation and CRP (
Ford et al., 2006;
Loucks, Berkman et al., 2006;
Loucks, Sullivan et al., 2006), or social isolation and CHD death in initially CHD-free individuals (
Eng et al., 2002;
House et al., 1982;
Kaplan et al., 1988;
Kawachi et al., 1996;
Orth-Gomer et al., 1993), our sample had a slightly lower proportion of socially isolated individuals (14.1%) compared to studies using similar indexing approaches (for example, 15.5% (
Loucks, Sullivan et al., 2006)). More recently, loneliness was associated with incident coronary heart disease among women (
Thurston & Kubzansky, 2009), and functional aspects of social support (for example, perceived emotional support) are predictive as well (
Lett et al., 2005), underscoring a need for further elaboration of the relative or synergistic effects of structural and functional aspects of social connections. An additional limitation is the reliance on names and birthdates to identify dates of death, which may have resulted in more missed deaths in comparison to more reliable identifiers, such as social security numbers. For example, some deaths may have been missed due to name changes resulting from marriage that may have in turn increased the individual’s social integration. In this case, missed deaths could have led to an overestimation of social integration’s protective effects. Finally, we assessed a single marker of systemic inflammation. Future research should include a more comprehensive assessment of systemic inflammation markers. As noted previously, one study found levels of IL-6, but not CRP, to be strongly associated with social integration level (
Loucks, Sullivan et al., 2006). Given that inflammation has more recently been implicated in a host of diseases and conditions, including diabetes, chronic pain, and depression (
Kiecolt-Glaser et al., 2003;
Maier & Watkins, 2003;
Miller, Maletic, & Raison, 2009;
Papanicolaou, Wilder, Manolagas, & Chrousos, 1998), the association found here between social isolation and elevated CRP strongly suggests additional clinical outcomes should be assessed.
Our findings add to the emerging literature investigating the inflammatory pathways linking social isolation and cardiovascular health. Additional studies are needed to determine the longitudinal contribution of inflammation to social isolation’s influences on CHD. Clarifying these pathways is crucial to the development of prevention efforts aimed at reducing the incidence and progression of CHD.
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