Effects of Life Events and Social Isolation on Stroke and Coronary Heart Disease
- Other version(s) of this article
You are viewing the most recent version of this article. Previous versions:
Abstract
The current coronavirus disease 2019 (COVID-19) pandemic represents a severe, life-changing event for people across the world. Life changes may involve job loss, income reduction due to furlough, death of a beloved one, or social stress due to life habit changes. Many people suffer from social isolation due to lockdown or physical distancing, especially those living alone and without family. This article reviews the association of life events and social isolation with cardiovascular disease, assembling the current state of knowledge for stroke and coronary heart disease. Possible mechanisms underlying the links between life events, social isolation, and cardiovascular disease are outlined. Furthermore, groups with increased vulnerability for cardiovascular disease following life events and social isolation are identified, and clinical implications of results are presented.
The current coronavirus disease 2019 (COVID-19) pandemic has led to pronounced acute professional and personal life changes. Lockdowns and physical distancing required many people to work from home, be furloughed from their jobs, given reduced work hours, or even lost jobs. Most leisure activities involving person contacts are abandoned. Social changes will worsen preexisting social isolation, especially in older people, who are at higher risk of social isolation per se.1 Thus, life event research, extremely popular in the 1960s to 1980s, has resurfaced. In contrast to general distress research, which focuses on general aspects of chronic stress responses independent from its source like chronically feeling tense, irritable, anxious, or having sleeping difficulties, life event research concentrates on distinct acute events leading to considerable changes in everyday life, which applies to the current acute COVID-19 pandemic with its resulting life changes. As outlined in the early seminal work by Holmes and Rahe,2 life events differ in the amount of stress, elicited by the required changes in usual activities (readjustment) following the experience of these life events. These changes are independent of the desirability of the event. Even those regarded as desirable by most people, such as having a baby or retirement, lead to considerable life changes, and can be associated with stress responses. Previous studies could already show that stressful life events are an important risk factor for major depressive episodes.3–6 These, in turn, increase the risk of a variety of diseases, especially vascular diseases such as stroke and coronary heart disease (CHD).7 Despite increasing cardiovascular disease (CVD) risk via increases in depressive symptoms, life events are an independent risk factor for a number of physical and mental illnesses (Graphic Abstract).8,9 Different life events such as death of a spouse, divorce, or unemployment can lead to reduced social contacts, resulting in social isolation (Graphic Abstract).5 The COVID-19 pandemic presents people worldwide with the experience of social isolation due to lockdowns and physical distancing. Social isolation has been shown to exert deleterious effects on vascular health.10 Future health policies should aim to prevent the negative consequences of the COVID-19 pandemic as a major life-changing event that carries the danger of long-term social isolation (Graphic Abstract).
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Life Events and CVD
There is a bidirectional causality between life events and CVD (Graphic Abstract). The present review focuses on life events as precursor to CVD. Surely, CVD represents an important life event itself, which considerably changes subsequent life experiences due to physical or mental disabilities, which is, however, beyond the scope of the present review.
Life Events and Stroke
Studies analyzing the influence of life events on stroke are rare. Instead, general psychological distress is more frequently evaluated.11–15 Case-control and prospective studies focusing on the influence of life event stress on stroke have yielded conflicting results.
Case-Control Studies
Within the case-control component of the multiethnic NOMASS (Northern Manhattan Stroke Study), there was no difference in life event stress 6 months before stroke between 655 patients with fatal and nonfatal ischemic stroke and 1087 controls matched for age, sex, and race-ethnicity.16 Neither in age (<55, 55–70, and >70), sex (men/women), or race-ethnic subgroups (White, Black, and Hispanic), nor when analyzing negative or severely threatening events, or ongoing stressful illnesses separately, significant associations between life events and stroke were observed.16 A case-control study, which recruited 150 younger working-age stroke cases consecutively admitted to a Spanish Stroke Unit and their neighbors as controls found that high life event stress was significantly associated with a composite of ischemic stroke, hemorrhagic stroke, and transitory ischemic attack. No significant interaction of life event stress with sex was noted.17 In another case-control study18 that included 113 patients with ischemic stroke, hemorrhagic stroke, or transitory ischemic attack and 109 age- and sex-matched control subjects, severe life events in the preceding year that posed a long-term threat for the individual were more common in cases than in controls. In a small case-control study, life event scores in the previous months did not significantly differ between 37 patients with ischemic stroke and 81 controls.19 In an early case-control study, 44 patients with subarachnoid hemorrhage experienced significantly more independent life events, meaning that these life events most probably were not brought about by the patient, in the 3 months before the hemorrhage compared with 325 controls during the same time period.20
Case Studies
In a patient cohort of 384 patients with stroke admitted to a Tel-Aviv hospital’s emergency room over a 1-year-period, higher life event stress was associated with more severe stroke in patients without history of cardiovascular disorders.21 In a case-crossover design study, that included 247 patients with ischemic stroke from the DEPRESS study (Depression Predictors After Stroke), exposure to ≥1 life events was more frequent during the month preceding stroke onset than during five one month control periods preceding this hazard period (odds ratio, 2.96 [95% CI, 2.19–4.00]).22
Prospective Studies
In the prospective multiethnic Women’s Health Initiative Observational Study cohort, which included 82 107 postmenopausal women, life event stress was not significantly associated with incident stroke during 14 years follow-up when adjusted for cardiovascular risk factors (alcohol use, cigarette smoking, hypertension, waist circumference, high cholesterol, diabetes, physical activity, and dietary quality). In a model adjusting only for age, race/ethnicity, education, income, marital status, and depressive symptoms, life event stress was significantly associated with stroke incidence (eg, hazard ratio, 1.14 [95% CI, 1.01–1.28] for high versus low life event stress scores). This suggests a mediating role of cardiovascular risk factors in the association between life events and stroke. Findings were similar for ischemic and hemorrhagic stroke.23
In the prospective Copenhagen City Heart Study including 9542 participants (mean age 58 years), major life events during lifetime were significantly associated with incident ischemic stroke during 10-year-follow-up even when adjusted for cardiovascular risk factors. No sex differences were observed.24
Meta-Analyses
A meta-analysis including 10 prospective cohort and 4 case–control studies showed that the estimated risk for total stroke in subjects exposed to general or work stress or to stressful life events was 1.33 (95% CI, 1.17–1.50). A similar picture was seen for fatal ischemic plus hemorrhagic stroke (1.45 [1.19–1.78]), fatal plus nonfatal ischemic stroke (1.40 [1.00–1.97]), and fatal plus nonfatal hemorrhagic stroke (1.73 [1.33–2.25]).25
Life Events and CHD
Case-Control Studies
In a small Italian case-control study, life event stress was significantly higher in 64 patients with recent CHD compared with 64 controls matched for age and sex.26 In another early Italian case-control study, 55 patients with myocardial infarctions (MI) reported a significantly higher number of life events in the previous year than 55 control in-patients with acute abdomen or trauma, matched for age, sex, marital status, and social class.27 Similarly, a more recent small Italian case-control study with 97 patients with acute CHD including 91 MI and 6 instable angina reported a significantly higher number of life events in the previous year than 97 healthy controls matched for age sex, marital status, and social class.28 In the large, multiethnic multicenter INTERHEART study (Effect of Potentially Modifiable Risk Factors Associated With Myocardial Infarction in 52 Countries), 11 119 patients with acute first MI reported significantly more stressful life events during the previous year than 13 648 controls. These differences were consistent across regions, in different ethnic groups, and in men and women.29
Prospective Studies
The National Epidemiologic Survey on Alcohol and Related Conditions showed that the number of past-year stressful life events was significantly associated with a composite outcome including self-reported incident arteriosclerosis, angina, or MI during a 3-year-follow-up of a large multiethnic cohort of 28 583 US adults (mean age 45 years).30 Specifically, the authors observed that each additional stressful life event was associated with a 15% greater odds of the composite outcome and in exploratory models with 8% greater odds for incident arteriosclerosis and 17% greater odds for angina whereas no significant association was observed for MI. In the Copenhagen City Heart Study including 8738 participants, major life events in childhood, adulthood and at work, singly and accumulated, were not significantly associated with incident CHD during 15 years of follow-up.24 Another analysis of the Copenhagen City Heart Study cohort showed that major life events in childhood, adulthood, and at work were also not significantly associated heart failure hospitalization. Effect estimates were similar for men and women.31 In a large cohort of 12 866 men 35 to 57 years of age who were at high CHD risk and randomized to a special risk factor intervention or usual care group in the MRFIT (Multiple Risk Factor Intervention Trial), the number of life events experienced during each of 6 years of follow-up was unrelated to risk in the subsequent year of CHD death or fatal plus nonfatal MI. When using angina symptoms as a more subjective cardiovascular end point, the number of life events was a significant predictor of angina.32 As already observed for the stroke outcome, life event stress was not significantly associated with CHD in the prospective multiethnic Women’s Health Initiative Observational Study when adjusted for cardiovascular risk factors. In a model adjusting only for age, race/ethnicity, education, income, marital status, and depressive symptoms, life event stress was significantly associated with CHD incidence (hazards ratio, 1.12 [95% CI, 1.01–1.25]) for high versus low life event stress scores), suggesting also a mediating role of cardiovascular risk factors in the association between life events and CHD.23 In contrast to the ischemic stroke outcome, the sum of major life events during lifetime was not significantly associated with incident MI during 10-year follow-up in the prospective Copenhagen City Heart Study when adjusted for cardiovascular risk factors.24 In addition, within a cohort of 868 middle-aged White men, life event stress during the previous year was not significantly associated with incident CHD during a 10-year follow-up.33 Also, in a large cohort of 9970 male members of the construction building workers trade union in Stockholm, aged 41 to 61 years, life event stress during the previous year was not significantly associated with incident hospitalization for MI during 12 to 15 months follow-up.34
Life Events and Combined CVD Outcomes
The COVID-19 pandemic imposes financial stress due to unemployment and furlough. A large population-based prospective cohort study on 4004 subjects in Sweden showed that financial stress increased the risk of incident CVD (fatal and nonfatal MI, ischemic stroke, and hospitalization due to angina) during an 11-year follow-up in men but not in women and especially in men living without a partner.35 In the Women’s Health Initiative Observational Study and Clinical Trials cohort including 10 785 postmenopausal Black women, life event stress was not significantly associated with a broad CVD composite during 12.5 years follow-up in multivariable models. In the Extension 2 subcohort (n=2765) assessing life event stress a second time about 7 years after baseline, the upper quartile of this updated life event stress was significantly associated with an about 61% greater hazard for subsequent CVD compared with the first quartile.36 Life events causing feelings of loss have specifically been associated with negative health consequences. During the COVID-19 pandemic, different life events such as death of a spouse, divorce, unemployment, and reduced physical contacts are associated with feelings of loss and isolation. In addition, life events and social isolation can interact, emphasizing the importance of assessing, and controlling social isolation. For example, in one study of 2320 male survivors of acute MI, high life stress and social isolation were each associated with an 2-fold increase in 3-year mortality rate.37 When the 2 factors occurred together, the mortality rate was 4-fold higher. Similar observations have also been made among healthy individuals. Among 752 men born in 1953 from a random sample of inhabitants of Gothenburg city in Sweden, the number of life events during the previous year was significantly associated with all-cause mortality during 7 years of follow-up. This association was stronger in participants with low social integration and low emotional support than in participants reporting high social integration and high emotional support.38
An overview of case-control studies assessing the association between life event stress and single or combined CVD outcomes is presented in Table 1; an overview of prospective studies assessing the association between life event stress and single or combined CVD outcomes is given in Table 2.
| Author, year, country | Ethnicity | Outcome | No. cases, m/f | Age cases, y | No. controls | Assessment instrument | Test statistic | Adjusted for |
|---|---|---|---|---|---|---|---|---|
| Stroke | ||||||||
| Abel et al,16 1999, United States | White, Black, Hispanic | Ischemic stroke | 363/292 | 69.8 | 1087 | GSRRS | OR, 1.01 (95% CI, 0.99–1.01) per 20-point increase 0.80 (0.59–1.07) Q2 vs Q1 | Education, hypertension, cardiac disease, diabetes, socialization |
| Egido et al,17 2012, Spain | Not stated | Ischemic stroke, hemorrhagic stroke, or TIA | 116/34 | 53.8 | 300 | SRRS | OR, 5.16 (95% CI, 2.53–10.52) SRRS score ≥150 vs <150 | Sex, energy drinks intake, Epworth scale score |
| House et al,18 1990, United Kingdom | Not stated | Ischemic stroke, hemorrhagic stroke, or TIA | 48/65 | 69.9 | 109 | LEDS | OR, 2.3 (95% CI, 1.1–4.9) ≥1 vs 0 severe life events | Unadjusted |
| Macko et al,19 1996, United States | Not stated | Ischemic stroke | 9/28 | 57.5 | 81 | Subjective evaluation of upset caused by 5 life events | Mean score | Unadjusted |
| Cases: 1.0±2.1 | ||||||||
| Controls: 1.6±2.8 | ||||||||
| Penrose,20 1972, United Kingdom | Not stated | SAH | 16/28 | 44.7 | 325 | Brown-Birley structured interview | % with independent life events | Unadjusted |
| Controls: 19 | ||||||||
| SAH with aneurysm: 28 | ||||||||
| SAH without aneurysm: 48 | ||||||||
| CHD | ||||||||
| Guarneri et al,26 2009, Italy | Not stated | Cardiac ischemia | 58/6 | 59.6 | 64 | SRRS | Mean score | Unadjusted |
| Cases: 119 | ||||||||
| Controls: 79 | ||||||||
| Magni et al,27 1983, Italy | Not stated | MI | 45/10 | 52.9 | 55 | Paykel’s interview for recent life events | Mean number of life events | Unadjusted |
| Cases: 2.51 | ||||||||
| Controls: 0.98 | ||||||||
| Rafanelli et al,28 2005, Italy | Not stated | CHD (MI or instable angina) | 76/21 | 65.5 | 97 | Paykel’s interview for recent life events | Mean number of life events | Unadjusted |
| Cases: 1.33±1.47 | ||||||||
| Controls: 0.22±0.41 | ||||||||
| Rosengren et al,29 2004, 52 countries | European, Chinese, Asian, Arab, Latin American, Black American, Colored African | MI | 8433/2686 | 58.2 | 13 648 | Interview about 9 stressful life events | OR, 1.48 (95% CI, 1.33–1.64) for ≥2 vs 0 life events | Age, sex, geographic region, smoking |
| Author, year, study, country | Ethnicity | Outcome | Total m/f | Follow-up, y | Age, y | Assessment instrument | Test statistic | Adjusted for |
|---|---|---|---|---|---|---|---|---|
| No. cases | ||||||||
| Andersen et al,39 2011, Copenhagen City Heart Study, Denmark | White | Ischemic heart disease | 3757/4981 | 15 | 57 | List of 11 major life events, modified version of the SRRS | HR (95% CI) f NS eg, 0.99 (0.68–1.45) for major life events in adulthood for men; eg, 1.12 (0.75–1.68) for major life events in adulthood for women | Age, cohabitation, education, parental MI, smoking, alcohol, physical activity, BMI |
| 653 | ||||||||
| Berntson et al,30 2017, National Epidemiologic Survey on Alcohol and Related Conditions, United States | White, Black, Hispanic, other | Arteriosclerosis, angina, or MI | 12 119/16 464 | 3 | 45 | List of 12 stressful life events | OR, 1.15 (95% CI, 1.11–1.19) per stressful life event | Age, sex, race/ethnicity, education, hypertension, hypercholesterolemia, diabetes, tobacco use, BMI |
| 1069 | ||||||||
| Felix et al,36 2019, Women’s Health Initiative Observational Study and Clinical Trials cohort, United States | Black | CVD (CHD, revascularization procedure, carotid artery disease, peripheral artery disease, stroke/TIA, heart failure, or CVD-related death) | 0/10 785 | 12.5 | 61 | Subjective evaluation of upset caused by 11 life events | HR, 1.32 (95% CI, 0.91–1.92) Q4 vs Q1 at age 55 | Social strain, diabetes, BMI, physical activity, hypertension history, antihyperlipidemia drugs, smoking, education |
| 1863 | ||||||||
| HR, 1.14 (95% CI, 0.94–1.40) Q4 vs Q1 at age 65 | ||||||||
| HR, 1.01 (95% CI, 0.86–1.19) Q4 vs Q1 at age 75 | ||||||||
| HR, 0.91 (95% CI, 0.70–1.18) Q4 vs Q1 at age 85 | ||||||||
| HR, 0.83 (0.56–1.22) Q4 vs Q1 at age 95 | ||||||||
| Felix et al,362019, Women’s Health Initiative Extension Study 2 subcohort, United States | Black | CVD (CHD, revascularization procedure, carotid artery disease, peripheral artery disease, stroke/TIA, heart failure, or CVD-related death) | 0/2765 | 5 | 75 | Subjective evaluation of upset caused by 11 life events | HR, 1.61 (95% CI, 1.04–2.51) Q4 vs Q1 | Diabetes, BMI, physical activity, hypertension history, antihyperlipidemia drugs, smoking, education |
| 202 | ||||||||
| Hollis et al,32 1990, Multiple Risk Factor Intervention Trial, United States | Not stated | CHD death, fatal or nonfatal MI, angina pectoris | 12 866/0 | 6 | 35–57 | List of 54 life events | HR (95% CI) NS for CHD death and MI, 1.08 (1.03–1.13) per additional life event in the preceding year for angina pectoris | Intervention, age, smoking, diastolic blood pressure, total cholesterol |
| Kershaw et al,23 2014, Women’s Health Initiative Observational Study, United States | White, Black, Hispanic, American, Indian/Alaska Native, Asian/Pacific Islander, other | CHD (clinical MI, definite silent MI, or death resulting from definite or possible CHD), stroke (ischemic and hemorrhagic) | 0/82 107 | 14 | 63 | Subjective evaluation of upset caused by 11 life events | HR (95% CI) CHD: 1.05 (0.94–1.17) for high vs low score | Age, race/ethnicity, education, income, marital status, depressive symptoms, alcohol use, smoking, hypertension, waist circumference, hypercholesterolemia, diabetes, physical activity, dietary quality |
| Stroke: 1.09 (0.97–1.23) for high vs low score | ||||||||
| Kornerup et al,24 2010, Copenhagen City Heart Study, Denmark | Not stated | MI, ischemic stroke | 4088/5454 | 10 | 58 | List of 11 major life events | HR (95% CI) MI: 1.07 (0.80–1.44) for >1 vs 0 life events | Age, sex, smoking, diabetes, physical activity, blood pressure- and cholesterol-lowering drugs, systolic blood pressure, BMI, atrial fibrillation, blood lipids |
| 443 MI | ||||||||
| 350 strokes | ||||||||
| Stroke: 1.53 (1.11–2.10) for >1 vs 0 life events | ||||||||
| Moore et al,33 1999, Not stated, Canada | White | Ischemic heart disease (angina pectoris, MI, or ischemic heart disease death) | 868/0 | 10 | ≤60 | Adapted from the SRRS, 49 life events | HR, 0.92 (95% CI, 0.50–1.70) Q4 of life event stress score vs rest | Age, hypertension, triglycerides, high-density lipoprotein cholesterol |
| 79 | ||||||||
| Rod et al,31 2011, Copenhagen City Heart Study, Denmark | Not stated | Heart failure hospitalization | 3700/4970 | 15 | 57 | List of 11 major life events | HR (95% CI) Number of major life events, separately for men and women NS eg, 0.75 (0.47–1.20) for ≥3 vs 0 major life event in adulthood for men; eg, 1.18 (0.84–1.65) for ≥3 vs 0 major life event in adulthood for women | Age, education, family history of MI, systolic blood pressure, diastolic blood pressure, total cholesterol, diabetes, physical activity, tobacco smoking, BMI, alcohol consumption |
| 711 | ||||||||
| Theorell et al,34 1975, Not stated, Sweden | Not stated | MI hospitalization | 9970/0 | 1 | 52 | SRRS | % with SRRS score ≥200 in relation to age-adjusted expected percentage 0.93, NS | Age |
Social Isolation and CVD
Similar to life events and CVD, social isolation, and CVD are bidirectionally linked. The present review focuses on social isolation as cause of CVD. Stroke or CHD considerably impairs social participation due to physical or mental disabilities, which is, however, beyond the scope of this review.
Social Isolation and Stroke
Many countries decided to restrict physical social contacts as measures to limit COVID-19 spreading. The new realities during this period of confinement such as working from home, temporary unemployment, and home-schooling of children imply social isolation, which takes time to adapt to and can cause feelings of loneliness (Graphic Abstract).
Studies analyzing stroke and CHD as separate outcomes of social relationships have comprehensively been summarized in the review and meta-analysis by Valtorta et al.40 Consequently, only the most relevant studies and those published after the above-mentioned review are stated due to reasons of space. The literature on social isolation distinguishes qualitative and quantitative aspects of social relationships. Qualitative aspects refer to the subjective evaluation of the quality of relationships such as feeling supported whereas quantitative aspects refer to the objective evaluation of quantitative measures such the number of contact persons or frequency of contacts.
In 479 054 individuals from the UK Biobank cohort study, both loneliness and social isolation were significantly associated with incident stroke (3471 events) during the 7-year follow-up.41 In 13 686 men and women from the Atherosclerosis Risk in Communities study, the quantitative aspect of social isolation, but not the qualitative aspect of social support was associated with incident stroke (905 events) during a median follow-up of 18.6 years.42 In the meta-analysis by Valtorta et al40 of 8 studies, social isolation, but not loneliness, was significantly associated with incident stroke.
Social Isolation and CHD
Likewise, studies analyzing CHD as outcome of qualitative/quantitative aspects of social relationships have comprehensively been summarized by Valtorta et al.40 Due to reasons of space, only the most relevant studies and studies published thereafter are presented.
In 479 054 individuals from the UK Biobank cohort study, both loneliness and social isolation were similar to stroke significantly associated with incident acute MI (5731 events) during the 7-year follow-up.41 The majority of empirical studies do not suggest a significant association between social isolation and CHD. Thus, in 28 369 US male health professionals, social isolation was not significantly associated with incident CHD (1816 events) during the 10-year follow-up.43 Also in 9573 adults enrolled in the Copenhagen City Heart Study, network diversity as an indicator for social isolation was not significantly associated with incident CHD (427 events) during the 6-year follow-up.44 Whereas the quantitative aspect of social isolation was strongly associated with incident stroke in the meta-analysis by Valtorta et al,40 social isolation showed a weaker association with incident CHD. Incident CHD was, however, rather predicted by the qualitative aspect of feeling lonely.
Social Isolation and Combined CVD Outcomes
Feeling lonely, but not being socially isolated, has been associated with incident CVD (fatal and nonfatal diagnoses of heart disease and stroke) during 5-year follow-up in one study including 5397 men and women aged over 50 years participating in the ELSA (English Longitudinal Study of Ageing).10 In the population-based Heinz Nixdorf Recall study cohort including 4139 participants aged 45 to 75 years, no significant associations between a social isolation index and incident CVD were noted, but associations between financial support and CVD were found.45 The combined evidence of these studies suggests that the subjective evaluation of the quality of relationships is important for cardiovascular health rather than the mere quantity of social contacts. In line with this idea, the World Health Organization suggests ameliorating subjective loneliness in times of restricted physical social contacts by keeping social contacts via telephone or online channels (https://www.who.int/campaigns/connecting-the-world-to-combat-coronavirus/healthyathome?gclid=CjwKCAjwmf_4BRABEiwAGhDfSesbszupl8mezc7MR-4aiOJa5wBLVMGVRnG5Yx6WPH-eS6mKLQnjUBoCU_oQAvD_BwE). However, longitudinal studies on the consequences of long-term social interaction without physical contact are lacking. Specifically physical touch fulfils important social relationship functions by stabilizing social binding via oxytocin hormone or attenuating stress by increasing serotonin and decreasing cortisol production.46
Mechanisms
There are many possible pathways how stress from social readjustment and social isolation might cause CVD (Graphic Abstract). By increasing adrenalin levels in the blood, stress increases sympathetic nervous system activity.47 By regulating heart rate and blood pressure, stress modulates cardiovascular reactivity.48–52 Stress furthermore increases blood lipoprotein, blood viscosity, platelet concentration, hematocrit, and hemoglobin level.48–50,53–55 Monkey studies revealed that stress can impair endothelium-dependent vasodilation of atherosclerotic arteries.56
Recurrent stress can induce sympathetic and hypothalamic—pituitary adrenal (HPA) axis dysregulation,57,58 which can result in increased inflammation, endothelial dysfunction, and, ultimately, atherosclerosis.59,60 Further supporting these mechanisms, stressful life events have been cross-sectionally associated with increased endothelial dysfunction61 including increased central arterial stiffness.62 In a cross-sectional analysis of 3276 participants from the Cardiovascular and Metabolic Diseases Etiology Research Center cohort (mean age 50.9 years), life events assessed via the Life Experience Questionnaire were not significantly associated with indicators of cardiovascular risk including the pulse pressure augmentation index and carotid intima media thickness. Only the subcategory of traumatic life events was associated with increased augmentation index in women.63 Endothelial dysfunction plays a critical role in the initiation and progression of atherosclerosis. In line with this hypothesis, the Multi-Ethnic Study of Atherosclerosis showed that flow-mediated dilation of the brachial artery was decreased, and ICAM-1 (intercellular adhesion molecule 1) was increased in high-stress compared with medium-stress and low-stress subjects.61 In a cohort of Danish men born in 1953, the total number of stressful events experienced during the life course was not associated with telomere length.64 In contrast, the number of stressful events during childhood was associated with short telomere length.64 Telomere shortening is considered to be an indicator of cumulative life-time inflammation and oxidative stress burden. In general, different stressors can increase blood lipid levels by modulating lipoprotein lipase and hepatic lipase.47 Empirical evidence supports a significant correlation between stress, blood urea, and liver enzyme (ALT [alanine amino transferase], AST [aspartate amino transferase]) levels.65 Free fatty acids, triglycerides, and total cholesterol were shown to increase and HDL (high-density lipoprotein) cholesterol levels shown to decrease in response to acute and chronic stress.47,66–68 Cortisone released during stressful life events increases glucogenesis and glycogenolysis, resulting in increased blood glucose levels.69,70 The increased glucose levels coincide with elevated energy requirements during stress. Cortisol secretion takes place in response to a variety of stressors.71
As a consequence of metabolic adjustments, CVD risk factors such as obesity, diabetes, hypertension, depression, and anxiety are more prevalent among people with higher than lower stress levels.72–75 Chronic stress exposure fosters atherogenic behaviors, including tobacco and alcohol abuse, high fat and carbohydrate consumption, and physical inactivity.36,73,74,76–78 Major life events assessed with a modified short version of the Social Readjustment Rating Scale were significantly associated with a summary index of allostatic load comprising 14 biomarkers (hsCRP [high-sensitivity C-reactive protein], interleukin-6, tumor necrosis factor-α, systolic and diastolic blood pressure, glycated hemoglobin, total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein), triglycerides, body mass index, waist/hip ratio, body fat, blood glucose) among 5512 members of the Copenhagen Aging and Midlife Biobank aged 49 to 63 years.79
Social isolation is also associated with similar physiological responses. Social isolation activates HPA axis response and cause inflammation like other life stressors.80 In the COVID-19 pandemic, a high number of people suffer from loss of physical social contacts and many high-risk older adults have lost their partner or spouse due to COVID-19 mortality. In the first study of its kind, Fagundes et al81 found that the major life event of spousal bereavement was associated with increased proinflammatory cytokine production by peripheral blood leukocytes stimulated in vitro by lipolysaccharide and reduced heart rate variability, which are both risk factors for cardiovascular morbidity and mortality, among widows and widowers compared with age-matched controls.
Subgroups With Increased Vulnerability
Multiple factors modify the association between life events and CVD. Due to reasons of space, only the factors age, sex/gender, race/ethnicity, partnership, sexual orientation, and depression are discussed in detail (Graphic Abstract).
Age
The majority of empirical evidence shows that younger age is associated with higher life event stress.23,36,73 Regarding the differential consequences of stressful life events for cardiovascular health in different age groups, research findings are, however, inconsistent. Younger persons who experienced major life events showed increased risk of harmful health behaviors and CVD risk factors such as smoking and poor fasting plasma glucose compared with older persons.76 Other literature suggests that older persons, in particular, are susceptible to the negative consequences of stressful life events. In older subjects, a dose-response relationship between the number of stressful life events and impaired systolic blood pressure recovery in response to orthostatic stress was noted.82 Deregulated blood pressure reinforces atherosclerosis predisposing older adults to cerebral microangiopathy.
Findings regarding social isolation and loneliness differ across different age groups and suggest that young adults and older adults have a higher prevalence, as they tend to live alone more often than their middle-aged counterparts.83 Literature on the association of social isolation and CVD in different age groups is scarce.84 In the population-based Heinz Nixdorf Recall study, social isolation was more strongly associated with CVD and all-cause mortality in participants <65 than ≥65 years.45 This observation is supported by a meta-analysis by Holt-Lunstad et al,85 which showed that social isolation and loneliness were more predictive of death in cohorts with an average age <65 than ≥65 years.
Sex/Gender
Literature on sex/gender differences in levels of experienced stress is inconsistent.86 Increased stress was at least partly explained by gender role stereotypes. For males, traditional stereotypes emphasize achievement and competition.87 Thus, men were suggested to experience higher stress because they are constantly striving to perform well in an increasingly competitive world.88 Yet, other studies found that women have greater stress levels than men, which was interpreted that women had less access to power and control.89 Increased stress in women was suggested to be associated with traditional gender role stereotypes emphasizing their for the well-being of family and friends in addition to employment duties.90–92 This suggests women have less time for their own needs than men.93 Some studies found similar stress levels in men and women, reporting that stress affects different life domains to different extent.90 Thus, men were found to experience greater stress in areas relevant to work and career and women in areas relevant to interpersonal relationships.94 A meta-analysis of 119 studies including 83 559 participants concluded that women report higher stress levels than men.86 This finding might be biased by differential reporting behavior due to social role differences in men and women. Finally, men and women differ with respect to their coping resources, women having more social support than men.95
Regarding the differential consequences of stressful life events for cardiovascular health in men and women, research findings are again inconsistent. A meta-analysis showed that perceived psychosocial stress elevates stroke risk more in women (hazards ratio, 1.90 [95% CI, 1.40–2.56]) than in men (hazards ratio, 1.24 [95% CI, 1.12–1.36]).25 The prevalence of smoking and poor fasting plasma glucose as important CVD risk factors associated with major life events was, however, similar in men and women.76 More recent studies suggest that the relationship between work stress and stroke96 or CHD97 does not differ significantly between men and women.
Sex differences regarding the effects of social isolation on CVD have only rarely been examined. In the Heinz Nixdorf Recall study, social isolation was more strongly associated with incident CVD and all-cause mortality in men than women.45 This observation is supported by the British Whitehall II cohort study, which showed that a low level of social contacts was significantly associated with increased all-cause and cardiovascular mortality in men but not in women.98 Biological factors, such as differences in sex hormone regulation, or psychosocial factors, such as different gender role expectations,99 may account for that.
Race/Ethnicity
Most studies on life events/social isolation and CVD do not specifically assess the role of race/ethnicity. Due to the relatively high incidence of CVD among certain racial/ethnic groups, notably among Blacks in the United States,100 studies examining the association between life events stress and CVD in these populations would close an important gap in the current literature. In addition to suffering from a disproportionately high CVD risk,101,102 Blacks report greater cumulative exposure to acute and chronic stressors than Whites, Hispanics, Asians, and Indians, including stressful living conditions and discrimination.23,73,74,103
Psychosocial stressors might influence cardiovascular health in Blacks in several ways. Perceived discrimination may foster unhealthy behaviors.104–106 Additionally, dysregulated stress responses, particularly extreme, unpredictable, and social threats, may result in HPA axis dysregulation associated with blunted cortisol responses to acute stress in Blacks,107 which in the long run can lead to insulin resistance.74,107 This proposed mechanism is supported by the association of life event stress with poor blood glucose control, which could profoundly contribute to the significant disparity in blood glucose control among Blacks compared with Whites.101,108 Apart from perceived discrimination, Blacks experience various psychosocial challenges, including limited access to health care through insurance,109 lower median household income,110 less access to healthy food,111 and higher exposure to crime112 than Whites. Moreover, there is evidence to suggest that racism compromises cardiovascular health.113 These factors may act independently and interact to increase CVD risk among Blacks.
Other
Partnership seems to protect from life event stress. Participants who reported higher stress levels were more likely divorced or separated than married.73 Partnership is also often closely related to social isolation. Married individuals are less likely isolated than those who never married or have been widowed.114 Studies on how the influence of social isolation on stroke and CHD is modified by marital status are lacking, because marital status is usually included in the measure of social isolation. For the outcome of CVD mortality, no moderating effect of marital status on the influence of other components such as number of close subjects, group participation, and religious service attendance was observed.115 Regarding the outcome of cardiovascular responses to stressors as a potential pathomechanism of stressful live events and social isolation on CVD, loneliness has been associated with increased cardiovascular reactivity even when controlling for marital status.116 Future research should account for partnership quality because marriage/cohabitation can represent stressors themselves.
Sexual orientation also has an important influence on social relationships. Lesbian, gay, and bisexual individuals, especially those of higher age, often suffer from deficient social relationships related to stigmatization of their sexual orientation. Lesbian, gay, and bisexual individuals often experience more negative life events including family estrangement, difficulties gaining social and legal recognition of partnerships, and thus more often live alone compared with heterosexuals,117,118 which has been shown to increase their CVD risk.119 In an American representative sample of the National Social Life, Health, and Aging Project, older lesbian, gay, and bisexual adults were significantly lonelier than heterosexuals. Loneliness was primarily determined by a lower likelihood of having a partner. To a lesser extent, feeling a lack of companionship, left out, or isolated from others was influenced by lower levels of family support and lower friendship quality.120 Lack of social integration among individuals with minority sexual orientations has been shown to have a harmful influence on mental health.121
History of psychiatric disorders, such as depression, increases CVD vulnerability in response to stressful life events. Stressful life events were more strongly associated with a composite outcome of arteriosclerosis, angina, and MI in adults with lifetime depressive disorder than in adults without lifetime depressive disorder.30 Reasons for this amplified relationship in persons with depressive disorder may be prolonged physiological and behavioral stress responses. Depressed adults display delayed recovery of sympathetic,122 HPA axis,123 cardiovascular,124,125 and inflammatory126 responses to laboratory-induced stress, suggesting that depression may interfere with the physiological decrease of stress responses after a stressor has terminated.57 Given the consistently higher rates of depression among women than men, sex-specific vulnerabilities with regard to life event stress and social isolation could be magnified.127
Many additional factors can modify the association between life events and CVD. Among those are for example trait-like dimensions of personality/coping (such as neuroticism, extraversion, resilience, optimism, dispositional negativity), environmental factors (eg, noise, air pollution), socioeconomic/sociocultural factors (income, status, neighborhood), or genetics, which affect the frequency, intensity, and duration with which life events are perceived and experienced. Discussing all these factors in more detail is beyond the scope of this review.
Clinical Implications
The available evidence on the relationship between major life-changing events and increased CVD risk highlights the need of screening for stressful life events in clinical settings (Graphic Abstract). This relates specifically to life events associated with reduced social contacts, since, as the legendary Greek philosopher Aristotle already said, man is by nature a social animal. Life changes and social isolation can increase CVD risk via various mechanisms (Graphic Abstract, chapter 4) including (1) stress responses via sympathetic and HPA axis dysregulation, which can lead to increased inflammation, endothelial dysfunction, and, ultimately, atherosclerosis, (2) atherogenic behaviors, such as smoking, alcohol abuse, unhealthy diet with high proportions as fat and carbohydrates, and physical inactivity leading to (3) an unfavorable CVD risk profile with hypertension, hypercholesterolemia, and diabetes. Screening for stressful life events thus opens the possibility to initiate CVD prevention efforts earlier and intensify CVD prevention efforts in individuals reporting high life event stress. Awareness of the cardiovascular health consequences of life event stress and the methods to assess life events needs to be increased to improve the identification of individuals at high CVD risk (Graphic Abstract). Traditional behavioral interventions that prevent CVD include smoking cessation, diet modification, and physical activity with greatest CVD risk reduction achieved when different risk behaviors are managed at the same time.128 Interventions that reduce stress associated with life-changing events should improve the patients’ treatment compliance.129 This requires that physicians recognize and emphasize the role of life events and their psychosocial consequences in patient counseling and treatment.130 Success of interventions to reduce life event stress should preferably be assessed by subjective measures because they are easier to implement and cheaper than physiological stress measures, need no technical instruments, and can be used online, as telephone interviews or video conferences compared with objective physiological stress measures. Further, subjective measures can assess the sources of stress like it is done in life event checklist and subjective evaluations of the stress response elicited by these events whereas physiological measures merely quantify the degree of the stress response. During the current COVID-19 pandemic, it is important to meet the negative health impact of life event stress and social isolation. Efficacy of interventions strongly depends on how specifically they target vulnerable groups (Graphic Abstract, chapter 5).131 With ongoing restrictions of physical contacts, internet-based interventions will have to be implemented, especially among vulnerable groups. The public health consequences of neglecting the needs of these groups are immense.
Sources of Funding
None.
Disclosures None.
Footnotes
References
- 1.
Cudjoe TKM, Kotwal AA . “Social distancing” amid a crisis in social isolation and loneliness.J Am Geriatr Soc. 2020; 68:E27–E29. doi: 10.1111/jgs.16527Google Scholar - 2.
Holmes TH, Rahe RH . The social readjustment rating scale.J Psychosom Res. 1967; 11:213–218. doi: 10.1016/0022-3999(67)90010-4CrossrefMedlineGoogle Scholar - 3.
Hammen C . Life events and depression: the plot thickens.Am J Community Psychol. 1992; 20:179–193. doi: 10.1007/BF00940835Google Scholar - 4.
Hammen C . Stress and depression.Annu Rev Clin Psychol. 2005; 1:293–319. doi: 10.1146/annurev.clinpsy.1.102803.143938CrossrefMedlineGoogle Scholar - 5.
Kessler RC . The effects of stressful life events on depression.Annu Rev Psychol. 1997; 48:191–214. doi: 10.1146/annurev.psych.48.1.191Google Scholar - 6.
Mazure CM . Life stressors as risk factors in depression.Clin Psychol. 1998; 5:291–313.Google Scholar - 7.
Hare DL, Toukhsati SR, Johansson P, Jaarsma T . Depression and cardiovascular disease: a clinical review.Eur Heart J. 2014; 35:1365–1372. doi: 10.1093/eurheartj/eht462CrossrefMedlineGoogle Scholar - 8.
Rahe RH, Arthur RJ . Life change and illness studies: past history and future directions.J Human Stress. 1978; 4:3–15. doi: 10.1080/0097840X.1978.9934972Google Scholar - 9.
Stults-Kolehmainen MA, Tuit K, Sinha R . Lower cumulative stress is associated with better health for physically active adults in the community.Stress. 2014; 17:157–168. doi: 10.3109/10253890.2013.878329Google Scholar - 10.
Valtorta NK, Kanaan M, Gilbody S, Hanratty B . Loneliness, social isolation and risk of cardiovascular disease in the english longitudinal study of ageing.Eur J Prev Cardiol. 2018; 25:1384–1386.Google Scholar - 11.
Jood K, Redfors P, Rosengren A, Blomstrand C, Jern C . Self-perceived psychological stress and ischemic stroke: a case-control study.BMC Med. 2009; 7:53. doi: 10.1186/1741-7015-7-53CrossrefMedlineGoogle Scholar - 12.
May M, McCarron P, Stansfeld S, Ben-Shlomo Y, Gallacher J, Yarnell J, Davey Smith G, Elwood P, Ebrahim S . Does psychological distress predict the risk of ischemic stroke and transient ischemic attack? The Caerphilly Study.Stroke. 2002; 33:7–12. doi: 10.1161/hs0102.100529LinkGoogle Scholar - 13.
O’Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ, ; INTERSTROKE Investigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study.Lancet. 2010; 376:112–123. doi: 10.1016/S0140-6736(10)60834-3CrossrefMedlineGoogle Scholar - 14.
Rosengren A, Tibblin G, Wilhelmsen L . Self-perceived psychological stress and incidence of coronary artery disease in middle-aged men.Am J Cardiol. 1991; 68:1171–1175. doi: 10.1016/0002-9149(91)90189-rCrossrefMedlineGoogle Scholar - 15.
Truelsen T, Nielsen N, Boysen G, Grønbaek M ; Copenhagen City Heart Study. Self-reported stress and risk of stroke: the Copenhagen City Heart Study.Stroke. 2003; 34:856–862. doi: 10.1161/01.STR.0000062345.80774.40LinkGoogle Scholar - 16.
Abel GA, Chen X, Boden-Albala B, Sacco RL . Social readjustment and ischemic stroke: lack of an association in a multiethnic population.Neuroepidemiology. 1999; 18:22–31. doi: 10.1159/000026192Google Scholar - 17.
Egido JA, Castillo O, Roig B, Sanz I, Herrero MR, Garay MT, Garcia AM, Fuentes M, Fernandez C . Is psycho-physical stress a risk factor for stroke? A case-control study.J Neurol Neurosurg Psychiatry. 2012; 83:1104–1110. doi: 10.1136/jnnp-2012-302420CrossrefMedlineGoogle Scholar - 18.
House A, Dennis M, Mogridge L, Hawton K, Warlow C . Life events and difficulties preceding stroke.J Neurol Neurosurg Psychiatry. 1990; 53:1024–1028. doi: 10.1136/jnnp.53.12.1024Google Scholar - 19.
Macko RF, Ameriso SF, Barndt R, Clough W, Weiner JM, Fisher M . Precipitants of brain infarction. Roles of preceding infection/inflammation and recent psychological stress.Stroke. 1996; 27:1999–2004. doi: 10.1161/01.str.27.11.1999LinkGoogle Scholar - 20.
Penrose RJ . Life events before subarachnoid haemorrhage.J Psychosom Res. 1972; 16:329–333. doi: 10.1016/0022-3999(72)90085-2Google Scholar - 21.
Carasso R, Yehuda S, Ben-Uriah Y . Personality type, life events and sudden cerebrovascular attack.Int J Neurosci. 1981; 14:223–225. doi: 10.3109/00207458108985837Google Scholar - 22.
Guiraud V, Touzé E, Rouillon F, Godefroy O, Mas JL . Stressful life events as triggers of ischemic stroke: a case-crossover study.Int J Stroke. 2013; 8:300–307. doi: 10.1111/j.1747-4949.2012.00810.xCrossrefMedlineGoogle Scholar - 23.
Kershaw KN, Brenes GA, Charles LE, Coday M, Daviglus ML, Denburg NL, Kroenke CH, Safford MM, Savla T, Tindle HA, . Associations of stressful life events and social strain with incident cardiovascular disease in the Women’s Health Initiative.J Am Heart Assoc. 2014; 3:e000687. doi: 10.1161/JAHA.113.000687LinkGoogle Scholar - 24.
Kornerup H, Osler M, Boysen G, Barefoot J, Schnohr P, Prescott E . Major life events increase the risk of stroke but not of myocardial infarction: results from the Copenhagen City Heart Study.Eur J Cardiovasc Prev Rehabil. 2010; 17:113–118. doi: 10.1097/HJR.0b013e3283359c18CrossrefMedlineGoogle Scholar - 25.
Booth J, Connelly L, Lawrence M, Chalmers C, Joice S, Becker C, Dougall N . Evidence of perceived psychosocial stress as a risk factor for stroke in adults: a meta-analysis.BMC Neurol. 2015; 15:233. doi: 10.1186/s12883-015-0456-4CrossrefMedlineGoogle Scholar - 26.
Guarneri MG, Nastri L, Assennato P, Li Puma A, Landi A, Bonanno B, Maggì GB, Annino G, Bono F, La Barbera D . [Heart ischemia and psychosomatics: the role of stressful events and lifestyles].Monaldi Arch Chest Dis. 2009; 72:77–83. doi: 10.4081/monaldi.2009.332Google Scholar - 27.
Magni G, Corfini A, Berto F, Rizzardo R, Bombardelli S, Miraglia G . Life events and myocardial infarction.Aust N Z J Med. 1983; 13:257–260. doi: 10.1111/j.1445-5994.1983.tb04653.xCrossrefMedlineGoogle Scholar - 28.
Rafanelli C, Roncuzzi R, Milaneschi Y, Tomba E, Colistro MC, Pancaldi LG, Di Pasquale G . Stressful life events, depression and demoralization as risk factors for acute coronary heart disease.Psychother Psychosom. 2005; 74:179–184. doi: 10.1159/000084003CrossrefMedlineGoogle Scholar - 29.
Rosengren A, Hawken S, Ounpuu S, Sliwa K, Zubaid M, Almahmeed WA, Blackett KN, Sitthi-amorn C, Sato H, Yusuf S ; INTERHEART Investigators. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study.Lancet. 2004; 364:953–962. doi: 10.1016/S0140-6736(04)17019-0CrossrefMedlineGoogle Scholar - 30.
Berntson J, Patel JS, Stewart JC . Number of recent stressful life events and incident cardiovascular disease: moderation by lifetime depressive disorder.J Psychosom Res. 2017; 99:149–154. doi: 10.1016/j.jpsychores.2017.06.008Google Scholar - 31.
Rod NH, Andersen I, Prescott E . Psychosocial risk factors and heart failure hospitalization: a prospective cohort study.Am J Epidemiol. 2011; 174:672–680. doi: 10.1093/aje/kwr144Google Scholar - 32.
Hollis JF, Connett JE, Stevens VJ, Greenlick MR . Stressful life events, Type A behavior, and the prediction of cardiovascular and total mortality over six years. MRFIT Group.J Behav Med. 1990; 13:263–280. doi: 10.1007/BF00846834Google Scholar - 33.
Moore L, Meyer F, Perusse M, Cantin B, Dagenais GR, Bairati I, Savard J . Psychological stress and incidence of ischaemic heart disease.Int J Epidemiol. 1999; 28:652–658. doi: 10.1093/ije/28.4.652CrossrefMedlineGoogle Scholar - 34.
Theorell T, Lind E, Flodérus B . The relationship of disturbing life-changes and emotions to the early development of myocardial infarction and other serious illnesses.Int J Epidemiol. 1975; 4:281–293. doi: 10.1093/ije/4.4.281Google Scholar - 35.
Carlsson AC, Starrin B, Gigante B, Leander K, Hellenius ML, de Faire U . Financial stress in late adulthood and diverse risks of incident cardiovascular disease and all-cause mortality in women and men.BMC Public Health. 2014; 14:17. doi: 10.1186/1471-2458-14-17CrossrefMedlineGoogle Scholar - 36.
Felix AS, Lehman A, Nolan TS, Sealy-Jefferson S, Breathett K, Hood DB, Addison D, Anderson CM, Cené CW, Warren BJ, . Stress, resilience, and cardiovascular disease risk among black women.Circ Cardiovasc Qual Outcomes. 2019; 12:e005284. doi: 10.1161/CIRCOUTCOMES.118.005284LinkGoogle Scholar - 37.
Ruberman W, Weinblatt E, Goldberg JD, Chaudhary BS . Psychosocial influences on mortality after myocardial infarction.N Engl J Med. 1984; 311:552–559. doi: 10.1056/NEJM198408303110902CrossrefMedlineGoogle Scholar - 38.
Rosengren A, Orth-Gomér K, Wedel H, Wilhelmsen L . Stressful life events, social support, and mortality in men born in 1933.BMJ. 1993; 307:1102–1105. doi: 10.1136/bmj.307.6912.1102CrossrefMedlineGoogle Scholar - 39.
Andersen I, Diderichsen F, Kornerup H, Prescott E, Rod NH . Major life events and the risk of ischaemic heart disease: does accumulation increase the risk?Int J Epidemiol. 2011; 40:904–913. doi: 10.1093/ije/dyr052CrossrefMedlineGoogle Scholar - 40.
Valtorta NK, Kanaan M, Gilbody S, Ronzi S, Hanratty B . Loneliness and social isolation as risk factors for coronary heart disease and stroke: systematic review and meta-analysis of longitudinal observational studies.Heart. 2016; 102:1009–1016. doi: 10.1136/heartjnl-2015-308790CrossrefMedlineGoogle Scholar - 41.
Hakulinen C, Pulkki-Råback L, Virtanen M, Jokela M, Kivimäki M, Elovainio M . Social isolation and loneliness as risk factors for myocardial infarction, stroke and mortality: UK Biobank cohort study of 479 054 men and women.Heart. 2018; 104:1536–1542. doi: 10.1136/heartjnl-2017-312663CrossrefMedlineGoogle Scholar - 42.
Nagayoshi M, Everson-Rose SA, Iso H, Mosley TH, Rose KM, Lutsey PL . Social network, social support, and risk of incident stroke: atherosclerosis risk in Communities study.Stroke. 2014; 45:2868–2873. doi: 10.1161/STROKEAHA.114.005815LinkGoogle Scholar - 43.
Eng PM, Rimm EB, Fitzmaurice G, Kawachi I . Social ties and change in social ties in relation to subsequent total and cause-specific mortality and coronary heart disease incidence in men.Am J Epidemiol. 2002; 155:700–709. doi: 10.1093/aje/155.8.700CrossrefMedlineGoogle Scholar - 44.
Barefoot JC, Grønbaek M, Jensen G, Schnohr P, Prescott E . Social network diversity and risks of ischemic heart disease and total mortality: findings from the Copenhagen City Heart Study.Am J Epidemiol. 2005; 161:960–967. doi: 10.1093/aje/kwi128CrossrefMedlineGoogle Scholar - 45.
Gronewold J, Kropp R, Lehmann N, Schmidt B, Weyers S, Siegrist J, Dragano N, Jöckel KH, Erbel R, Hermann DM ; Heinz Nixdorf Recall Study Investigative Group. Association of social relationships with incident cardiovascular events and all-cause mortality.Heart. 2020; 106:1317–1323. doi: 10.1136/heartjnl-2019-316250Google Scholar - 46.
Linden DJ . Touch: The Science of Hand, Heart and Mind. Penguin Books; 2015.Google Scholar - 47.
Bachen EA, Muldoon MF, Matthews KA, Manuck SB . Effects of hemoconcentration and sympathetic activation on serum lipid responses to brief mental stress.Psychosom Med. 2002; 64:587–594. doi: 10.1097/01.psy.0000021943.35402.8aGoogle Scholar - 48.
Malkoff SB, Muldoon MF, Zeigler ZR, Manuck SB . Blood platelet responsivity to acute mental stress.Psychosom Med. 1993; 55:477–482. doi: 10.1097/00006842-199311000-00001Google Scholar - 49.
Muldoon MF, Bachen EA, Manuck SB, Waldstein SR, Bricker PL, Bennett JA . Acute cholesterol responses to mental stress and change in posture.Arch Intern Med. 1992; 152:775–780.Google Scholar - 50.
Muldoon MF, Herbert TB, Patterson SM, Kameneva M, Raible R, Manuck SB . Effects of acute psychological stress on serum lipid levels, hemoconcentration, and blood viscosity.Arch Intern Med. 1995; 155:615–620.Google Scholar - 51.
Musante L, Treiber FA, Kapuku G, Moore D, Davis H, Strong WB . The effects of life events on cardiovascular reactivity to behavioral stressors as a function of socioeconomic status, ethnicity, and sex.Psychosom Med. 2000; 62:760–767. doi: 10.1097/00006842-200011000-00004Google Scholar - 52.
Menéndez Villalva C, Montes Martínez A, Núñez Losada C, Fernández Domínguez MJ, Gamarra Mondelo T, Buján Garmendia S . [Environmental stress and cardiovascular reactivity: the effect of stressful life events on hypertense patients].Aten Primaria. 2002; 30:631–637. doi: 10.1016/s0212-6567(02)79125-7Google Scholar - 53.
Peters A, McEwen BS . Stress habituation, body shape and cardiovascular mortality.Neurosci Biobehav Rev. 2015; 56:139–150. doi: 10.1016/j.neubiorev.2015.07.001CrossrefMedlineGoogle Scholar - 54.
Fenga C, Micali E, Cacciola A, Trimarchi G, Germanò D . Stressful life events and fibrinogen level in middle-aged teachers.Psychopathology. 2004; 37:64–68. doi: 10.1159/000077580Google Scholar - 55.
Levine SP, Towell BL, Suarez AM, Knieriem LK, Harris MM, George JN . Platelet activation and secretion associated with emotional stress.Circulation. 1985; 71:1129–1134. doi: 10.1161/01.cir.71.6.1129AbstractGoogle Scholar - 56.
Williams JK, Kaplan JR, Manuck SB . Effects of psychosocial stress on endothelium-mediated dilation of atherosclerotic arteries in cynomolgus monkeys.J Clin Invest. 1993; 92:1819–1823. doi: 10.1172/JCI116772CrossrefMedlineGoogle Scholar - 57.
McEwen BS . Protective and damaging effects of stress mediators.N Engl J Med. 1998; 338:171–179. doi: 10.1056/NEJM199801153380307CrossrefMedlineGoogle Scholar - 58.
McEwen BS . Stress, adaptation, and disease. Allostasis and allostatic load.Ann N Y Acad Sci. 1998; 840:33–44. doi: 10.1111/j.1749-6632.1998.tb09546.xCrossrefMedlineGoogle Scholar - 59.
Gu HF, Tang CK, Yang YZ . Psychological stress, immune response, and atherosclerosis.Atherosclerosis. 2012; 223:69–77. doi: 10.1016/j.atherosclerosis.2012.01.021CrossrefMedlineGoogle Scholar - 60.
Pickering TG . Stress, inflammation, and hypertension.J Clin Hypertens (Greenwich). 2007; 9:567–571. doi: 10.1111/j.1524-6175.2007.06301.xGoogle Scholar - 61.
Kershaw KN, Lane-Cordova AD, Carnethon MR, Tindle HA, Liu K . Chronic stress and endothelial dysfunction: The Multi-Ethnic Study of Atherosclerosis (MESA).Am J Hypertens. 2017; 30:75–80. doi: 10.1093/ajh/hpw103CrossrefMedlineGoogle Scholar - 62.
Bomhof-Roordink H, Seldenrijk A, van Hout HP, van Marwijk HW, Diamant M, Penninx BW . Associations between life stress and subclinical cardiovascular disease are partly mediated by depressive and anxiety symptoms.J Psychosom Res. 2015; 78:332–339. doi: 10.1016/j.jpsychores.2015.02.009Google Scholar - 63.
Jung SJ, Jeon Y, Lee G, Shim JS, Kim HC . Stressful life events and augmentation index: results from the Cardiovascular and Metabolic Diseases Etiology Research Center.Hypertens Res. 2020; 43:45–54. doi: 10.1038/s41440-019-0331-6Google Scholar - 64.
Osler M, Bendix L, Rask L, Rod NH . Stressful life events and leucocyte telomere length: do lifestyle factors, somatic and mental health, or low grade inflammation mediate this relationship? Results from a cohort of Danish men born in 1953.Brain Behav Immun. 2016; 58:248–253. doi: 10.1016/j.bbi.2016.07.154Google Scholar - 65.
Ahmadi A, Sodejani SA, Malekzadeh R, Poustchi H, Solati K . Study of correlation between chronic stressor, biochemical markers and hematologic indices in Shahrekord Cohort Study: a population-based cross-sectional study.Diabetes Metab Syndr. 2019; 13:2170–2174. doi: 10.1016/j.dsx.2019.05.006Google Scholar - 66.
Dimsdale JE, Herd JA . Variability of plasma lipids in response to emotional arousal.Psychosom Med. 1982; 44:413–430. doi: 10.1097/00006842-198211000-00004CrossrefMedlineGoogle Scholar - 67.
Fakhari A, Ebrahimzadeh ME, Shiva S, Fekrat S, Mohammadpoorasl A . Effects of mental stress on serum triglyceride level.Res J Biol Sci. 2007; 2:476–478.Google Scholar - 68.
Patterson SM, Gottdiener JS, Hecht G, Vargot S, Krantz DS . Effects of acute mental stress on serum lipids: mediating effects of plasma volume.Psychosom Med. 1993; 55:525–532. doi: 10.1097/00006842-199311000-00008Google Scholar - 69.
Chrousos GP . The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes.Int J Obes Relat Metab Disord. 2000; 24(suppl 2):S50–S55. doi: 10.1038/sj.ijo.0801278Google Scholar - 70.
Goldston DB, Kovacs M, Obrosky DS, Iyengar S . A longitudinal study of life events and metabolic control among youths with insulin-dependent diabetes mellitus.Health Psychol. 1995; 14:409–414. doi: 10.1037//0278-6133.14.5.409Google Scholar - 71.
Hammerfald K, Eberle C, Grau M, Kinsperger A, Zimmermann A, Ehlert U, Gaab J . Persistent effects of cognitive-behavioral stress management on cortisol responses to acute stress in healthy subjects–a randomized controlled trial.Psychoneuroendocrinology. 2006; 31:333–339. doi: 10.1016/j.psyneuen.2005.08.007Google Scholar - 72.
Brady SS, Matthews KA . Chronic stress influences ambulatory blood pressure in adolescents.Ann Behav Med. 2006; 31:80–88. doi: 10.1207/s15324796abm3101_12Google Scholar - 73.
Albert MA, Durazo EM, Slopen N, Zaslavsky AM, Buring JE, Silva T, Chasman D, Williams DR . Cumulative psychological stress and cardiovascular disease risk in middle aged and older women: Rationale, design, and baseline characteristics.Am Heart J. 2017; 192:1–12. doi: 10.1016/j.ahj.2017.06.012CrossrefMedlineGoogle Scholar - 74.
Gebreab SY, Diez-Roux AV, Hickson DA, Boykin S, Sims M, Sarpong DF, Taylor HA, Wyatt SB . The contribution of stress to the social patterning of clinical and subclinical CVD risk factors in African Americans: the Jackson Heart Study.Soc Sci Med. 2012; 75:1697–1707. doi: 10.1016/j.socscimed.2012.06.003CrossrefMedlineGoogle Scholar - 75.
Sims M, Glover LSM, Gebreab SY, Spruill TM . Cumulative psychosocial factors are associated with cardiovascular disease risk factors and management among African Americans in the Jackson Heart Study.BMC Public Health. 2020; 20:566. doi: 10.1186/s12889-020-08573-0CrossrefMedlineGoogle Scholar - 76.
Brewer LC, Redmond N, Slusser JP, Scott CG, Chamberlain AM, Djousse L, Patten CA, Roger VL, Sims M . Stress and achievement of cardiovascular health metrics: The american heart association life’s simple 7 in blacks of the jackson heart study.J Am Heart Assoc. 2018; 7:e008855.LinkGoogle Scholar - 77.
Dallman MF, Pecoraro N, Akana SF, La Fleur SE, Gomez F, Houshyar H, Bell ME, Bhatnagar S, Laugero KD, Manalo S . Chronic stress and obesity: a new view of “comfort food”.Proc Natl Acad Sci USA. 2003; 100:11696–11701. doi: 10.1073/pnas.1934666100CrossrefMedlineGoogle Scholar - 78.
Melamed S, Kushnir T, Strauss E, Vigiser D . Negative association between reported life events and cardiovascular disease risk factors in employed men: the CORDIS Study. Cardiovascular Occupational Risk Factors Determination in Israel.J Psychosom Res. 1997; 43:247–258. doi: 10.1016/s0022-3999(97)00120-7Google Scholar - 79.
Christensen DS, Dich N, Flensborg-Madsen T, Garde E, Hansen ÅM, Mortensen EL . Objective and subjective stress, personality, and allostatic load.Brain Behav. 2019; 9:e01386. doi: 10.1002/brb3.1386Google Scholar - 80.
Quadt L, Esposito G, Critchley HD, Garfinkel SN . Brain-body interactions underlying the association of loneliness with mental and physical health.Neurosci Biobehav Rev. 2020; 116:283–300. doi: 10.1016/j.neubiorev.2020.06.015Google Scholar - 81.
Fagundes CP, Murdock KW, LeRoy A, Baameur F, Thayer JF, Heijnen C . Spousal bereavement is associated with more pronounced ex vivo cytokine production and lower heart rate variability: mechanisms underlying cardiovascular risk?Psychoneuroendocrinology. 2018; 93:65–71. doi: 10.1016/j.psyneuen.2018.04.010Google Scholar - 82.
Feeney J, Dooley C, Finucane C, Kenny RA . Stressful life events and orthostatic blood pressure recovery in older adults.Health Psychol. 2015; 34:765–774. doi: 10.1037/hea0000194Google Scholar - 83.
Lim MH, Eres R, Vasan S . Understanding loneliness in the twenty-first century: an update on correlates, risk factors, and potential solutions.Soc Psychiatry Psychiatr Epidemiol. 2020; 55:793–810. doi: 10.1007/s00127-020-01889-7Google Scholar - 84.
Courtin E, Knapp M . Social isolation, loneliness and health in old age: a scoping review.Health Soc Care Community. 2017; 25:799–812. doi: 10.1111/hsc.12311Google Scholar - 85.
Holt-Lunstad J, Smith TB, Baker M, Harris T, Stephenson D . Loneliness and social isolation as risk factors for mortality: a meta-analytic review.Perspect Psychol Sci. 2015; 10:227–237. doi: 10.1177/1745691614568352CrossrefMedlineGoogle Scholar - 86.
Davis MC, Matthews KA, Twamley EW . Is life more difficult on Mars or Venus? A meta-analytic review of sex differences in major and minor life events.Ann Behav Med. 1999; 21:83–97. doi: 10.1007/BF02895038Google Scholar - 87.
Eisler RM, Skidmore JR . Masculine gender role stress. Scale development and component factors in the appraisal of stressful situations.Behav Modif. 1987; 11:123–136. doi: 10.1177/01454455870112001Google Scholar - 88.
Eisler RM, Skidmore JR, Ward CH . Masculine gender-role stress: predictor of anger, anxiety, and health-risk behaviors.J Pers Assess. 1988; 52:133–141. doi: 10.1207/s15327752jpa5201_12Google Scholar - 89.
Gove WR, Tudor JF . Adult sex roles and mental illness.AJS. 1973; 78:812–835. doi: 10.1086/225404Google Scholar - 90.
Cinamon RG, Rich Y . Gender differences in the importance of work and family roles: Implications for work–family conflict.Sex Roles. 2002; 47:531–541.Google Scholar - 91.
Duxbury LHiggins C, Lee C . Work-family conflict: a comparison by gender, family type, and perceived control.J Fam Issues. 1994; 15:449–466.Google Scholar - 92.
Grönlund A . More control, less conflict? Job demand–control, gender and work–family conflict.Gend Work Organ. 2007; 14:476–497.Google Scholar - 93.
Barnett RC, Baruch GK . Women’s involvement in multiple roles and psychological distress.J Pers Soc Psychol. 1985; 49:135–145. doi: 10.1037//0022-3514.49.1.135Google Scholar - 94.
Aneshensel CS PL . Structural contexts of sex differences in stress.Bamet RC BL, Baruch GK , eds. In: Gender and Stress. Free Press; 1987:75–95.Google Scholar - 95.
Dalgard OS, Dowrick C, Lehtinen V, Vazquez-Barquero JL, Casey P, Wilkinson G, Ayuso-Mateos JL, Page H, Dunn G ; ODIN Group. Negative life events, social support and gender difference in depression: a multinational community survey with data from the ODIN study.Soc Psychiatry Psychiatr Epidemiol. 2006; 41:444–451. doi: 10.1007/s00127-006-0051-5Google Scholar - 96.
Huang Y, Xu S, Hua J, Zhu D, Liu C, Hu Y, Liu T, Xu D . Association between job strain and risk of incident stroke: a meta-analysis.Neurology. 2015; 85:1648–1654. doi: 10.1212/WNL.0000000000002098CrossrefMedlineGoogle Scholar - 97.
Dragano N, Siegrist J, Nyberg ST, Lunau T, Fransson EI, Alfredsson L, Bjorner JB, Borritz M, Burr H, Erbel R, ; IPD-Work consortium. Effort-reward imbalance at work and incident coronary heart disease: a multicohort study of 90,164 individuals.Epidemiology. 2017; 28:619–626. doi: 10.1097/EDE.0000000000000666CrossrefMedlineGoogle Scholar - 98.
Stringhini S, Berkman L, Dugravot A, Ferrie JE, Marmot M, Kivimaki M, Singh-Manoux A . Socioeconomic status, structural and functional measures of social support, and mortality: The British Whitehall II Cohort Study, 1985-2009.Am J Epidemiol. 2012; 175:1275–1283. doi: 10.1093/aje/kwr461CrossrefMedlineGoogle Scholar - 99.
Friedler B, Crapser J, McCullough L . One is the deadliest number: the detrimental effects of social isolation on cerebrovascular diseases and cognition.Acta Neuropathol. 2015; 129:493–509. doi: 10.1007/s00401-014-1377-9CrossrefMedlineGoogle Scholar - 100.
Sacco RL, Boden-Albala B, Gan R, Chen X, Kargman DE, Shea S, Paik MC, Hauser WA . Stroke incidence among white, black, and Hispanic residents of an urban community: the Northern Manhattan Stroke Study.Am J Epidemiol. 1998; 147:259–268. doi: 10.1093/oxfordjournals.aje.a009445CrossrefMedlineGoogle Scholar - 101.
Bambs C, Kip KE, Dinga A, Mulukutla SR, Aiyer AN, Reis SE . Low prevalence of “ideal cardiovascular health” in a community-based population: the heart strategies concentrating on risk evaluation (Heart SCORE) study.Circulation. 2011; 123:850–857. doi: 10.1161/CIRCULATIONAHA.110.980151LinkGoogle Scholar - 102.
Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, ; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2019 update: A Report From the American Heart Association.Circulation. 2019; 139:e56–e528. doi: 10.1161/CIR.0000000000000659LinkGoogle Scholar - 103.
Sternthal MJ, Slopen N, Williams DR . Racial disparities in health: how much does stress really matter?Du Bois Rev. 2011; 8:95–113. doi: 10.1017/S1742058X11000087CrossrefMedlineGoogle Scholar - 104.
Sims M, Diez-Roux AV, Gebreab SY, Brenner A, Dubbert P, Wyatt S, Bruce M, Hickson D, Payne T, Taylor H . Perceived discrimination is associated with health behaviours among African-Americans in the Jackson Heart Study.J Epidemiol Community Health. 2016; 70:187–194. doi: 10.1136/jech-2015-206390CrossrefMedlineGoogle Scholar - 105.
Chilunga FP, Boateng D, Henneman P, Beune E, Requena-Méndez A, Meeks K, Smeeth L, Addo J, Bahendeka S, Danquah I, . Perceived discrimination and stressful life events are associated with cardiovascular risk score in migrant and non-migrant populations: The RODAM study.Int J Cardiol. 2019; 286:169–174. doi: 10.1016/j.ijcard.2018.12.056Google Scholar - 106.
Pascoe EA, Smart Richman L . Perceived discrimination and health: a meta-analytic review.Psychol Bull. 2009; 135:531–554. doi: 10.1037/a0016059CrossrefMedlineGoogle Scholar - 107.
Obasi EM, Shirtcliff EA, Cavanagh L, Ratliff KL, Pittman DM, Brooks JJ . Hypothalamic-pituitary-adrenal reactivity to acute stress: an investigation into the roles of perceived stress and family resources.Prev Sci. 2017; 18:923–931. doi: 10.1007/s11121-017-0759-3CrossrefMedlineGoogle Scholar - 108.
Effoe VS, Carnethon MR, Echouffo-Tcheugui JB, Chen H, Joseph JJ, Norwood AF, Bertoni AG . The american heart association ideal cardiovascular health and incident type 2 diabetes mellitus among blacks: The jackson heart study.J Am Heart Assoc. 2017; 6:e005008.LinkGoogle Scholar - 109.
Thomasson MA . Racial differences in health insurance coverage and medical expenditures in the united states: a historical perspective.Soc Sci Hist. 2006; 30:529–550.Google Scholar - 110.
Guzman GG . United State Census Bureau. Household income: 2016. American Community survey Briefs. Acsbr/16–02, Us Census Bureau. 2017:1–7.Google Scholar - 111.
Kirkpatrick SI, Dodd KW, Reedy J, Krebs-Smith SM . Income and race/ethnicity are associated with adherence to food-based dietary guidance among US adults and children.J Acad Nutr Diet. 2012; 112:624.e6–635.e6. doi: 10.1016/j.jand.2011.11.012CrossrefGoogle Scholar - 112.
Unger E, Diez-Roux AV, Lloyd-Jones DM, Mujahid MS, Nettleton JA, Bertoni A, Badon SE, Ning H, Allen NB . Association of neighborhood characteristics with cardiovascular health in the multi-ethnic study of atherosclerosis.Circ Cardiovasc Qual Outcomes. 2014; 7:524–531. doi: 10.1161/CIRCOUTCOMES.113.000698LinkGoogle Scholar - 113.
Wyatt SB, Williams DR, Calvin R, Henderson FC, Walker ER, Winters K . Racism and cardiovascular disease in African Americans.Am J Med Sci. 2003; 325:315–331. doi: 10.1097/00000441-200306000-00003CrossrefMedlineGoogle Scholar - 114.
Wenger GC, Davies R, Shahtahmasebi S, Scott A . Social isolation and loneliness in old age: review and model refinement.Ageing Soc. 1996; 16:333–358.Google Scholar - 115.
Alcaraz KI, Eddens KS, Blase JL, Diver WR, Patel AV, Teras LR, Stevens VL, Jacobs EJ, Gapstur SM . Social isolation and mortality in us black and white men and women.Am J Epidemiol. 2019; 188:102–109. doi: 10.1093/aje/kwy231CrossrefMedlineGoogle Scholar - 116.
Cacioppo JT, Cacioppo S . Social relationships and health: the toxic effects of perceived social isolation.Soc Personal Psychol Compass. 2014; 8:58–72. doi: 10.1111/spc3.12087CrossrefMedlineGoogle Scholar - 117.
Kim HJ, Fredriksen-Goldsen KI . Living arrangement and loneliness among lesbian, gay, and bisexual older adults.Gerontologist. 2016; 56:548–558. doi: 10.1093/geront/gnu083Google Scholar - 118.
Kuyper L, Fokkema T . Loneliness among older lesbian, gay, and bisexual adults: the role of minority stress.Arch Sex Behav. 2010; 39:1171–1180. doi: 10.1007/s10508-009-9513-7Google Scholar - 119.
Fredriksen-Goldsen KI, Kim HJ, Barkan SE, Muraco A, Hoy-Ellis CP . Health disparities among lesbian, gay, and bisexual older adults: results from a population-based study.Am J Public Health. 2013; 103:1802–1809. doi: 10.2105/AJPH.2012.301110Google Scholar - 120.
Hsieh N, Liu H . Social relationships and loneliness in late adulthood: disparities by sexual orientation.J Marriage Fam. 2020. https://doi.org/10.1111/jomf.12681Google Scholar - 121.
Hsieh N . Explaining the mental health disparity by sexual orientation:The importance of social resources.Soc Ment Health. 2014; 4:129–146.Google Scholar - 122.
Gold SM, Zakowski SG, Valdimarsdottir HB, Bovbjerg DH . Higher Beck depression scores predict delayed epinephrine recovery after acute psychological stress independent of baseline levels of stress and mood.Biol Psychol. 2004; 67:261–273. doi: 10.1016/j.biopsycho.2003.12.001Google Scholar - 123.
Burke HM, Davis MC, Otte C, Mohr DC . Depression and cortisol responses to psychological stress: a meta-analysis.Psychoneuroendocrinology. 2005; 30:846–856. doi: 10.1016/j.psyneuen.2005.02.010Google Scholar - 124.
Ehrenthal JC, Herrmann-Lingen C, Fey M, Schauenburg H . Altered cardiovascular adaptability in depressed patients without heart disease.World J Biol Psychiatry. 2010; 11:586–593. doi: 10.3109/15622970903397714Google Scholar - 125.
Salomon K, Clift A, Karlsdóttir M, Rottenberg J . Major depressive disorder is associated with attenuated cardiovascular reactivity and impaired recovery among those free of cardiovascular disease.Health Psychol. 2009; 28:157–165. doi: 10.1037/a0013001Google Scholar - 126.
Miller GE, Rohleder N, Stetler C, Kirschbaum C . Clinical depression and regulation of the inflammatory response during acute stress.Psychosom Med. 2005; 67:679–687. doi: 10.1097/01.psy.0000174172.82428.ceCrossrefMedlineGoogle Scholar - 127.
Van de Velde S, Bracke P, Levecque K . Gender differences in depression in 23 european countries. Cross-national variation in the gender gap in depression.Soc Sci Med (1982). 2010; 71:305–313.Google Scholar - 128.
Dong C, Rundek T, Wright CB, Anwar Z, Elkind MS, Sacco RL . Ideal cardiovascular health predicts lower risks of myocardial infarction, stroke, and vascular death across whites, blacks, and hispanics: the northern Manhattan study.Circulation. 2012; 125:2975–2984. doi: 10.1161/CIRCULATIONAHA.111.081083LinkGoogle Scholar - 129.
Rozanski A, Blumenthal JA, Kaplan J . Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy.Circulation. 1999; 99:2192–2217. doi: 10.1161/01.cir.99.16.2192LinkGoogle Scholar - 130.
Holt-Lunstad J, Smith TB . Loneliness and social isolation as risk factors for CVD: implications for evidence-based patient care and scientific inquiry.Heart. 2016; 102:987–989. doi: 10.1136/heartjnl-2015-309242Google Scholar - 131.
Dickens AP, Richards SH, Greaves CJ, Campbell JL . Interventions targeting social isolation in older people: a systematic review.BMC Public Health. 2011; 11:647. doi: 10.1186/1471-2458-11-647Google Scholar
eLetters(0)
eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.
Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.