Access to this full-text is provided by Springer Nature.
Content available from Current Cardiology Reports
This content is subject to copyright. Terms and conditions apply.
PSYCHOLOGICAL ASPECTS OF CARDIOVASCULAR DISEASES (A STEPTOE AND IM KRONISH ,
SECTION EDITORS)
Loneliness and Risk for Cardiovascular Disease: Mechanisms
and Future Directions
Elise Paul
1
&Feifei Bu
1
&Daisy Fancourt
1
Accepted: 9 March 2021
#The Author(s) 2021
Abstract
Purpose of review In this review, we synthesise recent research on the association between loneliness and cardiovascular disease
(CVD). We present evidence for mechanisms underlying this association and propose directions for future research.
Recent findings Loneliness is related to increased risk of early mortality and CVD comparable to other well-established risk
factors such as obesity or smoking.
Summary Loneliness has been linked to higher rates of incident CVD, poorer CVD patient outcomes, and early mortality from
CVD. Loneliness likely affects risk for these outcomes via health-related behaviours (e.g. physical inactivity and smoking),
biological mechanisms (e.g. inflammation, stress reactivity), and psychological factors (e.g. depression) to indirectly damage
health.
Keywords Loneliness .Cardiovascular disease .Epidemiology .Health policy .Health promotion
Introduction
Accumulating evidence suggests that psychosocial risk factors
such as loneliness are significant contributors to a wide range
of negative health outcomes, including early all-cause mortal-
ity [1,2], incident cardiovascular disease (CVD) [3•], and all-
cause mortality in patients with CVD [4]. There are several
indications that loneliness, or the subjective distress resulting
from a discrepancy between desired and perceived social re-
lationships [5], is widespread. National surveys in the UK find
that 5–7% of adults feel lonely often or always [6–8]. Others
find that nearly half (43%) of older adults (aged 60 and over)
report feeling lonely [9]. Many of the groups more likely to be
lonely are also those at an increased risk for CVD. For exam-
ple, loneliness is more common amongst individuals of lower
socioeconomic status (SES), poorer health, older age, and
cognitive and physical impairment [10,11]. These factors
are in turn associated with higher CVD risk [12–16]. This
has led to loneliness itself being identified as a public health
concern [17] and developments in policy such as the estab-
lishment of a Minister for Loneliness in the UK in 2018, and
the national roll-out of “social prescribing”in the NHS, the
goal of which is for every general practitioner (GP) to be able
to refer patients experiencing loneliness to voluntary services
and community activities by the year 2023 [18].
A related but more objective construct, social isolation, has
been operationalised as the number of persons with whom an
individual has contact or lives, engagement in volunteering or
work, and membership in social organisations or clubs [19,
20]. Although social isolation and loneliness are related and
can occur together, they can also be experienced independent-
ly of one another [21]. Meta-analyses find that social isolation
has comparable associations with all-cause mortality [1•]and
CVD to loneliness [3•]. Whilst this review focuses specifically
on loneliness rather than social isolation in relation to CVD,
where studies have accounted for both, we report both sets of
findings for comparison.
This article is part of the Topical Collection on Psychological Aspects of
Cardiovascular Diseases
*Daisy Fancourt
d.fancourt@ucl.ac.uk
Elise Paul
e.paul@ucl.ac.uk
Feifei Bu
f.bu@ucl.ac.uk
1
Department of Behavioural Science and Health, University College
London, 1-19 Torrington Place, London WC1E 7HB, UK
https://doi.org/10.1007/s11886-021-01495-2
/ Published online: 7 May 2021
Current Cardiology Reports (2021) 23: 68
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
In this review, we provide a broad overview of current
knowledge concerning whether and how loneliness influences
risk for CVD incidence, prognosis, and CVD-related mortal-
ity. We begin by focusing on evidence directly linking lone-
liness with these outcomes. We then consider (1) psycholog-
ical, (2) biological, and (3) behavioural mechanisms by which
loneliness may increase the risk for CVD, emphasising find-
ings from methodologically stronger studies when available.
We conclude with a summary of the limitations of existing
research as well as recommendations for future work in this
area.
Loneliness and cardiovascular disease:
the evidence
Evidence linking loneliness with CVD comes from prospec-
tive studies (and meta-analyses of these studies) using
population-based and CVD patient samples. In the most re-
cent large-scale meta-analysis linking these outcomes, the
pooled relative risk for incident coronary heart disease
(CHD) and stroke in individuals with high versus low levels
of loneliness or social isolation was 1.29 (95% confidence
interval (CI) = 1.04 to 1.59) in 16 longitudinal studies [3•].
There were no significant differences in the magnitude of risk
when studies examining either social isolation or loneliness
were pooled separately, or in relative risk for CVD outcomes
by gender, risk of confounding, or risk of measurement error.
Since this meta-analysis, other studies have repeated these
findings. For example, using data from adults aged 40–69 in
the large prospective population-based UK Biobank study,
Hakulinen et al [22] found that in separate regression models,
both loneliness and social isolation were associated with in-
creased risk for incident acute myocardial infarction and first
stroke when adjusting for demographics. Similarly, a large
prospective Danish study showed independent associations
of both loneliness (hazard ratio (HR) = 1.20; 95% CI = 1.03
to 1.40) and social isolation (HR = 1.23; 95% CI = 1.04 to
1.46) with CVD [23].
However, there have been mixed findings as to whether
subjective feelings of loneliness or the objective construct of
social isolation is more important for CVD. A 10-year follow-
up study of Taiwanese adults with CVD found evidence for
the role of social isolation (HR = 1.16; 95% CI = 1.07 to 1.27)
but not loneliness (HR = 0.92; 95% CI = 0.80 to 1.06) with
increased risk of all-cause mortality after accounting for both
simultaneously and adjusting for other established risk factors
[4]. Similar findings were reported using data from the Danish
DenHeart study of 13,000 CVD patients, where living alone
but not loneliness was associated with risk for cardiac events
(myocardial infarction, stroke, ventricular tachycardia/
ventricular fibrillation, and cardiac arrest) assessed from na-
tional registers in men (HR = 1.39; 95% CI = 1.05 to 1.85) at
1-year follow-up [24]. Furthermore, two other sets of analyses
using data from the large population-based English
Longitudinal Study of Ageing (ELSA) found that loneliness,
but not indices of social isolation, was associated with in-
creased risk for incident CVD outcomes including mortality.
In the first, loneliness was associated with 30% higher risk of
CVD incidence at 5-year follow-up, whilst social isolation
was not [25]. A second study using the ELSA data found that
lonelinessbut not social isolation associated with self-reported
and hospital admission CVD events using objective registry
data independent of sociodemographic factors [19]. So, stud-
ies remain inconclusive as to whether loneliness or social iso-
lation are stronger predictors of CVD and CVD-related
outcomes.
It is also possible that not everyone is at equal risk from
social factors. For example, there have been some differential
findings for men and women with respect to loneliness. Using
data from the Swedish Gothenburg H70 Birth Cohort Studies,
loneliness was a predictor of cardiovascular mortality in wom-
en (HR = 2.42; 95% CI = 1.04–5.65), but not in men (HR =
1.52; 95% CI = 0.78–2.96) independent of living alone [26].
Additionally, in a prospective study of population-based
Finnish men (ages 42–61) who were followed for an average
of 23 years, loneliness but not social isolation predicted CVD
mortality (HR = 1.12; 95% CI = 1.01 to 1.24), even whilst
adjusting for depressive symptoms and other confounding
variables [27].
In sum, the majority of studies reviewed support subjective
feelings of loneliness independent of the objective measure of
social isolation as an important risk factor for incident CVD
and CVD events in CVD patients. Whilst the specifics of the
evidence are somewhat mixed, variation across study out-
comes may depend in part on the covariates included in anal-
yses. But there is nonetheless repeated evidence from both
self-reported and objective registry data of a relationship be-
tween social factors and various CVD outcomes.
Mechanisms linking loneliness and CVD
To date, a number of psychological, biological, and behav-
ioural pathways to health and mortality from loneliness
have been identified [28,29]. Several researchers who have
conceptualised the relationships amongst these variables
begin with the observation that humans are social creatures,
and that proximity to other humans is necessary for survival
[30,31]. Perceived social isolation is therefore a source of
threat and danger, which activates behavioural and psycho-
logical mechanisms via biological and molecular pathways
[29–31]. These mechanisms in turn lead to increased risk
for premature mortality and disease [28,32]. Identifying
these pathways is crucial for developing appropriate inter-
ventions and prevention targets [28•]. Below, we review the
68 Page 2 of 7 Curr Cardiol Rep (2021) 23: 68
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
recent evidence for these pathways whilst acknowledging
that the mechanisms also likely interact with each other and
operate bidirectionally.
Psychological mechanisms
Loneliness is an established risk factor for mental ill health in
meta-analyses, including depressive [33] and anxious symp-
toms [34], and thoughts of suicide and suicidal behaviour [11,
34,35].
Depression in particular is hypothesised to be a mechanism
linking loneliness with poor health outcomes such as CVD
[28,34]. Displays of depressive behaviour may provide a
non-verbal signal to others that support and connection are
needed [30]. Whilst depression and loneliness have been
hypothesised to be bidirectional, recent research has specifi-
cally identified loneliness as a precursor to major depressive
disorder (MDD) 2 years later, but has not found the associa-
tion operating the other way [36]. However, it is likely that
depression is not the sole mediator between loneliness and
CVD as two recent prospective large studies found that the
relationship between loneliness and CVD mortality persisted
even whilst adjusting for depressive symptoms [19,27].
Another psychological mechanism that could explain the
link between loneliness and CVD is stress. Stress is a key
aspect of the experience and definition of loneliness [5].
Humans are inherently social animals and perceived isolation
may activate a stress response designed to facilitate survival in
the short-term by seeking proximity to other humans, but also
by producing hypervigilance to threats to compensate for the
lack of mutual protection [30,31]. Psychological stress has
been shown to result from loneliness, along with biological
stress responses (see “biological mechanisms”below), and
stress-related health behaviours (see “behavioural mecha-
nisms”)[37,38]. Increased stress can in turn lead to compro-
mised physiological resilience [39]. Excessive worries over
time that are not attenuated by the removal of stressors can
also become more generalised anxiety, which has been shown
to be bidirectionally related to loneliness [36].
Additionally, research has also examined other negative
behaviours including anger and hostility in relation to lone-
liness, finding that these behaviours are heightened in lone-
ly individuals, perhaps in part because increased vigilance
for social threats in the absence of perceived social connect-
edness may protect lonely individuals in the short term [30].
However, these negative states, along with stress and de-
pression, can also act as a short-term precipitant of major
cardiac events such as acute coronary syndrome [40,41].
Therefore, evidence suggests that negative moods, stress,
and poor mental health are all pathways connecting loneli-
ness to cardiovascular events.
Biological mechanisms: neuroendocrine,
immune, cardiometabolic, physiological,
and epigenetic
Evidence for biological pathways through which loneliness
impacts CVD comes from both human and animal studies
[30,32]. Mortality risk from loneliness remains elevated even
when controlling for psychological and behavioural factors,
suggesting a role for biological mechanisms [28•]. Underlying
many of these biological pathways are psychological mecha-
nisms discussed above including depression and chronic ele-
vated stress [28,29], This is likely because hormonal, vascu-
lar, and immune responses are set off by the danger to one’s
survival from perceived social isolation and loneliness [28,32,
40,42]. These biological responses in turn can, when chronic
and sustained, lead to adverse health consequences which
place the individual at risk for premature mortality and disease
development. Some of these key biological pathways are
outlined below.
Neuroendocrine pathways The stress associated with loneli-
ness has led to much research focused on atypical (exaggerat-
ed or blunted) neuroendocrine responses to stress as a major
pathway through which subjective feelings of loneliness in-
fluence CVD risk [28,32,42,43]. Loneliness activates the
body’s central stress response system—the hypothalamic pi-
tuitary adrenal (HPA) axis—in order to prepare the body to
deal with potential threats that may occur as a result of per-
ceived social isolation [32,42]. The HPA axis sets into motion
a“flight or fight”response by secreting the stress hormone
cortisol, which typically shows higher levels upon morning
awakening and a blunted circadian rhythm across the day
[42•]. Over time, chronic stress can lead to chronically elevat-
ed cortisol levels, which are associated with CVD incidence
and poorer prognosis, as well as CVD risk factors such as
diabetes and systolic blood pressure [44].
The majority of the available evidence supports an ex-
aggerated HPA response in association with loneliness;
larger increases in cortisol upon awakening, higher concen-
trations of circulating cortisol, and diminished sensitivity of
glucocorticoid receptors have all been found in lonely in-
dividuals [32•]. Specifically in reaction to stressful events,
momentary, day-to-day sampling studies have found higher
levels of cortisol reactivity in lonely compared to non-
lonely individuals [45,46]. However, there is still some
inconsistency in the literature: a systematic review of stud-
ies measuring neuroendocrine responses to acute
laboratory-induced stressors such as giving a public speech
found that although most studies reviewed reported exag-
gerated stress responses in lonelier individuals, one study
found blunted cortisol production in lonelier women but not
men, whilst two others reported no difference in cortisol
levels between lonely and non-lonely individuals [43].
Page 3 of 7 68Curr Cardiol Rep (2021) 23: 68
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Responses have also not been as clearly found for other
hormones. Studies examining loneliness and neuropeptides
have found no association with catecholamines (e.g. epineph-
rine, norepinephrine, dopamine) secreted in response to sig-
nals from the sympathetic nervous system during acutely
stressful events [47,48]. Therefore, further research on the
role of stress hormones in mediating the relationship between
loneliness and CVD using larger longitudinal studies is
needed.
Immune function A second possible biological mechanism
linking loneliness with CVD is weakened immunity through
increased inflammation [28,31,32]. Cytokines (inflammatory
proteins within the immune system) not only coordinate the
body’s inflammatory response, but also initiate so-called
“sickness behaviours”, which include fatigue and social with-
drawal and are a part of individuals’response to illness [31,
49]. The resulting inflammation may enable sick individuals
to prepare for the possibility of infection or harm [31,50].
Therefore, proinflammatory response that occurs in loneliness
may be seen as a protection in the short term against threats to
safety, as humans who are disconnected from others are more
vulnerable to illness [31]. However, this inflammation may
also increase CVD risk when sustained.
In terms of specific cytokines and other inflammatory
markers associated with loneliness, a systematic review of
the evidence linking loneliness and inflammatory reactions
to acute laboratory-induced stress (e.g. a performance task or
pharmacological induction with amphetamines) found loneli-
ness to be associated with increased proinflammatory cyto-
kines and glycoproteins such as IL-6, tumour necrosis factor
alpha (TNFa), interleukin-1 beta (IL-1B), monocyte
chemoattractant protein 1 (MCP-1), and fibrinogen [43].
However, a more recent meta-analysis focusing on observa-
tional studies of loneliness, social isolation, and inflammation
found higher levels of interleukin-6 (IL-6) but not fibrinogen
in association with loneliness [51]. This study also found no
relationship with the inflammatory marker C-reactive protein
(CRP) [51]. Even though CRP is a biomarker associated with
depression (which we have already discussed as one psycho-
logical pathway linking loneliness with CVD) [52], the rela-
tionship between CRP and loneliness has also not been shown
by other studies, including a study that found no evidence that
CRP acts as a mediator between loneliness and depression
[53], and another study finding that loneliness was associated
with higher inflammatory markers such as insulin-like growth
factor 1 (IGF-1) but not CRP or fibrinogen, even though social
isolation was related to these factors [54]. So, it appears that
only some inflammatory markers are related to loneliness.
Additionally, in their recent review, Li and Xia [32]argued
that another biological mechanism underlying the association
between psychosocial stress due to loneliness and CVD is
oxidative stress. Longitudinal research on this topic is needed
given evidence for a bi-directional relationship between lone-
liness and immune response [55]. However, it highlights the
breadth of immune markers now being considered in relation
to loneliness.
Cardiometabolic response A third possible pathway through
which loneliness increases the risk for CVD is cardiometabol-
ic changes such as elevated blood pressure [28,43] and heart
rate variability [43]. In a recent meta-analysis, loneliness was
related to elevated diastolic blood pressure, increased vascular
resistance, and lower heart rate variability in response to acute
laboratory-based stressors [43]. A more recent narrative re-
view reported lonely individuals to have greater total periph-
eral vascular resistance and increased risk of hypertension
[32]. However, findings from the ELSA epidemiological
study (not included in the Brown et al. [43] review) showed
that social isolation but not loneliness was associated with
increases in both systolic and diastolic blood pressure [20].
Since these reviews, one study of healthy young women
(18–29 years) found that those with greater levels of chronic
loneliness had lower resting HRV and significantly greater
increases in HRV after exposure to laboratory-induced state
of loneliness [56]. Women who were chronically lonely also
showed blunted HRV reactivity to a cognitive challenge task
[56].
Psychosocial stress associated with loneliness may also
influence CVD via changes in gut microbiota. Activation of
the HPA axis initiates an immune response that in turn de-
creases microbial diversity, and leads to further HPA axis
activation [57]. These stress-induced changes in gut microbi-
ota have been shown to increase risk for CVD in clinical
associations in human studies and experimental studies in an-
imals [58,59]. However, research has yet to determine wheth-
er the stress associated with loneliness in particular induces
changes in gut microbiota which are in turn associated with
CVD.
In considering other biological pathways, small genetic
contributions to loneliness have been reported [60] and chron-
ic social isolation in mice and rats has been shown to lead to
epigenetic changes in the brain [61,62]. However, research on
whether loneliness induces epigenetic changes in humans is
needed, particularly changes in the epigenome that are asso-
ciated with CVD risk.
Behavioural mechanisms
Finally, the quality of one’ssocialrelationshipsmayhavean
indirect effect on CVD by promoting healthy behaviours such
as exercise, healthy eating, and not smoking or abusing alco-
hol [63]. Feeling lonely on the other hand may impair the
capacity to self-regulate and avoid negative behaviours such
as excessive alcohol use which reduce stress and tension in the
68 Page 4 of 7 Curr Cardiol Rep (2021) 23: 68
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
short-term, but are ultimately harmful for health in the long-
term [30]. Evidence supporting these behavioural mechanisms
comes from studies showing loneliness is associated with a
lack of physical activity [20,64], smoking [20,65,66], poor
diet [65], and problematic alcohol use [67–69].
In other studies, the association between loneliness and
CVD has been found to be attenuated when adjusting for
behavioural factors that could lie on the causal pathway and
thereby act as pathways to CVD. In models that adjusted for
potential mechanisms such as physical inactivity, smoking,
and body mass index, the relationship between loneliness
and mortality has been shown to be attenuated in participants
who had earlier acute myocardial infarction [22]. However,
one recent longitudinal study of older adults (ELSA) showed
that the impact of loneliness on CVD persisted, even when
accounting for physical inactivity, smoking, and alcohol use
[19], suggesting that these behavioural factors may only par-
tially explain the relationship with CVD-related outcomes and
also that more research is needed to establish the direction of
these associations. Further, whether it is loneliness or social
isolation that has the strongest association with health behav-
iours is still being questioned as another study using data from
the ELSA cohort found that social isolation but not loneliness
at baseline was associated with a number of health risk behav-
iours (e.g. decreased likelihood of regular physical activity,
lower fruit and vegetable intake, smoking) [70]. Lonely indi-
viduals who smoked were, however, less likely to have
stopped smoking at follow-up than non-lonely individuals
[70].
In sum, alongside psychological and biological pathways
connecting loneliness to CVD risks, there are also a number of
potential behavioural pathways that likely interact with other
pathways. For example, sedentary behaviours are themselves
associated with higher depression and inflammatory response
[71,72]. This highlights both the range of mechanisms
connecting loneliness to CVD but also the interconnectedness
of these mechanisms.
Conclusions and implications
Research demonstrates that loneliness is an independent and
modifiable risk factor for CVD. The available evidence impli-
cates psychological factors such as stress, depression, atypical
physiological reactivity, and neuroendocrine responses to
stress, increased inflammation, and harmful behaviours such
as smoking, drinking alcohol, and poor diet as possible
mechanisms.
Evidence of effective interventions for loneliness is limited
[9]. A review of interventions to reduce social isolation and
loneliness in older adults found that whilst most did report
effectiveness, the quality of evidence was weak [73].
Although participants in social-prescribing interventions
(e.g. group exercise, arts classes) report satisfaction with the
programmes and reduced feelings of loneliness [74,75], there
have to date not been studies examining mortality or CVD
outcomes of these non-medical interventions (social prescrib-
ing) [28•]. Therefore, in addition to deeper exploration of the
magnitude of the relationship between loneliness and CVD
risk amongst different populations (including groups at low
and high risk of developing CVD) and the mechanisms un-
derlying this relationship (in particular how combinations of
mechanisms can act synergistically with one another), future
research is also encouraged to investigate interventions that
could help to reduce the negative health effects of loneliness.
Such research could play an important role in the design of
holistic care strategies for people at risk of or living with CVD
and help to reduce the burden of managing CVD for health
and social care services.
Funding This paper was supported by the MARCH Mental Health
Network funded by the Cross-Disciplinary Mental Health Network Plus
initiative supported by UK Research and Innovation [ES/S002588/1].
Additionally, DF is supported by the Wellcome Trust [205407/Z/16/Z]
and the project received additional funding support through the ESRC
project WELLCOMM [ES/T006994/1] and the Leverhulme Trust [PLP-
2018-007].
Declarations
Conflict of Interest The authors have no conflicts of interest to declare.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing, adap-
tation, distribution and reproduction in any medium or format, as long as
you give appropriate credit to the original author(s) and the source, pro-
vide a link to the Creative Commons licence, and indicate if changes were
made. The images or other third party material in this article are included
in the article's Creative Commons licence, unless indicated otherwise in a
credit line to the material. If material is not included in the article's
Creative Commons licence and your intended use is not permitted by
statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/.
References
Papers of particular interest, published recently, have been
highlighted as:
•Of importance
1.•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;10:227–37
Page 5 of 7 68Curr Cardiol Rep (2021) 23: 68
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Important because it is the most recent meta-analysis on lone-
liness and mortality.
2. Rico-Uribe LA, Caballero FF, Martín-María N, Cabello M, Ayuso-
Mateos JL, Miret M. Association of loneliness with all-cause mor-
tality: a meta-analysis. PLoS One. 2018;13:e0190033.
3.•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 longi-
tudinal observational studies. Heart. 2016;102:1009–16
Important because it is the most recent meta-analysis on lone-
liness and CVD.
4. Yu B, Steptoe A, Chen L-J, Chen Y-H, Lin C-H, Ku P-W. Social
isolation, loneliness, and all-cause mortality in patients with cardio-
vascular disease: a 10-year follow-up study. Psychosom Med.
2020;82:208–14.
5. Peplau LA, Perlman D. Perspectives on loneliness. In: Loneliness: a
sourcebook of current theory, research and practice. New York:
John Wiley; 1982. p. 1–17.
6. Li LZ, Wang S. Prevalence and predictors of general psychiatric
disorders and loneliness during COVID-19in the United Kingdom.
Psychiatry Res. 2020;291:113267.
7. Office for National Statistics (2018)Loneliness-what characteristics
and circumstances are associated with feeling lonely?
8. Office for National Statistics. Coronavirus and loneliness. Great:
Britain - Office for National Statistics; 2020.
9. National Academies of Sciences, Engineering, and Medicine
(2020) Social isolation and loneliness in older adults: opportunities
for the health care system. https://doi.org/10.17226/25663
10. Hajek A, König H-H. Which factors contribute to loneliness among
older Europeans? Findings from the survey of health, ageing and
retirement in Europe: determinants of loneliness. Arch Gerontol
Geriatr. 2020;89:104080.
11. Solmi M, Veronese N, Galvano D, Favaro A, Ostinelli EG,
Noventa V, et al. Factors associated with loneliness: an umbrella
review of observational studies. J Affect Disord. 2020;271:131–8.
12. Calderón-Larrañaga A, Vetrano DL, Ferrucci L, Mercer SW,
Marengoni A, Onder G, et al. Multimorbidity and functional
impairment–bidirectional interplay, synergistic effects and com-
mon pathways. J Intern Med. 2019;285:255–71.
13. de Mestral C, Stringhini S. Socioeconomic status and cardiovascu-
lar disease: an update. Curr Cardiol Rep. 2017;19:115.
14. Ferrucci L, Fabbri E. Inflammageing: Chronic inflammation in age-
ing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15:
505–22.
15. Lahey R, Khan SS. Trends in obesity and risk of cardiovascular
disease. Curr Epidemiol Rep. 2018;5:243–51.
16. Rosengren A, Smyth A, Rangarajan S, Ramasundarahettige C,
Bangdiwala SI, AlHabib KF, et al. Socioeconomic status and risk
of cardiovascular disease in 20 low-income, middle-income, and
high-income countries: the Prospective Urban Rural
Epidemiologic (PURE) study. Lancet Glob Health. 2019;7:e748–
60.
17. Jeste DV, Lee EE, Cacioppo S. Battling the modern behavioral
epidemic of loneliness: suggestions for research and interventions.
JAMA Psychiatry. 2020;77:553–4.
18. HM Government (2018) PM launches Government’s first loneli-
ness strategy. In: GOV.UK. https://www.gov.uk/government/news/
pm-launches-governments-first-loneliness-strategy. Accessed 29
Oct 2020
19. Bu F, Zaninotto P, Fancourt D. Longitudinal associations between
loneliness, social isolation and cardiovascular events. Heart.
2020;106:1394–9.
20. Shankar A, McMunn A, Banks J, Steptoe A. Loneliness, social
isolation, and behavioral and biological health indicators in older
adults. Health Psychol: official journal of the Division of Health
Psychology, American Psychological Association. 2011;30:377–
85.
21. Perissinotto CM, Covinsky KE (2014) Living alone, socially iso-
lated or lonely—what are we measuring? Springer
22. Hakulinen C, Pulkki-Raback 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;104:1536–42.
23. Christiansen J, Lund R, Qualter P, Andersen CM, Pedersen SS,
Lasgaard M. Loneliness, social isolation, and chronic disease out-
comes. Ann Behav Med. 2020. https://doi.org/10.1093/abm/
kaaa044.
24. Christensen AV, Juel K, Ekholm O, Thrysøe L, Thorup CB,
Borregaard B, et al. Significantly increased risk of all-cause mor-
tality among cardiac patients feeling lonely. Heart. 2020;106:140–
6.
25. 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;25:1387–
96.
26. Novak M, Waern M, Johansson L, Zettergren A, Ryden L,
Wetterberg H, et al. Cardiovascular and all-cause mortality attrib-
utable to loneliness in older Swedish men and women. BMC
Geriatr. 2020;20:201.
27. Kraav S-L, Awoyemi O, Junttila N, Vornanen R, Kauhanen J,
Toikko T, Lehto SM, Hantunen S, Tolmunen T (2020) The effects
of loneliness and social isolation on all-cause, injury, cancer, and
CVD mortality in a cohort of middle-aged Finnish men. A prospec-
tive study. Aging Mental Health 1–10
28.•Hodgson S, Watts I, Fraser S, Roderick P, Dambha-Miller H.
Loneliness, social isolation, cardiovascular disease and mortality:
a synthesis of the literature and conceptual framework. J R Soc
Med. 2020;113:185–92 Key article because it provides a frame-
work for mechanisms linking loneliness with cardiovascular
disease.
29. Xia N, Li H. Loneliness, social isolation, and cardiovascular health.
Antioxid Redox Signal. 2018;28:837–51.
30. Cacioppo S, Capitanio JP, Cacioppo JT. Toward a neurology of
loneliness. Psychol Bull. 2014;140:1464–504.
31. Eisenberger NI, Moieni M, Inagaki TK, Muscatell KA, Irwin MR.
In sickness and in health: the co-regulation of inflammation and
social behavior. Neuropsychopharmacology. 2017;42:242–53.
32.•Li H, Xia N. The role of oxidative stress in cardiovascular disease
caused by social isolation and loneliness. Redox Biol. 2020;37:
101585 Key article because it provides a framework for biolog-
ical mechanisms linking loneliness with cardiovascular disease.
33. Lee SL, Pearce E, Ajnakina O, Johnson S, Lewis G, Mann F,
Pitman A, Solmi F, Sommerlad A, Steptoe A (2020) The associa-
tion between loneliness and depressive symptoms among adults
aged 50 years and older: a 12-year population-based cohort study.
Lancet Psychiatry
34. Park C, Majeed A, Gill H, Tamura J, Ho RC, Mansur RB, et al. The
effect of loneliness on distinct health outcomes: a comprehensive
review and meta-analysis. Psychiatry Res. 2020;294:113514.
35. McClelland H, Evans JJ, Nowland R, Ferguson E, O’Connor RC.
Loneliness as a predictor of suicidal ideation and behaviour: a sys-
tematic review and meta-analysis of prospective studies. J Affect
Disord. 2020;274:880–96.
36. Domènech-Abella J, Mundó J, Haro JM, Rubio-Valera M. Anxiety,
depression, loneliness and social network in the elderly: longitudi-
nal associations from The Irish Longitudinal Study on Ageing
(TILDA). J Affect Disord. 2019;246:82–8.
37. Cacioppo JT, Hawkley LC, Crawford LE, Ernst JM, Burleson MH,
Kowalewski RB, et al. Loneliness and health: potential mecha-
nisms. Psychosom Med. 2002;64:407–17.
68 Page 6 of 7 Curr Cardiol Rep (2021) 23: 68
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
38. Hawkley LC, Burleson MH, Berntson GG, Cacioppo JT. Loneliness
in everyday life: cardiovascular activity, psychosocial context, and
health behaviors. J Pers Soc Psychol. 2003;85:105–20.
39. Hawkley LC, Cacioppo JT. Aging and loneliness: Downhill quick-
ly? Curr Dir Psychol Sci. 2007;16:187–91.
40. Kivimäki M, Steptoe A. Effects of stress on the development and
progression of cardiovascular disease. Nat Rev Cardiol. 2018;15:
215–29.
41. Whooley MA, Wong JM. Depression and cardiovascular disorders.
Ann Rev Clin Psychol. 2013;9:327–54.
42.•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
Key article because it provides a framework for mechanisms
linking loneliness with cardiovascular disease.
43. Brown EG, Gallagher S, Creaven AM. Loneliness and acute stress
reactivity: a systematic review of psychophysiological studies.
Psychophysiology. 2018;55:e13031.
44. Iob E, Steptoe A. Cardiovascular disease and hair cortisol: a novel
biomarker of chronic stress. Curr Cardiol Rep. 2019;21:116.
45. Doane LD, Adam EK. Loneliness and cortisol: momentary, day-to-
day, and trait associations. Psychoneuroendocrinology. 2010;35:
430–41.
46. Drake EC, Sladek MC, Doane LD. Daily cortisol activity, loneli-
ness, and coping efficacy in late adolescence: a longitudinal study
of the transition to college. Int J Behav Dev. 2016;40:334–45.
47. Edwards KM, Bosch JA, Engeland CG, Cacioppo JT, Marucha PT.
Elevated macrophage migration inhibitory factor (MIF) is associat-
ed with depressive symptoms, blunted cortisol reactivity to acute
stress, and lowered morning cortisol. Brain Behav Immun.
2010;24:1202–8.
48. Gevonden M, Booij J, van den Brink W, Heijtel D, van Os J, Selten
JP. Increased release of dopamine in thestriata of young adults with
hearing impairment and its relevance for the social defeat hypothe-
sis of schizophrenia. JAMA Psychiatry. 2014;71:1364–72.
49. Dantzer R, Kelley KW. Twenty years of research on cytokine-
induced sickness behavior. Brain Behav Immun. 2007;21:153–60.
50. Leschak CJ, Eisenberger NI. Two distinct immune pathways
linking social relationships with health: inflammatory and antiviral
processes. Psychosom Med. 2019;81:711–9.
51. Smith K, Gavey S, Ridell NE, Kontari P, Victor C. The association
between loneliness, social isolation and inflammation: a systematic
review and meta-analysis. Neurosci Biobehav Rev. 2020;112:519–41.
52. Osimo EF, Baxter LJ, Lewis G, Jones PB, Khandaker GM.
Prevalence of low-grade inflammation in depression: a systematic
review and meta-analysis of CRP levels. Psychol Med. 2019;49:
1958–70.
53. Vingeliene S, Hiyoshi A, Lentjes M, Fall K, Montgomery S.
Longitudinal analysis of loneliness and inflammation at older ages:
English longitudinal study of ageing. Psychoneuroendocrinology.
2019;110:104421.
54. Walker E, Ploubidis G, Fancourt D. Social engagement and loneli-
ness are differentially associated with neuro-immune markers in
older age: time-varying associations from the English
Longitudinal Study of Ageing. Brain Behav Immun. 2019;82:
224–9.
55. Cole SW, Capitanio JP, Chun K, Arevalo JM, Ma J, Cacioppo JT.
Myeloid differentiation architecture of leukocyte transcriptome dy-
namics in perceived social isolation. Proc Natl Acad Sci. 2015;112:
15142–7.
56. Roddick CM, Chen FS. Effects of chronic and state loneliness on
heart rate variability in women. Ann Behav Med. 2020. https://doi.
org/10.1093/abm/kaaa065.
57. Makris AP, Karianaki M, Tsamis KI, Paschou SA. The role of the
gut-brain axis in depression: endocrine, neural, and immune path-
ways. Hormones. 2020;20:1–12. https://doi.org/10.1007/s42000-
020-00236-4.
58. Witkowski M, Weeks TL, Hazen SL. Gut microbiota and cardio-
vascular disease. Circ Res. 2020;127:553–70.
59. Kazemian N, Mahmoudi M, Halperin F, Wu JC, Pakpour S. Gut
microbiota and cardiovascular disease: opportunities and chal-
lenges. Microbiome. 2020;8:36.
60. Spithoven W, Cacioppo S, Goossens L, Cacioppo JT. Genetic con-
tributions to loneliness and their relevance to the evolutionary the-
ory of loneliness. Perspect Psychol Sci. 2019;14:3.
61. Bludau A, Royer M, Meister G, Neumann ID, Menon R. Epigenetic
regulation of the social brain. Trends Neurosci. 2019;42:471–84.
62. Arzate-Mejia R, Lottenbach Z, Schindler V, Jawaid A, Mansuy I
(2020) Long-term impact of social isolation and molecular under-
pinnings. Front Gen
63. Cacioppo JT, Patrick W (2008) Loneliness: human nature and the
need for social connection. W W Norton & Co
64. Schrempft S, Jackowska M, Hamer M, Steptoe A. Associations
between social isolation, loneliness, and objective physical activity
in older men and women. BMC Public Health. 2019;19:74.
65. Leigh-Hunt N, Bagguley D, BashK, Turner V, Turnbull S, Valtorta
N, et al. An overview of systematic reviews on the public health
consequences of social isolation and loneliness. Public Health.
2017;152:157–71.
66. Wootton RE, Greenstone HS, Abdellaoui A, Denys D, Verweij KJ,
Munafò MR, Treur JL (2020) Bidirectional effects between loneli-
ness, smoking and alcohol use: evidence from a Mendelian ran-
domization study. Addiction
67. Canham SL, Mauro PM, Kaufmann CN, Sixsmith A. Association
of alcohol use and loneliness frequency among middle-aged and
older adult drinkers. J Aging Health. 2016;28:267–84.
68. Purser GL (2020) The combined effect of functional independence,
loneliness, and social engagement on older adult drinking levels. J
Soc Work Pract Addict 1–12
69. Segrin C, McNelis M, Pavlich CA. Indirect effects of loneliness on
substance use through stress. Health Commun. 2018;33:513–8.
70. Kobayashi LC, Steptoe A. Social isolation, loneliness, and health
behaviors at older ages: longitudinal cohort study.Ann Behav Med.
2018;52:582–93.
71. Hamer M, Poole L, Messerli-Bürgy N. Television viewing, C-
reactive protein, and depressive symptoms in older adults. Brain
Behav Immun. 2013;33:29–32.
72. Paolucci EM, Loukov D, Bowdish DM, Heisz JJ. Exercise reduces
depression and inflammation but intensity matters. Biol Psychol.
2018;133:79–84.
73. Gardiner C, Geldenhuys G, Gott M. Interventions to reduce social
isolation and loneliness among older people: an integrative review.
Health Soc Care Commun. 2018;26:147–57.
74. Bickerdike L, Booth A, Wilson PM, Farley K, Wright K. Social
prescribing: less rhetoric and more reality. A systematic review of
the evidence. BMJ Open. 2017;7:e013384.
75. Foster A, Thompson J, Holding E, Ariss S, Mukuria C, Jacques R,
et al. Impact of social prescribing to address loneliness: a mixed
methods evaluation of a national social prescribing programme.
Health Soc Care Commun. 2020. https://doi.org/10.1111/hsc.
13200.
Publisher’sNote Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.
Page 7 of 7 68Curr Cardiol Rep (2021) 23: 68
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com
