International Review of Psychiatry

ISSN: 0954-0261 (Print) 1369-1627 (Online) Journal homepage: http://www.tandfonline.com/loi/iirp20

Panic disorder and cardiovascular diseases: an

overview

Sergio Machado, Federica Sancassiani, Flavia Paes, Nuno Rocha, Eric Murillo-
Rodriguez & Antonio Egidio Nardi

To cite this article: Sergio Machado, Federica Sancassiani, Flavia Paes, Nuno Rocha, Eric
Murillo-Rodriguez & Antonio Egidio Nardi (2017): Panic disorder and cardiovascular diseases: an
overview, International Review of Psychiatry, DOI: 10.1080/09540261.2017.1357540

To link to this article: http://dx.doi.org/10.1080/09540261.2017.1357540

Published online: 12 Sep 2017.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=iirp20

Download by: [University of Calgary] Date: 14 September 2017, At: 06:17

 INTERNATIONAL REVIEW OF PSYCHIATRY, 2017
https://doi.org/10.1080/09540261.2017.1357540

REVIEW

Panic disorder and cardiovascular diseases: an overview

Sergio Machadoa,b,c, Federica Sancassianid, Flavia Paesb, Nuno Rochac,e, Eric Murillo-Rodriguezc,f,g and
Antonio Egidio Nardia
a
Physical Activity Neuroscience Laboratory, Salgado de Oliveira University (UNIVERSO), Niter
oi, RJ, Brazil; bLaboratory of Panic &
Respiration (LABPR), Institute of Psychiatry (IPUB), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil; cIntercontinental
Neuroscience Research Group; dDepartment of Public Health and Clinical and Molecular Medicine, University of Cagliari, Italy; eSchool
of Allied Health Sciences, Polytechnic Institute of Porto, Porto, Portugal; fLaboratorio de Neurociencias Moleculares e Integrativas,
Escuela de Medicina Divisi
on Ciencias de la Salud, Universidad An
ahuac Mayab, M
erida, Yucat
an, M
exico; gGrupo de Investigaci
on en
Envejecimiento, Divisi
on Ciencias de la Salud, Universidad An
ahuac Mayab, M
erida, Yucat
an, M
exico

ABSTRACT ARTICLE HISTORY

The association between panic disorder (PD) and cardiovascular diseases (CVD) has been exten- Received 9 February 2017
Downloaded by [University of Calgary] at 06:17 14 September 2017

sively studied in recent years and, although some studies have shown anxiety disorders co-exist- Revised 19 May 2017
ing or increasing the risk of heart disease, no causal hypothesis has been well established. Thus, Accepted 17 July 2017
a critical review was performed of the studies that evaluated the association between PD and
cardiovascular diseases; synthesizing the evidence on the mechanisms mediators that theoretic- KEYWORDS
ally would be the responsible for the causal pathway between PD and CVD, specifically. This Panic disorder;
overview shows epidemiological studies, and discusses biological mechanisms that could link PD cardiovascular disease;
to CVD, such as pleiotropy, heart rate variability, unhealthy lifestyle, atherosclerosis, mental pleiotropy; heart rate
stress, and myocardial perfusion defects. This study tried to provide a comprehensive narrative variability; unhealthy
synthesis of previously published information regarding PD and CVD and open new possibilities lifestyle and atherosclerosis
of clinical management and pathophysiological understanding. Some epidemiological studies
have indicated that PD could be a risk factor for CVD, raising morbidity and mortality in PD, sug-
gesting an association between them. These studies argue that PD pathophysiology could cause
or potentiate CVD. However, there is no evidence in favour of a causal relationship between PD
and CVD. Therefore, PD patients with suspicions of cardiovascular symptoms need redoubled
attention.

Introduction anxiety disorder has been shown to be strongly associ-

Mental illnesses have been commonly associated with
various physical and mental comorbidities (Seldenrijk
et al., 2015). Among mental illnesses, major depressive
disorder has been shown to be strongly related to
some anxiety disorder (Desouky, Abdellatif Ibrahem,
& Salah Omar, 2015), as well as to cardiovascular dis-
eases (Linke et al., 2009). Some evidence has shown
that depressive individuals, having a comorbid anxiety
disorder, have a strong association with some cardio-
vascular disease (Rutledge et al., 2009).
Among the various anxiety disorders, panic dis-
order (PD), according to the diagnostic guidelines of
the American Psychiatric Association, is one of the
most common anxiety disorders worldwide (Wittchen
et al., 2011), leading to disability (Baxter et al., 2014),
and to public health burden in terms of economic
costs (Coley, Saul, & Seybert, 2009). In general,
ated with some cardiovascular diseases such as high
risk of cardiovascular mortality, coronary artery dis-
ease, stroke, heart failure (Emdin et al., 2016), and
reduction in heart rate variability (HRV) (Chalmers,
Quintana, Abbott, & Kemp, 2014). However, anxiety
was not associated with some cardiovascular events
such as non-fatal myocardial infarction, non-fatal
stroke, non-fatal heart failure, and atrial fibrillation
(Emdin et al., 2016). In addition, only a few anxiety
disorders have been associated with some cardiovascu-
lar diseases, such as phobic anxiety being associated
with an increased risk of coronary heart disease and
post-traumatic stress disorder that was associated with
a stroke risk (Emdin et al., 2016). Specifically in
patients with PD, there is evidence of an association
of PD with cardiovascular disease (CVD) (Tully et al.,
2015), cardiomyopathies (Kahn et al., 1990), arrhyth-
mias, and reductions in HRV (Chalmers et al., 2014).

CONTACT Sergio Machado secm80@gmail.com Laboratory of Panic & Respiration (LABPR), Institute of Psychiatry (IPUB), Federal University of Rio
de Janeiro (UFRJ), Rio de Janeiro, Brazil
ß 2017 Institute of Psychiatry and Johns Hopkins University
 2 S. MACHADO ET AL.
Although the literature demonstrates a strong asso-
ciation of PD with cardiovascular diseases, these
results may be due to reverse causality, i.e. a serious
cardiovascular disease may develop greater anxiety
rather than anxiety provoke cardiovascular disease. In
addition, some factors, such as past manifestation of
PD, greater susceptibility to PD, agoraphobic state or
sub-clinic symptoms, seem to be relevant for the
development of CVD and consequent association with
PD (Caldirola et al., 2016). In addition to the clinical
condition of patients with PD, the qualifications of
the psychiatric diagnoses were highly heterogeneous
(Caldirola et al., 2016). Thus, despite substantial evi-
dence that PD is associated with incidents of cardio-
vascular disease, this causal association remains
unclear.
Downloaded by [University of Calgary] at 06:17 14 September 2017
PD patients generally describe a set of symptoms
overlapping those with CVD (Carmin, Ownby,
Wiegartz, & Kondos, 2008). However, PD patients
persevere in emergency rooms (Fleet & Beitman,
1997) and outpatient examinations due to chest pain
(Rutledge et al., 2001) regardless of negative results
from cardiological evaluation (Rohacek et al., 2012).
For Abed, Kloub, and Moser, (2014), in general, anx-
iety disorder is related to cardiovascular diseases,
being mediated by biological and environmental fac-
tors. Among the biological pathways, inflammation,
hyperlipidemia, hypercoagulation, increased sympa-
thetic activity, and decreased parasympathetic activity
were noted. Behavioural pathways are explained by
smoking, poor diet, obesity, inactive lifestyle, medica-
tion non-adherence, and poor enrollment in rehabili-
tation programmes. Esler (2017) supports the idea
that the sympathetic nervous system is the habitual
mediator between acute and chronic psychological
substrates and cardiovascular disease.
In line with this, the study aims to (1) perform a
critical review of the studies that evaluated the associ-
ation between PD and cardiovascular diseases; and (2)
synthesize the evidence on the mechanisms mediators
that theoretically would be the responsible for the
causal pathway between PD and CVD, specifically.
Methods
The present overview tries to provide a comprehen-
sive narrative synthesis of previously published infor-
mation regarding panic disorder and cardiovascular
diseases, including electronic or paper-based journal
articles, expert commentaries, and personal experience
in the field from the authors. It also critically dis-
cusses the state of the art on panic disorder and
cardiovascular diseases from a theoretical and context-
ual point of view.
An electronic search was performed in the data-
bases of PubMed/MEDLINE and Web of Science
(Web of Science Core Collection). The search was
completed using the key-words: ‘panic attack’, ‘panic
disorder’, ‘cardiovascular disease’, ‘coronary artery dis-
ease’, ‘coronary heart disease’, and ‘myocardial
ischemia’. Included papers and important reviews
regarding panic disorder and cardiovascular disease
were also manually screened for additional relevant
studies.
Results
Does PD predict poorer prognosis in established
CVD?
A large-scale community study showed a significant
relationship between PD and cardiac death (Kawachi,
Sparrow, Vokonas, & Weiss, 1994). Although the
authors observed this relationship between PD and
cardiac death, no significant association between PD
and myocardial infarction was revealed. Another
interesting finding revealed by the study is that mor-
tality was primarily due to sudden death, as the data
show, an increase of 3–6-times the risk of myocardial
ischemia and sudden death (Kawachi et al., 1994).
In addition, Coryell, Noyes, and Clancy, (1982), in
a retrospective study, tried to demonstrate the rela-
tionship between PD and increased risk of mortality
from CVD patients. They found that, after 35 years of
hospitalization, the mortality rate from CVD was
twice as high as expected for PD patients compared to
age, sex and length of hospital group.
Epidemiological studies
The increase in CVD prevalence in PD patients is
quite intriguing. According to the type of sample ana-
lysed, the rates of CVD comorbid in PD patients are
very high, at 15-times higher compared to healthy
individual rates (Young et al., 1987). Smoller et al.
(2007) published the first large-scale studies examin-
ing the association between panic attacks (PA) and
the incidence of CVD and mortality.
Smoller et al. (2007) examined 3369 women from
the Women’s Health Initiative (WHI), and found
that those with PA had 4.20-times (95%
CI ¼ 1.76–9.99) more risk of developing CVD and
dying from CVD than women without PA. The
main limitation of these studies is the fact that PAs
were evaluated instead of PD, which surely had little

or no impact on the external validity of the study.
In addition, male patients were not included and, in
relation to PD symptoms, several features that are
found in PD are found in patients with pre-clinical
CVDs. Therefore, it is reasonable that individuals,
when arriving for the first time in the emergency
room, are wrongly diagnosed as suffering a PA
because of the impreciseness of existing diagnostic
tools (Preter et al. 2011).
PD and CVD: is there an association?
In the year 1998, a critical review was conducted by
Fleet and Beitman (1998), where six studies were ana-
lysed to analyse an association between PD and car-
diovascular mortality. We used studies of prospective
and retrospective characteristics, suggesting a link
Downloaded by [University of Calgary] at 06:17 14 September 2017
between PD and cardiovascular death.
Later, again in a study led by Fleet, Lavoie, and
Beitman (2000), the focus of the study was to critic-
ally review the relationship between panic disorder
(PD) and CVD. The prevalence of PD in both cardiac
patients and patients with CVD varied from 10–50%.
Despite the results, the cause-and-effect relationship
was not well established, since PD was prevalent in
these patients with CVD, but not clarified to what
extent PD offers risk or causes some worsening in
CVD.
A meta-analysis conducted by Tully et al. (2015)
was used as the study population, only patients with
PD and patients diagnosed with PD with other associ-
ated anxiety comorbidities. However, this sample of
patients did not have any coronary artery disease
prior to PD. According to all the eligibility criteria, 12
articles were selected, totalling 1,131,612 people and
58,111 events of coronary artery disease. The results
indicated a 1.47-times higher risk ratio for coronary
artery disease in people with PD, and this value was
significant, even after the diagnosis of angina was
withdrawn. This risk was higher in women compared
to men, as the risk decreased with age. There was also
an association of PD with other adverse cardiovascu-
lar events, including death from coronary artery dis-
ease, ventricular fibrillation, sudden cardiac death,
and acute myocardial infarction (fatal or non-fatal).
In addition, the most common cardiovascular event
associated with PD (953,888 patients) was myocardial
infarction (18,541), and was found in six studies.
However, despite the results demonstrated, the reverse
causality cannot be ruled out. There was evidence of
great heterogeneity in outcomes for the following fac-
tors: socioeconomic status, diabetes, and disease fol-
low-up time.
INTERNATIONAL REVIEW OF PSYCHIATRY 3
In research conducted by Fleet et al. (2000), it was
suggested that there is a PD association and a reduc-
tion in heart rate variability (HRV), being a possible
mechanism related to CVD. This possible association
between PD and reduction in HRV was investigated
by Chalmers et al. (2014), where patients with anxiety
disorder were used as a population, including patients
with PD. In general, patients with PD (n ¼ 447) pre-
sented reductions in HRV in relation to the control
group.
Out of 35 patients with panic disorder and 35
healthy subjects, eight patients and one healthy sub-
ject had a higher rate of myocardial changes, includ-
ing left ventricular enlargement. There was an
increase in ventricular myocardial mass in seven
patients with panic disorder. Consistent with an asso-
ciation between PD and idiopathic dilated cardiomy-
opathy, this study suggests that some patients with a
panic disorder may have sub-clinical myocardial
changes (Kahn et al., 1990).
Different anxiety disorders were associated with a
high risk of different cardiovascular events, such as
stroke, coronary heart disease, heart failure, and car-
diovascular death (Emdin et al., 2016). However, anx-
iety was not associated with atrial fibrillation. In
addition, the type of anxiety also directly impacted
the outcome of association with cardiovascular dis-
ease. For example, phobic anxiety was associated with
a higher risk of coronary heart disease than other
anxiety disorders, and post-traumatic stress disorder
was associated with an increased risk of stroke. Thus,
the type of anxiety may present different results of
association with cardiovascular diseases.
A study examined the impact of three different
anxiety disorders (panic, social phobia and agorapho-
bia, generalized anxiety) on the appearance of non-
fatal cardiovascular disease (CVD) (Batelaan, ten
Have, van Balkom, Tuithof, & de Graaf, 2014).
During a 3-year follow-up, 62 people (1.2%) devel-
oped CVD. Basal generalized anxiety disorder was
strongly associated with the onset of cardiovascular
disease (adjusted odds ratio ¼3.39). The authors sug-
gest that further research should focus on the bio-
logical foundations of this association to further
elucidate this major association with generalized anx-
iety disorder.
At this moment, the association between PD and
CVD is unclear. However, some studies propose
pathophysiological mechanisms that supposedly would
connect them. In general, anxiety disorder is related
to cardiovascular diseases, being mediated by bio-
logical and environmental factors. Among the
 4 S. MACHADO ET AL.
biological pathways, inflammation, hyperlipidemia,
hypercoagulation, increased sympathetic activity, and
decreased parasympathetic activity were noted.
Behavioural pathways are explained by smoking, poor
diet, obesity, inactive lifestyle, medication non-adher-
ence, and poor enrolment in rehabilitation pro-
grammes (Abed et al., 2014). In line with this, we will
discuss the main mediators that theoretically would be
responsible for the causal pathway between PD and
CVD, specifically; pleiotropy, chronic changes in heart
rate variability (HRV), unhealthy lifestyle, and
atherosclerosis.
Pleiotropy
Pleiotropy refers to the phenomenon in genetics
whereby a DNA variant influences two or more seem-
Downloaded by [University of Calgary] at 06:17 14 September 2017
ingly unrelated phenotypic traits (Hughes & Leips,
2017). This phenomenon deals with a mutation in a
pleiotropic gene that often presents a specific effect
on several traits simultaneously due to the gene cod-
ing for a product used by a set of cells or different
targets that have the same signalling function (Hall,
Moore, & Ritchie, 2016). According to the findings
from a recent transcriptome study published by
Gormanns et al. (2011), where important changes in
the enzymatic activity related to glycolysis and vascu-
lar growth/modelling were observed in anxious
patients, we hypothesize that there is a common
underlying genetic vulnerability between PD and
CVD, which could explain part of this association.
Chronic changes in heart rate variability
It is well known that the reduction of vagal tonus
activity is one of the main risk factors for increased
mortality (Fatisson, Oswald, & Lalonde, 2016). The
decrease in heart rate variability (HRV), a major
marker for vagal tone, is an important prognostic fac-
tor for the development of cardiac events in CVD
individuals (Bigger et al., 1992; Pipilis, Flather,
Ormerod, & Sleight, 1991). This decrease in HRV is
also known as ‘autonomic inflexibility’, since it seems
to indicate the inability of higher cortical structures,
such as the prefrontal cortex, to inhibit inferior areas,
such as the amygdala. The increased mortality of
patients with reduced HRV was observed in different
settings, such as intensive care units and emergency
rooms, when compared with controls without com-
promising vagal activity (Peterson, Krzyzaniak,
Coimbra, & Chang, 2012; Pontet et al., 2003).
In addition, the study of Pittig, Arch, Lam, and
Craske, (2013) revealed that, when compared to
healthy individuals, PD patients showed reduced
HRV. In another interesting study, Diveky et al.
(2013) observed that cognitive-behavioural therapy
(CBT) led to an increase in HRV in PD patients com-
pared to controls. Although the findings are still pre-
liminary, the evidence indicates autonomic
inflexibility as a possible mediating factor of the rela-
tionship between PD and CVD.
Unhealthy lifestyle
A prevalence of 45.8% of PD individuals with very
low levels of physical activity was observed in an epi-
demiological study (Smoller et al., 2007), which has
previously been observed in the literature (de Mello
et al., 2013; de Souza Moura et al., 2015; Wegner
et al., 2014). However, there is no evidence on
whether this relationship is causal (Wegner et al.,
2014). It is known that different benefits are observed
through different exercise protocols in PD (Broocks
et al., 1998). For example, with aerobic training, sev-
eral physiological mechanisms are exacerbated, such
as HR, breathing, sweating, among others, which jus-
tify the decrease of PA. This is due to the fact that
the avoidance of threatening interoceptive stimuli is a
hallmark of PD.
Recently, the study conducted by Belem da Silva,
Schuch, Costa, Hirakata, and Manfro, (2014) revealed
similar findings to those described above, suggesting
that PD patients and higher symptomatic symptoms
present lower levels of PA. Nevertheless, it is still
unclear whether there is a common trait between PD
and low levels of PA, and whether this possible trait
could lead to the cause of the lower levels of PA and
the latter development of PD in life. In addition, PD
is also associated with other unhealthy lifestyles, such
as smoking (Mojtabai & Crum, 2013) and overweight
(Smith et al., 2013). Thus, the variability in the associ-
ation between PD and CVD is due to risk factors con-
trol and reduction in magnitude. Therefore, unhealthy
lifestyles seem to be partially responsible for the rela-
tionship between PD and DCV.
Atherosclerosis
Atherosclerosis is an inflammatory process in vascular
endothelium that is responsible for the development
of CVD. Prospective studies revealed an association
between increased anxiety symptoms and poor vascu-
lar health at rest. Paterniti et al. (2001) showed that
PD patients with higher scores of state and trait anx-
iety (Spielberger, 1989) had increased intima-media
thickness (IMT) 4 years later. In line with this, Belem

da Silva et al. (2015) reported a positive association
between anxiety symptoms (Hamilton, 1959) and a
worse flow mediated dilation (%FMD) examined by 8
years later in PD patients with no history of prior
CVD. Although many people received a PD diagnosis
throughout life, no significant differences in FMD
were found between remitted vs current PD patients.
Otherwise, Cicek et al. (2012) demonstrated a positive
cross-sectional association between PD and changes in
pulse-wave velocity (PWV). Thus, atherosclerosis can
be considered a factor responsible for CVD develop-
ment in PD patients without history of CVD.
However, the way the symptoms are examined (e.g.
cross-sectionally vs longitudinally; using symptom
scales vs diagnostic scales) seems to influence results.
Using HAMA scale, for example, it is possible to sig-
nal sub-clinical CVD symptoms. Intriguingly,
Downloaded by [University of Calgary] at 06:17 14 September 2017
Stillman, Moser, Fiedorowicz, Robinson, and Haynes,
(2013) observed that infarcted patients with high lev-
els of anxiety had increased atherosclerosis compared
to those with low levels of anxiety. These results sug-
gest a possible role for the relationship between pre-
existing cardiovascular diseases, such as forearm
resistance vessels, and anxiety symptoms in general.
In an interesting case series, Soares-Filho et al. (2014)
demonstrated in patients with PD and without CVD
that the only case that presented SPECT perfusion
defects after 35% CO2 inhalation occurred in an indi-
vidual who did not report a panic attack (PA). Some
possible pathophysiological mechanisms are discussed,
such as perfusion defects induced by startle response,
a redistribution of blood flow in response to a CO2-
induced vasodilatation in certain coronary vessels and
a decreased tendency of PD-free individuals to refer
PD-like symptoms. A myriad of factors are suggested,
such as pre-existing atherosclerosis, adrenergic reactiv-
ity, and altered interoception (i.e. the ability to detect
our own bodily physiological changes) interact for the
genesis of CVD in individuals pre-disposed with PD.
Mental stress
Mental stress occurs when a person is influenced by
external stimuli, leading to a mental/emotional imbal-
ance, where the demands of a situation are seen as
exceeding the personal resources that the individual
can bring about them at that moment (Jiang et al.,
1996). Literature suggests that PA is more strong than
a mental stress test, and it seems that PA induces true
ischemia in CVD patients. PA leads to an intense sym-
pathetic cardiac activation and increased adrenaline
secretion from 2–6-times the normal value. Another
way of sympathetic activation may happen during
INTERNATIONAL REVIEW OF PSYCHIATRY 5
neuropeptide Y (NPY) release of the cardiac sympa-
thetic nerve in the coronary sinus, which could be
associated with coronary vasospasm (Esler et al., 2004).
Studies have shown that mental stress-induced
ischemia is linked to several factors, such as fatal and
non-fatal cardiac events, age, baseline ejection frac-
tion, and left ventricular myocardial infarction (Jiang
et al., 1996). The authors observed that mental stress-
induced ischemia is a reliable predictor for cardiac
events compared with exercise stress test. On the
other hand, PD could be considered a spontaneous
‘mental stressor’, like a mental stress test. Thus, due
to sympathetically-mediated increases in heart rate
(HR), blood pressure (BP), and ventricular contractil-
ity during PAs, an increase in myocardial O2 demand
is observed, probably leading to myocardial ischemia
(Hickam, Cargill, & Golden, 1948). In contrast, Fleet
et al. (2014) compared CVD patients with and with-
out PD and normal exercise stress test and showed
that CO2-induced panic was not associated with
induced myocardial ischemia, and other mechanisms,
such as vasospasm or a reduction in coronary flow,
seem to be involved (Loures, Sant Anna, Baldotto,
Sousa, & Nobrega, 2002). Other studies propose that
ischemia induced by mental stress could be associated
with endothelial dysfunction in atherosclerotic vessels,
limiting coronary vasodilatation during mental stress.
During mental stress, atherosclerotic arteries fail to
dilate, probably in response to changes in the activa-
tion of a2 and sz2 adrenoceptor and increased release
of noradrenaline, which induces muscle contraction of
a patient’s arteries (Dakak, Quyyumi, Eisenhofer,
Goldstein, & Cannon, 1995; Krantz, Kop, Santiago, &
Gottdiener, 1996).
Myocardial perfusion defects
Regarding myocardial perfusion defects, the classic
study of Fleet et al. (2005) demonstrated that a pos-
sible myocardial ischemia triggered by an induced PA
was provoked in CVD patients who inhaled 35% car-
bon dioxide (CO2). They found that, in patients who
had PA, 80.9% presented myocardial perfusion
defects, in contrast to patients who did not have PA,
with 46.4% of myocardial perfusion defects. All
patients used medications to CVD control; however,
results still demonstrate that PAs can induce myocar-
dial perfusion defects.
Final considerations
Our review tried to provide a comprehensive narrative
synthesis of previously published information
 6 S. MACHADO ET AL.
regarding PD and CVD and open new possibilities of
clinical management and pathophysiological under-
standing. Some epidemiological studies have indicated
that PD could be a risk factor for CVD, raising
morbidity and mortality in PD, and suggesting an
association between them (O'Connor et al., 2010;
Soares-Filho et al., 2014). These studies argue that PD
pathophysiology could cause or potentiate CVD
(Atmaca, Yavuzkir, Izci, Gurok, & Adiyaman, 2012;
Baumert et al., 2009; Broocks et al., 1998; Diveky
et al., 2012; Klein, Cnaani, Harel, Braun, & Ben-Haim,
1995; Martinez, Garakani, Kaufmann, Aaronson, &
Gorman, 2010; McCraty, Atkinson, Tomasino, &
Stuppy, 2001; Soares-Filho et al., 2012; Tanabe,
Harada, Sugihara, Ogawa, & Inoue, 2004; Yeragani,
Pohl, Balon, Jampala, & Jayaraman, 2002; Yeragani
Downloaded by [University of Calgary] at 06:17 14 September 2017
et al., 1993; Yeragani et al., 2000). However, there is
no evidence in favour of a causal relationship between
PD and CVD. Therefore, PD patients with suspicions
of cardiovascular symptoms need redoubled attention.
In line with this, cardiologists must be trained to
identify PD patients and offer them appropriate treat-
ment. In addition, there is a need for further longitu-
dinal studies, including survival curve measures or, in
the absence of any feasible randomization, accurate
Cox regression models.
Disclosure statement
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the
paper.
References
Abed, M. A., Kloub, M. I., & Moser, D. K. (2014). Anxiety
and adverse health outcomes among cardiac patients: A
biobehavioral model. The Journal of Cardiovascular
Nursing, 29, 354–363. doi:10.1097/JCN.0b013e318292b235
Atmaca, M., Yavuzkir, M., Izci, F., Gurok, M. G., &
Adiyaman, S. (2012). QT wave dispersion in patients
with panic disorder. Neuroscience Bulletin, 28, 247–252.
doi:10.1007/s12264-012-1237-3
Batelaan, N. M., ten Have, M., van Balkom, A. J., Tuithof,
M., & de Graaf, R. (2014). Anxiety disorders and onset
of cardiovascular disease: The differential impact of
panic, phobias and worry. Journal of Anxiety Disorders,
28, 252–258. doi:10.1016/j.janxdis.2013.12.003
Baumert, M., Lambert, G. W., Dawood, T., Lambert, E. A.,
Esler, M. D., McGrane, M., … Nalivaiko, E. (2009).
Short-term heart rate variability and cardiac norepineph-
rine spillover in patients with depression and panic dis-
order. American Journal of Physiology. Heart and
Circulatory Physiology, 297, H674–H679. doi:10.1152/
ajpheart.00236.2009
Baxter, A. J., Scott, K. M., Ferrari, A. J., Norman, R. E.,
Vos, T., & Whiteford, H. A. (2014). Challenging the
myth of an “epidemic” of common mental disorders:
Trends in the global prevalence of anxiety and depression
between 1990 and 2010. Depression and Anxiety, 31,
506–516. doi:10.1002/da.22230
Belem da Silva, C. T., Schuch, F., Costa, M., Hirakata, V., &
Manfro, G. G. (2014). Somatic, but not cognitive, symp-
toms of anxiety predict lower levels of physical activity in
panic disorder patients. Journal of Affective Disorders,
164, 63–68. doi:10.1016/j.jad.2014.04.007
Belem da Silva, C. T., Vargas da Silva, A. M., Costa, M.,
Sant'anna, R. T., Heldt, E., & Manfro, G. G. (2015).
Increased anxiety levels predict a worse endothelial func-
tion in patients with lifetime panic disorder: Results from
a naturalistic follow-up study. International Journal of
Cardiology, 179, 390–392. doi:10.1016/j.ijcard.2014.10.170
Bigger, J. T., Fleiss, J. L., Steinman, R. C., Rolnitzky, L. M.,
Kleiger, R. E., & Rottman, J. N. (1992). Frequency
domain measure of heart period variability and mortality
after myocardial infarction. Circulation, 85, 164–171.
doi:10.1161/01.CIR.85.1.164
Broocks, A., Bandelow, B., Pekrun, G., George, A., Meyer,
T., Bartmann, U., … Ruther, E. (1998). Comparison of
aerobic exercise, clomipramine, and placebo in the treat-
ment of panic disorder. The American Journal of
Psychiatry, 155, 603–609. doi:10.1176/ajp.155.5.603
Caldirola, D., Schruers, K. R., Nardi, A. E., De Berardis, D.,
Fornaro, M., & Perna, G. (2016). Is there cardiac risk in
panic disorder? An updated systematic review. Journal of
Affect Disorders, 194, 38–49. doi:10.1016/j.jad.2016.01.003
Carmin, C. N., Ownby, R. L., Wiegartz, P. S., & Kondos,
G. T. (2008). Women and non-cardiac chest pain:
Gender differences in symptom presentation. Archives of
Women’s Mental Health, 11, 287–293. doi:10.1007/
s00737-008-0021-x
Chalmers, J. A., Quintana, D. S., Abbott, M. J., & Kemp,
A. H. (2014). Anxiety disorders are associated with
reduced heart rate variability: A meta-analysis. Frontiers
in Psychiatry, 5, 80. doi:10.3389/fpsyt.2014.00080
Cicek, Y., Durakoglugil, M. E., Kocaman, S. A., Guveli, H.,
Cetin, M., Erdogan, T., … Canga, A. (2012). Increased
pulse wave velocity in patients with panic disorder:
Independent vascular influence of panic disorder on
arterial stiffness. Journal of Psychosomatic Research, 73,
145–148. doi:10.1016/j.jpsychores.2012.05.012
Coley, K. C., Saul, M. I., & Seybert, A. L. (2009). Economic
burden of not recognizing panic disorder in the emer-
gency department. The Journal of Emergency Medicine,
36, 3–7. doi:10.1016/j.jemermed.2007.06.002
Coryell, W., Noyes, R., & Clancy, J. (1982). Excess mortality
in panic disorder. A Comparison with Primary Unipolar
Depression. Archives of General Psychiatry, 39, 701–703.
doi:10.1001/archpsyc.1982.04290060051010
Dakak, N., Quyyumi, A. A., Eisenhofer, G., Goldstein, D. S.,
& Cannon, R.O. 3rd. (1995). Sympathetically mediated
effects of mental stress on the cardiac microcirculation of
patients with coronary artery disease. The American
Journal of Cardiology, 76, 125–130. doi:10.1016/S0002-
9149(99)80043-5
de Mello, M. T., Lemos, V. A., Antunes, H. K., Bittencourt,
L., Santos-Silva, R., & Tufik, S. (2013). Relationship

between physical activity and depression and anxiety
symptoms: A population study. Journal of Affective
Disorders, 141, 241–246. doi:10.1016/j.jad.2013.01.035
de Souza Moura, A. M., Lamego, M. K., Paes, F., Ferreira
Rocha, N. B., Simoes-Silva, V., Rocha, S. A., …
Machado, S. (2015). Effects of aerobic exercise on anxiety
disorders: A systematic review. CNS & Neurological
Disorders Drug Targets, 14, 1184–1193. doi:10.2174/
1871527315666151111121259
Desouky, D.-S., Abdellatif Ibrahem, R., & Salah Omar, M.
(2015). Prevalence and comorbidity of depression, anxiety
and obsessive compulsive disorders among Saudi second-
ary school girls, Taif Area, KSA. Archives of Iranian
Medicine, 18, 234–238. doi:015184/AIM.008
Diveky, T., Prasko, J., Kamaradova, D., Grambal, A.,
Latalova, K., Silhan, P., … Tonhajzerova, I. (2013).
Comparison of heart rate variability in patients with
panic disorder during cognitive behavioral therapy pro-
gram. Psychiatria Danubina, 25, 62–67.
Downloaded by [University of Calgary] at 06:17 14 September 2017
Diveky, T., Prasko, J., Latalova, K., Grambal, A.,
Kamaradova, D., Silhan, P., … Tonhajzerova, I. (2012).
Heart rate variability spectral analysis in patients with
panic disorder compared with healthy controls. Neuro
Endocrinology Letters, 33, 156–166.
Emdin, C. A., Odutayo, A., Wong, C. X., Tran, J., Hsiao,
A. J., & Hunn, B. H. (2016). Meta-analysis of anxiety as a
risk factor for cardiovascular disease. The American
Journal of Cardiology, 118, 511–519. doi:10.1016/
j.amjcard.2016.05.041
Esler, M. (2017). Mental stress and human cardiovascular
disease. Neuroscience and Biobehavioral Reviews, 74,
269–276. doi:10.1016/j.neubiorev.2016.10.011
Esler, M., Alvarenga, M., Lambert, G., Kaye, D., Hastings,
J., Jennings, G., … Richards, J. (2004). Cardiac sympa-
thetic nerve biology and brain monoamine turnover in
panic disorder. Annals of the New York Academy of
Sciences, 1018, 505–514. doi:10.1196/annals.1296.062
Fatisson, J., Oswald, V., & Lalonde, F. (2016). Influence dia-
gram of physiological and enviromental factors affecting
heart rate variability: An extended literature review.
Heart International, 11, e32–e40. doi:10.5301/
heartint.5000232
Fleet, R. P., & Beitman, B. D. (1997). Unexplained chest
pain: When is it panic disorder? Clinical Cardiology, 20,
187–194. doi:10.1002/clc.4960200303
Fleet, R. P., & Beitman, B. D. (1998). Cardiovascular death
from panic disorder and panic-like anxiety: A critical
review of the literature. Journal of Psychosomatic
Research, 44, 71–80. doi:10.1016/S0022-3999(97)00135-9
Fleet, R., Foldes-Busque, G., Gregoire, J., Harel, F., Laurin,
C., Burelle, D., & Lavoie, K. (2014). A study of myocar-
dial perfusion in patients with panic disorder and low
risk coronary artery disease after 35% CO2 challenge.
Journal of Psychosomatic Research, 76, 41–45.
doi:10.1016/j.jpsychores.2013.08.003
Fleet, R., Lavoie, K., & Beitman, B. D. (2000). Is panic dis-
order associated with coronary artery disease? A critical
review of the literature. Journal of Psychosomatic Research,
48, 347–356. doi:10.1016/S0022-3999(99)00101-4
Fleet, R., Lesperance, F., Arsenault, A., Gregoire, J., Lavoie,
K., Laurin, C., … Frasure-Smith, N. (2005). Myocardial
perfusion study of panic attacks in patients with coronary
INTERNATIONAL REVIEW OF PSYCHIATRY 7
artery disease. The Amercian Journal of Cardiology, 96,
1064–1068. doi:10.1016/j.amjcard.2005.06.035
Gormanns, P., Mueller, N. S., Ditzen, C., Wolf, S.,
Holsboer, F., & Turck, C. W. (2011). Phenome-transcrip-
tome correlation unravels anxiety and depression related
pathways. Journal of Psychiatric Research, 45, 973–979.
doi:10.1016/j.jpsychires.2010.12.010
Hall, M. A., Moore, J. H., & Ritchie, M. D. (2016).
Embracing complex associations in common traits:
Critical considerations for precision medicine. Trends in
Genetics: TIG, 32, 470–484. doi:10.1016/j.tig.2016.06.001
Hamilton, M. (1959). The assessment of anxiety states by
rating. The British Journal of Medical Psychology, 32,
50–55. doi:10.1111/j.2044-8341.1959.tb00467.x
Hickam, J. B., Cargill, W. H., & Golden, A. (1948).
Cardiovascular reactions to emotional stimuli. Effect
on the cardiac output, arteriovenous oxygen differ-
ence, arterial pressure, and peripheral resistance. The
Journal of Clinical Investigation, 27, 290–298.
doi:10.1172/JCI101946
Hughes, K. A., & Leips, J. (2017). Pleiotropy, constraint,
and modularity in the evolution of life histories: Insights
from genomic analyses. Annals of the New York Academy
of Sciences, 1389, 76–91. doi:10.1111/nyas.13256
Jiang, W., Babyak, M., Krantz, D. S., Waugh, R. A.,
Coleman, R. E., Hanson, M. M., … Blumenthal, J. A.
(1996). Mental stress-induced myocardial ischemia and
cardiac events. JAMA, 275, 1651–1656. doi:10.1001/
jama.1996.03530450041030
Kahn, J. P., Gorman, J. M., King, D. L., Fyer, A. J.,
Liebowitz, M. R., & Klein, D. F. (1990). Cardiac left ven-
tricular hypertrophy and chamber dilatation in panic dis-
order patients: Implications for idiopathic dilated
cardiomyopathy. Psychiatry Research, 32, 55–61.
doi:10.1016/0165-1781(90)90135-R
Krantz, D. S., Kop, W. J., Santiago, H. T., & Gottdiener,
J. S. (1996). Mental stress as a trigger of myocardial
ischemia and infarction. Cardiology Clinics, 14, 271–287.
doi:10.1016/S0733-8651(05)70280-0
Kawachi, I., Sparrow, D., Vokonas, P. S., & Weiss, S. T.
(1994). Symptoms of anxiety and risk of coronary heart
disease. The Normative Aging Study. Circulation, 90,
2225–2229. doi:10.1161/01.CIR.90.5.2225
Klein, E., Cnaani, E., Harel, T., Braun, S., & Ben-Haim,
S. A. (1995). Altered heart rate variability in panic dis-
order patients. Biological Psychiatry, 37, 18–24.
doi:10.1016/0006-3223(94)00130-U
Linke, S. E., Rutledge, T., Johnson, B. D., Vaccarino, V.,
Bittner, V., Cornell, C. E., … Bairey Merz, C. N.
(2009). Depressive symptom dimensions and cardiovas-
cular prognosis among women with suspected myocar-
dial ischemia: A report from the National Heart,
Lung, and Blood Institute-sponsored Women's
Ischemia Syndrome Evaluation. Archives of General
Psychiatry, 66, 499–507. doi:10.1001/
archgenpsychiatry.2009.27
Loures, D. L., Sant Anna, I., Baldotto, C. S., Sousa, E. B., &
Nobrega, A. C. (2002). Mental stress and cardiovascular
system. Arquivos Brasileiro De Cardiologia, 78, 525–530.
doi:10.1590/S0066-782X2002000500012
Martinez, J. M., Garakani, A., Kaufmann, H., Aaronson,
C. J., & Gorman, J. M. (2010). Heart rate and blood
 8 S. MACHADO ET AL.
pressure changes during autonomic nervous system chal-
lenge in panic disorder patients. Psychosomatic Medicine,
72, 442–449. doi:10.1097/PSY.0b013e3181d972c2
McCraty, R., Atkinson, M., Tomasino, D., & Stuppy, W. P.
(2001). Analysis of twenty-four hour heart rate variability
in patients with panic disorder. Biological Psychology, 56,
131–150. doi:10.1016/S0301-0511(01)00074-6
Mojtabai, R., & Crum, R. M. (2013). Cigarette smoking and
onset of mood and anxiety disorders. American Journal
of Public Health, 103, 1656–1665. doi:10.2105/
AJPH.2012.300911
O'Connor, C. M., Jiang, W., Kuchibhatla, M., Silva, S. G.,
Cuffe, M. S., Callwood, D. D., … Krishnan, R. (2010).
Safety and efficacy of sertraline for depression in patients
with heart failure: Results of the SADHART-CHF
(Sertraline Against Depression and Heart Disease in
Chronic Heart Failure) trial. Journal of the American
College of Cardiology, 56, 692–699. doi:10.1016/
j.jacc.2010.03.068
Downloaded by [University of Calgary] at 06:17 14 September 2017
Paterniti, S., Zureik, M., Ducimetiere, P., Touboul, P., Feve,
J., & Alp
erovitch, A. (2001). Sustained anxiety and 4-year
progression of carotid atherosclerosis. Arteriosclerosis,
Thrombosis, and Vascular Biology, 21, 136–141.
doi:10.1161/01.ATV.21.1.136
Peterson, C. Y., Krzyzaniak, M., Coimbra, R., & Chang,
D. C. (2012). Vagus nerve and postinjury inflamatory
response. Archives of Surgery, 147, 76–80. doi:10.1001/
archsurg.2011.237
Pipilis, A., Flather, M., Ormerod, O., & Sleight, P. (1991).
Heart rate variability in acute myocardial infarction and
its association with infarct site and clinical course. The
American Journal of Cardiology, 67, 1137–1139.
doi:10.1016/0002-9149(91)90880-T
Pittig, A., Arch, J. J., Lam, C.W.R., & Craske, M. G. (2013).
Heart rate and heart rate variability in panic, social anx-
iety, obsessive–compulsive, and generalized anxiety disor-
ders at baseline and in response to relaxation and
hyperventilation. International Journal of
Psychophysiology: Official Journal of the International
Organization of Psychophysiology, 87, 19–27. doi:10.1016/
j.ijpsycho.2012.10.012
Pontet, J., Contreras, P., Curbelo, A., Medina, J., Noveri, S.,
Bentancourt, S., & Migliaro, E. R. (2003). Heart rate vari-
ability as early marker of multiple organ dysfunction syn-
drome in septic patients. Journal of Critical Care, 18,
156–163. doi:10.1016/j.jcrc.2003.08.005
Preter, M., Lee, S. H., Petkova, E., Vannucci, M., Kim, S., &
Klein, D. F. (2011). Controlled cross-over study in nor-
mal subjects of naloxone-preceding-lactate infusions;
respiratory and subjective responses: Relationship to
endogenous opioid system, suffocation false alarm theory
and childhood parental loss. Psychological Medicine, 41,
385–393. doi:10.1017/S0033291710000838
Rohacek, M., Bertolotti, A., Gr€ utzm€uller, N., Simmen, U.,
Marty, H., Zimmermann, H., … Spyridon, A. (2012).
The challenge of triaging chest pain patients: The bernese
university hospital experience. Emergency Medicine
International, 2012, 975614. doi:10.1155/2012/975614
Rutledge, T., Linke, S. E., Krantz, D. S., Johnson, B. D.,
Bittner, V., Eastwood, J. A., … Merz, C. N. (2009).
Comorbid depression and anxiety symptoms as predic-
tors of cardiovascular events: Results from the NHLBI-
sponsored Women's Ischemia Syndrome Evaluation
(WISE) study. Psychosomatic Medicine, 71, 958–964.
doi:10.1097/PSY.0b013e3181bd6062
Rutledge, T., Reis, S. E., Olson, M., Owens, J., Kelsey, S. F.,
Pepine, C. J. … Women’s Ischemia Syndrome Evaluation
(WISE). (2001). History of anxiety disorders is associated
with a decreased likelihood of angiographic coronary
artery disease in women with chest pain: The WISE study.
Journal of the American College of Cardiology, 37, 780–785.
doi:10.1016/S0735-1097(00)01163-3
Seldenrijk, A., Vogelzangs, N., Batelaan, N. M., Wieman, I.,
van Schaik, D. J., & Penninx, B. J. (2015). Depression,
anxiety and 6-year risk of cardiovascular disease. Journal
Psychosomatic Research, 78, 123–129. doi:10.1016/
j.jpsychores.2014.10.007
Smith, K. J., B
eland, M., Clyde, M., Gari
epy, G., Pag
e, V.,
Badawi, G., … Schmitz, N. (2013). Association of dia-
betes with anxiety: A systematic review and meta-ana-
lysis. Journal of Psychosomatic Research, 74, 89–99.
doi:10.1016/j.jpsychores.2012.11.013
Smoller, J. W., Pollack, M. H., Wassertheil-Smoller, S.,
Jackson, R. D., Oberman, A., Wong, N. D., & Sheps, D.
(2007). Panic attacks and risk of incident cardiovascular
events among postmenopausal women in the Women’s
Health Initiative Observational Study. Archives of General
Psychiatry, 64, 1153–1160. doi:10.1001/archpsyc.64.10.1153
Soares-Filho, G. L., Machado, S., Arias-Carri
on, O., Santulli,
G., Mesquita, C. T., Cosci, F., … Nardi, A. E. (2014).
Myocardial perfusion imaging study of CO2-induced
panic attack. The American Journal of Cardiology, 113,
384–388. doi:10.1016/j.amjcard.2013.09.035
Soares-Filho, G.L.F., Mesquita, C. T., Mesquita, E. T., Arias-
Carri
on, O., Machado, S., Gonz
alez, M. M., … Nardi,
A. E. (2012). Panic attack triggering myocardial ischemia
documented by myocardial perfusion imaging study. A
case report. International Archives of Medicine, 5, 24.
doi:10.1186/1755-7682-5-24
Spielberger, C. D. (1989). State-trait anxiety inventory: bibli-
ography (2th ed.). Palo Alto, CA: Consulting
Psychologists Press.
Stillman, A. N., Moser, D. J., Fiedorowicz, J., Robinson,
H. M., & Haynes, W. G. (2013). Association of anxiety
with resistance vessel dysfunction in human atheroscler-
osis. Psychosomatic Medicine, 75, 537–544. doi:10.1097/
PSY.0b013e31829a0ae3
Tanabe, Y., Harada, H., Sugihara, S., Ogawa, T., & Inoue,
Y. (2004). 123I-Metaiodobenzylguanidine myocardial
scintigraphy in panic disorder. Journal of Nuclear
Medicine: Official Publication, Society of Nuclear
Medicine, 45, 1305–1308.
Tully, P. J., Turnbull, D. A., Beltrame, J., Horowitz, J.,
Cosh, S., Baumeister, H., & Wittert, G. A. (2015). Panic
disorder and incident coronary heart disease: a systematic
review and meta-regression in 1131612 persons and
58111 cardiac events. Psychological Medicine, 45,
2909–2920. doi:10.1017/S0033291715000963
Wegner, M., Helmich, I., Machado, S., Nardi, A. E., Arias-
Carrion, O., & Budde, H. (2014). Effects of exercise on
anxiety and depression disorders: Review of meta-analy-
ses and neurobiological mechanisms. CNS & Neurological
Disorders Drug Targets, 13, 1002–1014. doi:10.2174/
1871527313666140612102841

Wittchen, H. U., Jacobi, F., Rehm, J., Gustafsson, A.,
Svensson, M., J€onsson, B., … Steinhausen, H. C. (2011).
The size and burden of mental disorders and other disor-
ders of the brain in Europe 2010. European
Neuropsychopharmacology, 21, 655–679. doi:10.1016/
j.euroneuro.2011.07.018
Yeragani, V. K., Pohl, R., Balon, R., Jampala, V. C., &
Jayaraman, A. (2002). Twenty-four-hour QT interval
variability: Increased QT variability during sleep in
patients with panic disorder. Neuropsychobiology, 46, 1–6.
doi:10.1159/000063568
Yeragani, V. K., Pohl, R., Berger, R., Balon, R., Ramesh, C.,
Glitz, D., … Weinberg, P. (1993). Decreased heart rate
Downloaded by [University of Calgary] at 06:17 14 September 2017
INTERNATIONAL REVIEW OF PSYCHIATRY 9
variability in panic disorder patients: A study of power-
spectral analysis of heart rate. Psychiatry Research, 46,
89–103.
Yeragani, V. K., Pohl, R., Jampala, V. C., Balon, R., Ramesh,
C., & Srinivasan, K. (2000). Increased QT variability in
patients with panic disorder and depression. Psychiatry
Research, 93, 225–235. doi:10.1016/S0165-1781(00)00119-0
Young, L. D., Richter, J. E., Anderson, K. O., Bradley, L. A.,
Katz, P. O., McElveen, L., … Snyder, R. M. (1987). The
effects of psychological and environmental stressors on
peristaltic esophageal contractions in healthy volunteers.
Psychophysiology, 24, 132–141. doi:10.1111/j.1469-
8986.1987.tb00265.x