The role of stress in heart failure – ground for sex specific pathophysiology
In the last hundred years modern society went through numerous changes in life style, dietary habits, work load, physical activity and other environmental factors. As a species we are not well adapted to new demands. Higher levels of stress hormones provoke various effects, especially gradual chang...
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Інститут молекулярної біології і генетики НАН України
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irk-123456789-1537042019-06-15T01:30:41Z The role of stress in heart failure – ground for sex specific pathophysiology Heffer, M. Zibar, L. Viljetic, B. Makarovic, Z. Reviews In the last hundred years modern society went through numerous changes in life style, dietary habits, work load, physical activity and other environmental factors. As a species we are not well adapted to new demands. Higher levels of stress hormones provoke various effects, especially gradual change in the sensitivity of adrenergic, glucocorticoid and insulin receptors. All these changes are mutually associated and they gradually lead to metabolic syndrome, obesity, diabetes, heart failure and other types of pathology depending on genetic makeup and environmental factors. The aim of this paper is to summarize current knowledge concerning the impact of stress on cardiac function. Whereas stress response is sex specific we would emphasize a potential difference in pathophysiology of ischemic heart failure in men and women. Modern medicine has misinterpreted autonomous nervous system functions for years and this was reflected in heart failure (HF) and arterial hypertension therapy. Stress before the onset of menopause has a lesser effect on cardiac function compared to stress after menopause. Postmenopausal women have a significantly higher risk of heart disease, which is related to the diminished protection of the female hormonal cycle, but low doses of estrogen have not proven protective in postmenopausal women. Potential new targets of sexspecific cardiac therapy would come from better understanding of the molecular mechanisms exerted by nuclear receptors for steroid hormones, transcription factors involved in heart remodeling, cross-talk in adrenergic signaling pathways and their down-stream molecules. Keywords: heart failure, stress, adrenergic receptors, sex specific. За останнє століття сучасне суспільство зазнало багаточисельних змін у способі життя (звичках, харчуванні, навантаженнях, фізичній активності), а також під впливом чинників довкілля. Як біологічний вид ми не дуже добре адаптувалися до нових умов. Вищі рівні гормонів стресу спричиняють різні ефекти, поступово змінюється чутливість адренергічних, глюкокортикоїдних і інсулінових рецепторів. Усі ці зміни взаємопов’язані і залежно від генетичних і екологічних факторів призводять до таких метаболічних синдромів, як ожиріння, цукровий діабет, серцева недостатність тощо. Оскільки відповідь на стрес залежить і від статі, потрібно враховувати можливу різницю у патофізіології серцевої недостатності у чоловіків і жінок. Протягом багатьох років функції вегетативної нервової системи невірно трактувалися сучасною медициною, що відбилося на терапії серцевої недостатності і гіпертензії. Вплив стресу на серцеву функцію у перід до і після менопаузи різниться. У жінок у постменопаузі значно підвищується ризик серцево-судинних захворювань, який визначається зниженням захисної функції жіночого гормонального циклу. Глибше вивчення молекулярних механізмів дії ядерних рецепторів стероїдних гормонів, факторів транскрипції, які беруть участь у ремоделюванні серця, перехресних адренергічних сигнальних шляхів та їхніх ефекторних молекул призведе до постановки нових задач для гендер-специфічної терапії. Ключові слова: серцева недостатність, стрес, адренергічні рецептори, статева специфічність. За последнее столетие современное общество претерпело многочисленные изменения в образе жизни (привычках, способе питании, нагрузках, физической активности), а также под влиянием факторов окружающей среды. Как биологический вид мы не очень хорошо адаптировались к новым условиям. Более высокие уровни гормонов стресса приводят к различным эффектам, постепенно меняется чувствительность адренергических, глюкокортикоидных и инсулиновых рецепторов. Все эти изменения взаимосвязаны и в зависимости от генетической и экологических факторов приводят к таким метаболическим синдромам, как ожирение, сахарный диабет, сердечная недостаточность и др. Поскольку ответ на стресс зависит и от пола, нужно учитывать возможную разницу в патофизиологии сердечной недостаточности у мужчин и женщин. В течение многих лет функции вегетативной нервной системы неверно трактовались современной медициной, что отразилось на терапии сердечной недостаточности и гипертензии. Влияние стресса на сердечную функцию в период до и после менопаузы различается. У женщин в постменопаузе значительно повышается риск сердечно-сосудистых заболеваний, определяемый снижением защитной функции женского гормонального цикла. Более углубленное изучение молекулярных механизмов действия ядерных рецепторов стероидных гормонов, факторов транскрипции, участвующих в ремоделировании сердца, перекрестных адренергических сигнальных путей и их эффекторных молекул приведет к постановке новых задач для гендер-специфической терапии. Ключевые слова: сердечная недостаточность, стресс, адренергические рецепторы, половая специфичность. 2011 Article The role of stress in heart failure – ground for sex specific pathophysiology / Heffer M., Zibar L., Viljetic B., Makarovic Z. // Вiopolymers and Cell. — 2011. — Т. 27, № 2. — С. 93-106. — Бібліогр.: 140 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000088 http://dspace.nbuv.gov.ua/handle/123456789/153704 616.1 + 612.176 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| language |
English |
| topic |
Reviews Reviews |
| spellingShingle |
Reviews Reviews Heffer, M. Zibar, L. Viljetic, B. Makarovic, Z. The role of stress in heart failure – ground for sex specific pathophysiology Вiopolymers and Cell |
| description |
In the last hundred years modern society went through numerous changes in life style, dietary habits, work
load, physical activity and other environmental factors. As a species we are not well adapted to new demands. Higher levels of stress hormones provoke various effects, especially gradual change in the
sensitivity of adrenergic, glucocorticoid and insulin receptors. All these changes are mutually associated
and they gradually lead to metabolic syndrome, obesity, diabetes, heart failure and other types of pathology
depending on genetic makeup and environmental factors. The aim of this paper is to summarize current
knowledge concerning the impact of stress on cardiac function. Whereas stress response is sex specific we
would emphasize a potential difference in pathophysiology of ischemic heart failure in men and women.
Modern medicine has misinterpreted autonomous nervous system functions for years and this was reflected
in heart failure (HF) and arterial hypertension therapy. Stress before the onset of menopause has a lesser
effect on cardiac function compared to stress after menopause. Postmenopausal women have a significantly
higher risk of heart disease, which is related to the diminished protection of the female hormonal cycle, but
low doses of estrogen have not proven protective in postmenopausal women. Potential new targets of sexspecific cardiac therapy would come from better understanding of the molecular mechanisms exerted by
nuclear receptors for steroid hormones, transcription factors involved in heart remodeling, cross-talk in
adrenergic signaling pathways and their down-stream molecules.
Keywords: heart failure, stress, adrenergic receptors, sex specific. |
| format |
Article |
| author |
Heffer, M. Zibar, L. Viljetic, B. Makarovic, Z. |
| author_facet |
Heffer, M. Zibar, L. Viljetic, B. Makarovic, Z. |
| author_sort |
Heffer, M. |
| title |
The role of stress in heart failure – ground for sex specific pathophysiology |
| title_short |
The role of stress in heart failure – ground for sex specific pathophysiology |
| title_full |
The role of stress in heart failure – ground for sex specific pathophysiology |
| title_fullStr |
The role of stress in heart failure – ground for sex specific pathophysiology |
| title_full_unstemmed |
The role of stress in heart failure – ground for sex specific pathophysiology |
| title_sort |
role of stress in heart failure – ground for sex specific pathophysiology |
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Інститут молекулярної біології і генетики НАН України |
| publishDate |
2011 |
| topic_facet |
Reviews |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/153704 |
| citation_txt |
The role of stress in heart failure – ground for sex specific pathophysiology / Heffer M., Zibar L., Viljetic B., Makarovic Z. // Вiopolymers and Cell. — 2011. — Т. 27, № 2. — С. 93-106. — Бібліогр.: 140 назв. — англ. |
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| fulltext |
The role of stress in heart failure – ground for sex
specific pathophysiology
M. Heffer1, L. Zibar2, B. Viljetic3, Z. Makarovic4
1Department of Medical Biology, School of Medicine, Josip Juraj Strossmayer University of Osijek
4, Huttlerova St., Osijek, Croatia, 31000
2Department of Pathophysiology, School of Medicine, Josip Juraj Strossmayer University of Osijek
4, Huttlerova St., Osijek, Croatia, 31000
3Department of Chemistry, Biochemistry and Clinical Chemistry, School of Medicine, Josip Juraj Strossmayer University of Osijek 4,
Huttlerova St., Osijek, Croatia, 31000
4Department of Cardiology, Clinical Hospital Osijek
4, Huttlerova St., Osijek, Croatia, 31000
mheffer@mefos.hr
In the last hundred years modern society went through numerous changes in life style, dietary habits, work
load, physical activity and other environmental factors. As a species we are not well adapted to new de-
mands. Higher levels of stress hormones provoke various effects, especially gradual change in the
sensitivity of adrenergic, glucocorticoid and insulin receptors. All these changes are mutually associated
and they gradually lead to metabolic syndrome, obesity, diabetes, heart failure and other types of pathology
depending on genetic makeup and environmental factors. The aim of this paper is to summarize current
knowledge concerning the impact of stress on cardiac function. Whereas stress response is sex specific we
would emphasize a potential difference in pathophysiology of ischemic heart failure in men and women.
Modern medicine has misinterpreted autonomous nervous system functions for years and this was reflected
in heart failure (HF) and arterial hypertension therapy. Stress before the onset of menopause has a lesser
effect on cardiac function compared to stress after menopause. Postmenopausal women have a significantly
higher risk of heart disease, which is related to the diminished protection of the female hormonal cycle, but
low doses of estrogen have not proven protective in postmenopausal women. Potential new targets of sex-
specific cardiac therapy would come from better understanding of the molecular mechanisms exerted by
nuclear receptors for steroid hormones, transcription factors involved in heart remodeling, cross-talk in
adrenergic signaling pathways and their down-stream molecules.
Keywords: heart failure, stress, adrenergic receptors, sex specific.
Introduction. America’s top 15 most prescribed drugs
by dispensed prescriptions published on the internet
pages (www.forbes.com/2010/05/11/; source – IMS
National Prescription Audit) belong to the top six cate-
gories: pain killers, blood pressure and cholesterol
lowering drugs, medication of hypothyroidism, anxie-
ty/depression and type two diabetes. Six out of top 15
are blood pressure lowering medications. A huge mar-
ket of 83 million dollars in the year 2010 belongs to the
second most prescribed medication – simvastatin – a
drug efficient in cholesterol lowering. If Dr. Hans
Selye, the scientist who established stress reaction,
would be asked to interprete such data, he would re-
cognize population based symptoms of the most com-
mon modern disease – chronic stress. Number of scien-
tific publications on this subject doubles every few
years, but it seems like we still do not have a handle on
the large scale health risks caused by the new pande-
93
ISSN 0233–7657. Biopolymers and Cell. 2011. Vol. 27. N 2. P. 93–106
Institute of Molecular Biology and Genetics NAS of Ukraine, 2011
mic. Trained as medical doctors, we often look after pa-
tients as removed from their social environment and
make conclusions based on the currently presented
isolated set of symptoms. In this paper we try to bring
together pieces of knowledge connecting autonomous
nervous regulation of the heart’s function, major signa-
ling pathways executing molecular instructions in
stress response and the role of stress in the development
of heart failure. Special notice should be taken of sex-
specific molecular mechanisms, suggesting a differen-
ce in pathophysiology.
The anatomy of cardiac innervations. Two bran-
ches of the autonomous nervous system, parasympa-
thetic and sympathetic, fight for the same targets, op-
posing and/or modulating each other. Each branch
consists of efferent and afferent fibers. The efferent
parasympathetic innervations of heart (Fig. 1) originate
in medullar nuclei (nucleus ambiguous, nucleus tractus
solitarius and dorsal motor nucleus), whose axons fol-
low vagal nerve to intrinsic ganglia located on epicar-
dial surface of atria [1]. Postganglionic fibers of intrin-
sic ganglia cross AV groove, penetrate myocardium
and terminate in subendocardium (more atrial then
ventricular) modulating SA and AV nodal function [2].
Acetylcholine, exclusive neurotransmitter of the effe-
rent parasympathetic branch, operates through nicoti-
nic receptor on preganglionic neurons and muscarinic
receptors expressed on cardiomyocytes [3]. The densi-
ty of muscarinic receptors is much higher in the atria
compared to the ventricles [4], this is reflected in a
lesser effect on the contractility than on the heart rate.
Along predominant subtype M2, receptors M3 and M4
are up-regulated in the heart failure (HF) [5]. Musca-
rinic receptors on cardiomyocytes and conductive sys-
tem are Gi protein-coupled, causing decrease in cellu-
lar cAMP and decreasing contractile forces and ve-
locity [3].
More prolific efferent cardiac sympathetic inner-
vations originate from the intermediolateral cell co-
lumn of the spinal cord (commonly from T1 till T5),
follow spinal nerves until superior, middle and stellate
cervical ganglion as well as upper thoracic ganglia [2].
The postganglionic fibers arising from sympathetic
trunk follow the coronary arteries and penetrate myo-
cardium. Neurotransmitter of the sympathetic branch is
norepinephrine, but cotransmission of epinephrine is
well documented in panic disorder [6] and essential
hypertension [7], in which case catecholamine level re-
leased by sympathetic nerves is increased for 10 %.
Another neurotransmitter, neuropeptide Y (NPY) is
readily found in sympathetic nerve of gut and liver [8]
of healthy individuals, but also is acutely released du-
ring maximal aerobic exercise at high rates of cardiac
nerve firing and chronically released in patients with
HF [9]. Catecholamine work through two major classes
of adrenergic receptors (AR), α (α1 α2) and β (β1, β2, β3),
members of the super family of G protein-coupled
receptors (Fig. 2). Different subtypes of α-ARs regu-
late cardiac contractility and peripheral resistance; α1A-
and α1B-constitute the majority of cardiac α-ARs [10],
α1D – is predominant AR of human coronary arteries
[11], while three subtypes of α2-AR (α2A, α2B and α2C)
mediate vasodilatation of arteries, vasoconstriction of
veins, platelet aggregation and various endocrine
responses to the sympathetic stimulation [12]. Taking a
94
HEFFER M. ET AL.
Fig. 1. The anatomy of sympathetic and parasympathetic efferent
connections of the heart
closer look at cardiac distribution of α1-ARs reveals
much higher amount of α1B- then of α1A-AR and much
higher amount of α1-ARs in the ventricles than in the
atria [4].
The cardiac response to catecholamine stimulation
in healthy mammalian heart is predominantly mediated
by β-AR as follows; 70–80 % by β1, 20–30 % by β2 and
β3 account just minimal contribution [4, 13]. Using the
functional criteria, sensitivity toward typical β3-AR
agonist CGP-12177 in β3-knockout mice [14, 15], as
well as molecular cloning techniques [16] it has been
established that β1-AR exist in multiple active con-
formations functionally opposing each other. All adre-
nergic receptors respond to both, norepinephrine and
epinephrine, but they are not equally sensitive to these
stimuli and the final outcome of the ligand binding de-
pends on the intracellular signaling pathway. Increased
force of contraction, accelerated relaxation and increa-
sed beating rate are outcome of the activation of Gs
protein by β1- and β2-AR, followed by activation of ade-
nylate cyclase, production of cAMP and activation of
protein kinase A (PKA) [17]. PKA mediates short-term
inotropic effect by phosphorylation of few Ca2+ chan-
nels or pumps (sarcolemmal L-type Ca2+ channels,
phospholamban – sarcoplasmatic Ca2+ pump and sarco-
plasmatic SR Ca2+ release channels) and proteins redu-
cing myofilament Ca2+ affinity (troponin I and myosin
binding protein C). Prolonged activation of this signa-
ling pathway either leads to long-term enhancement of
contractility (24 hours) or myocyte apoptosis and nec-
rosis, due to intracellular Ca2+ increase and activation
of Ca2+ calmodulin-dependent protein kinase II
(CaMKII) [18, 19]. A low-affinity site (or isoform) of
β1-AR is 40-fold more efficient in arrhythmic potency
through Ca2+ induced Ca2+ release than the regular
β1-AR [20]. Receptors β2 and β3 provide protection from
adverse outcome through coupling Gi and activating
phosphatidylinositol 3-kinase (PI3K)-protein kinase B,
which determines cell survival [21] or nitric oxide
(NO) production, which inhibits myocyte contraction
[22, 23]. Differently than in dogs and rodents, β3-
response is negligible in primates [24]. The low-af-
finity form of β1-AR has chronotropic and arrhythmic
effects [20, 25, 26]. The variety of catecholamine re-
ceptors provides functional differences either on the
level of receptor itself (distribution, affinity for ligand
and G protein, mechanism of density regulation) or on
the down-stream levels (signaling mechanism). When
cardiomyocytes or intrinsic ganglion cells express mo-
re than one receptor (what they usually do) final res-
ponse depends on signaling cross-talk, a very interes-
ting field for pharmacological investigation and inter-
vention. Most of these studies were done on animal
models (rat, dog or rabbit) and the results need further
justification in human medicine.
Both branches of autonomous nervous system also
posses afferent fibers (Fig. 3) providing feedback im-
pulses for local reflexes and informing higher integ-
rative centers (nucleus of the solitary tract, nucleus dor-
salis n. vagi, medial and ventral forebrain). The sparse
number of cardiac visceral sensory neurons sits in the
dorsal root ganglia (C6-T8) or in nodose ganglion [27,
28]. Although their function is maintaining balance
between sympathetic and parasympathetic stimulation
during aging is crucial, they have just recently been in-
vestigated [29]. Aging is accompanied with a severe re-
duction of sympathetic afferent neurons; the number of
neurons in old rats was just 15 % of the number in juve-
nile animals. Physiological and pathophysiological
conditions leading to the preservation or smaller reduc-
tion in the number of autonomous neurons have not be-
en investigated yet.
The interconnection of parasympathetic and sym-
pathetic fibers becomes even more complicated after
95
THE ROLE OF STRESS IN HEART FAILURE – GROUND FOR SEX SPECIFIC PATHOPHYSIOLOGY
The adrenergic signaling pathways
H H CA H CA
H
H
"1A $1LA / $1< "1B "1D
Gq Gq Gq
Phospholipase C Adenyl cyclase
Adenyl cyclase
ERK
"2A "2B "2C
Gi Gi Gi
? Gs/ Gi Gi
PI3K
eNOS
NO
ATP cAMP
cAMP ATP cAMP
PIP2 IP3 DAG
Ca2+
cAMP
> $2 $3>
Gs
Smooth muscle
contraction
Smooth muscle relaxation
Inhibition of transmitter
release
Ca2+
Heart muscle contraction
Smooth muscle relaxation
Glycogenolysis
Fig. 2. Family of adrenergic receptors and their down-stream signal-
ling pathways; H – heart; CA – coronary artery
finding sympathetic efferent neurons in intramural
places [1]. Armour suggested three levels of cardiac au-
tonomous regulation; the simplest one, intrinsic and
working on short range-bit to bit; the second one on the
level of cardiac plexus and nodose ganglion, working
on middle range-minutes or hours; the tertiary level
located in the medulla oblongata and cortical centers
providing long lasting changes (days, months or even
years).
Cardiac innervations are still not fully understood
and further studies need to deal with effects of over-
stimulation, sex-specific aging and potential of re-
generation.
Sympathetic excitation in the development of
cardiovascular pathology. HF is associated with de-
creased inotropic response. At first glance, pharmaco-
logical treatment at the level of α1 and β1-AR should le-
ad to an improvement. Non-selective agonists, inclu-
ding epinephrine and norepinephrine, have adverse ef-
fects like hypertension and arrhythmia [30] due to α-
AR stimulation. The development of more selective
agonist for β1-AR was the next logical step. Dopamine
infusion at intermediate doses stimulates predominant-
ly cardiac β1-AR, while lower doses work just on dopa-
mine receptors in splanhnic and renal arterial bed [31].
Dopamine was neglected as a possible compound for
long term treatment because of the respiratory depres-
sant effect [32] and overall unpredictable outcomes in
HF [33]. Neither one of the next generation, more se-
lective β1-AR agonist (prenalterol, xamoterol, dobuta-
mine), was more successful [34–36]. Creation of a hi-
ghly selective agonist was the ultimate goal till the end
of the nineties. Some tried to overcome receptor speci-
ficity barriers by designing inhibitors of down-stream
signaling molecules. Milrinone and enoximone are se-
lective inhibitors of cAMP-specific phosphodiesterase
(PDE) III isoenzyme in myocardium and smooth mus-
cle, prolonging the half life of cAMP and increasing
intracellular Ca2+, both without benefit over placebo
[37, 38] in long term treatment of ischemic heart failu-
re. Milrinone was found to be beneficial in treatment of
dilated cardiomyopathies, treatment of low output syn-
drome following cardiac surgery and patients with con-
gestive HF prior to cardiac surgery due to a combinati-
on of anti-apoptotic and positive inotropic effects [39].
The large, randomized, double blind placebo-
controlled clinical trials were over and over pointing to
either the goal of finding selective agonist was tricky to
achieve or the concept of sympathomimethic boost to
failing heart was wrong. The paradigm of the failing
heart craving more sympathetic stimulation was fed by
findings of both anatomical and functional cardiac
sympathetic denervation. Chidsey and Braunwald per-
formed studies on excised atrial tissue obtained during
heart surgery [40] and found a significant reduction of
norepinephrine concentration in the failing heart. Al-
lman and coworkers interpreted positron emission
tomography with carbon-11-hydroxyephedrine (radio-
isotope taken up by sympathetic nerves) after acute
myocardial infarction as patchy denervation [41]. Also,
progression of HF is accompanied with β-AR selective
down regulation [42, 43]. Approximate ratio of 50:50
β1/β2-AR is not just shifted in favor of β2-AR, yet both
receptors become uncoupled of their down-steam sig-
naling pathways and desensitized to adrenergic stimu-
96
HEFFER M. ET AL.
Fig. 3. The anatomy of sympathetic and parasympathetic afferent con-
nections of the heart
lation [44–46]. All of this data justified the use of β-AR
agonist, but clinical results were showing the opposite.
One of the crucial pieces in the puzzle came from
Cohn and coworkers’ study [47] in which they mea-
sured plasma norepinephrine at supine rest and found
high correlation between concentration of norepineph-
rine in venous blood and risk of mortality. The concen-
trations of resting norepinephrine in their study remain
stable on successive days, and were a sign of general
sympathetic-nervous-system activation, while epine-
phrine was a marker of acute stress response [48] and
variable from day to day. Similar data were coming out
of succeeding studies [49, 50] proving that in untreated
patients with congestive heart disease cardiac norepi-
nephrine spillover was increased as much as 50-fold,
that corresponded to the levels in healthy adult during
near maximal exertion. Increased cardiac adrenergic
drive preceded generalized sympathetic activation [51]
and manifested as 4–5 times higher than normal nor-
epinephrine spillover in the mild HF, as well as in a he-
art with a predisposition for ventricular tachycardia and
ventricular fibrillation [52]. Along with norepinephrine
the spillover of NPY [8], neuropeptide which is not
subjected to neuronal reuptake and have been shown to
cause coronary vasoconstriction, inhibiting vagal acti-
vity and triggering ventricular arrhythmias through
Y(2) receptors [53], also increases. Beside peripheral
drive, in the rat coronary ligation model, norepinephri-
ne is also increased in the central nervous system in the
locus coeruleus and nucleus in which its project – para-
ventricular nucleus of the hypothalamus – the one
which participates in the regulation of autonomous ner-
vous system [54, 55].
In the meantime, transgenic mice with overexpres-
sion of β1-AR and β2-AR were generated [56]. Initial
observations, performed on young animals, show no
cardiac pathology with up to 60-fold overexpression of
β2-AR [57] – the promising target for restoration in he-
art failure. Longer observation, however, reveals quite
a different picture; both transgenic models, overexp-
ressing β1-AR [58] or β2-AR [59] develop cardiomyo-
pathy and heart failure. The same result was obtained
with mice overexpressing down-stream signaling mo-
lecule for both adrenergic receptors; cardiac stimulato-
ry G protein alpha subunit-Gsα [60, 61] and alpha cata-
lytic subunit (Cα) of PKA [62].
All these studies concluded that selective down re-
gulation of β-AR in patients with HF is a compensatory
and protective mechanism, shifting paradigm from
sympathetic stimulation toward blocking. In the begin-
ning, β-blockers were introduced as a therapy to control
the tachycardia associated with HF which unexpec-
tedly reduced mortality in acute myocardial infarction
[63]. Although few trials were conducted in following
years, the first large randomized clinical trial showed
clear evidence of mortality benefit was released in
1999 [64, 65]. Currently three types of β-blockers clas-
sified as β1-AR selective, non-selective β-AR blockers
and non-selective β/α-AR blockers are in use. Interes-
tingly, non-selective β/α-AR blockers like carvedilol
result in vasodilatation secondary to α-AR blockade
lowering aortic pressure and are proving to be superior
over more selective blockers [66].
Nowdays we have overall acceptance of HF deve-
lopment is connected with progressive remodeling of
cardiac sympathetic response. Although we know how
to alleviate consequences of this response, we still do
not know enough about the trigger of changes, early
signs, risk factors, sex specific dynamic and therapy.
The adrenergic receptors behavior under acute
and chronic stress. In 1936 Dr. Hans Selye presented
his finding of General Adaptation Syndrome explai-
ning how various nocuous agents (exposure to cold,
surgical injury, excessive muscular exercise, sublethal
intoxication) produced the same typical response in
experimental animals [67]. He described three stages of
the syndrome development: the initial one expressed as
a general alarm (decrease in size of lymphoid organs
and fat tissue, fall of body temperature, formation of
erosions in digestive tract), the phase of building up
resistance and the phase of exhaustion after a period of
a prolonged stress. The article was a cornerstone in the
field of neuropsychiatry, kicking up an avalanche of
studies and helping to reveal the effect of hormones and
stress on the brain function. Today we understand
stress as a multi-system response to challenges threate-
ning homeostasis, having bearable or overwhelming
allostatic load and potential health consequences [68].
All of the situations like the first jump with para-
chute (as well as consequent jumps), running in front of
an enraged bull, waiting for a big exam, being threaten
with a gun, have in common the surge of epinephrine
97
THE ROLE OF STRESS IN HEART FAILURE – GROUND FOR SEX SPECIFIC PATHOPHYSIOLOGY
and co-released cortisol from adrenal gland into the
bloodstream. These two hormones activate responses
in multiple organs having adrenergic or cortisol recep-
tors, particularly response of the stress axis, the hypo-
thalamic-pituitary-adrenal (HPA) axis, and sympathe-
tic-adrenal medullary system. The mark of HPA acti-
vation is elevation of corticotropin releasing factor
(CRF), synthesized by a discrete population of neurons
in parvocellular part of the paraventricular nucleus in
the hypothalamus and released into hypophyseal-portal
circulation [69]. Neuropeptide arginine vasopressin
(AVP) is co-released at the same nerve endings. CRF
stimulates synthesis and release of adenocorticotropic
hormone (ACTH) from the anterior lobe of the pituita-
ry gland while binding of arginine vasopressin to V1b
pituitary receptors enhance release of ACTH in the sys-
tem circulation [70]. ACTH induces glucocorticoid
production and its release from the adrenal cortex.
Besides numerous physiological and metabolic effects
(suppression of immune, reproductive and digestive
organs, inhibition of growth, glucolysis, proteolysis
and lipolysis), glucocorticoids are one of the six known
transcriptional activators of epinephrine synthesizing
enzyme phenylethanolamine N-methyltransferase
(PNMT) [71–73]. This enzyme is confined in its distri-
bution just to the adrenal medulla and adrenalin syn-
thesizing neurons of the brain stem in healthy indivi-
duals, consequently producing more epinephrine. At
the same time, a parallel track is also being activated;
the sympathetic system releases norepinephrine stimu-
lating target organs having adrenergic receptors, inclu-
ding adrenal medulla. Epinephrine regulates its own
production by inhibiting PNMT [74]. It is one of many
inhibitory loops throughout HPA axis, bringing all
players back to basal level.
In between various animal models of stress (foot
shock, electric shocks, forced swimming, forced run-
ning, etc.) immobilization on wooden board is conside-
red a putative model of posttraumatic stress disorders
(PTSD). Single and repeated exposures induce dysre-
gulation of the resting activity of the HPA axis [75],
observed as increase in resting corticosterone levels
[76, 77]. Dysregulation of HPA triggers multiple chan-
ges in target organs. The transcriptome in the adrenal
medulla after acute and chronic stress exposure is very
different; the number of transcripts significantly diffe-
red in the rat medulla after single immobilization – it
was bigger (651 up and 487 down) than after immo-
bilization on six consecutive days (370 up and 195 do-
wn) [78]. Transcription factors and cell signaling mo-
lecules go through the largest changes accompanied
with transcripts related to growth factors, apoptosis,
neurosecretion, heat shock proteins, structural proteins,
chemokines, cytokines, metabolism and proteases.
Immediate cardiovascular response to raised levels
of epinephrine at the beginning of the stress response is
increased blood pressure and heart rate, respectively.
The heart is very sensitive to the changes of adrenergic
levels, because 95 % of norepinephrine released on the
sympathetic nerves is being recaptured [79]. In stress
response, levels of epinephrine are major drive of car-
diac performance. Hence, changes in norepinephrine
reuptake mechanism and/or neurotransmitter load wo-
uld sensitize the heart to arrhythmia development du-
ring intense sympathetic activation, as during panic at-
tacks, for example [6].
In a model of foot shock stress Basani reported su-
persensitivity of isolated rat heart pacemaker to β2-se-
lective agonists [80] suggesting increased β2-signaling.
At the same time right atria were subsensitive to se-
lective β1-agonist. Observed remodeling of adrenergic
receptors was canceled by treatment with the mife-
pristone, glucocorticoid receptor antagonist, indicating
involvement of glucocorticoid mediated mechanism
[81]. Similar experiments repeated on female rats de-
monstrated more elevated plasma corticosterone in fe-
male versus male animals, independent of estrus cycle,
the same changes of adrenergic receptors during diest-
rus and lack of changes in estrus [82]. This data sug-
gests a role of sex steroids at least in remodeling of fe-
male heart. Changes in adrenergic receptors also take
place in adipose tissue manifested as decreased expres-
sion of the β1- and β3-AR accompanied with increase ex-
pression of β2-AR [83] and reflected in altered sensi-
tivity to insulin [84]. While increase of β2-signaling du-
ring stress response could be interpreted as protective
because it was directing heart from activation of PKA,
Ca2+ overload and apoptosis caused by β1-AR, on the
other hand, raises insulin resistance in fat tissue, which
is a bad strategy on the long term, leading to a «thrifty
metabolism». However, recently used fluorescence re-
sonance energy transfer (FRET) microscopy demonst-
98
HEFFER M. ET AL.
rated particularity in distribution of adrenergic recep-
tors in cardiomyocytes of failing heart [85]. Besides
being more expressed, β2-AR in failing heart are redist-
ributed from their common place at tranverse tubules to
the cell crest – compartment of cAMP production re-
served for β1-AR. Final outcome is β2-AR coupled to
different signaling mechanism and behaving like β1-
AR, also proved in the development of cardiomyopa-
thies in β2-AR transgenic animals [59, 86]. To make
stress response of the heart even more complicated, dif-
ferent heart regions express different shift in adrener-
gic receptors; murine right ventricules express decrea-
sed level of β2-AR [87].
The adrenergic receptor remodeling is accompa-
nied by the changes in the level of catecholamine. Ele-
vated urinary concentrations of norepinephrine and
epinephrine are observed in patients with posttraumatic
stress disorder (PTSD) [88, 89]. Stress elevates the
expression of PNMT mRNA [90] in a glucocorticoid
dependent manner, especially after repeated immobili-
zation stress, but not only at the adrenal medulla and
neurons of the brain steam, but also at sympathetic
nerve endings and cardiac tissue [91, 92]. Epinephrine
is increased after the first immobilization, while levels
of norepinephrine rise after the seventh immobilization
[87]. Epinephrine is also found in the samples of blood
from coronary sinus, released by the sympathetic ner-
ves of heart in patients with essential hypertension [7]
this was considered pathophysiological mechanism in
the development of this disease. No association was fo-
und between polymorphism of β2-AR, the most frequ-
ent arterial adrenergic receptor, and hypertension and
obesity [93]. However, the gene polymorphism in the
rate-limiting enzyme in catecholamine biosynthesis,
tyrosine hydroxylase (TH), is connected with stress-in-
duced blood pressure changes [94]. On the other hand,
angiotensin II AT1 receptor blockers (ARBs), com-
monly used in the clinical treatment of arterial hyper-
tension profoundly modify the response to the stress,
preventing the peripheral and central sympathetic acti-
vation [95]. ARBs, transportable across the blood-
brain barrier, are a potential treatment of stress related
and anxiety disorders [96, 97].
In most brain regions β1-ARs comprise > 80 % of
adrenergic receptors [98]. Single exposure to restrained
stress significantly decreases levels of β1-AR mRNA in
the hypopthalamus, but repeated exposure brings back
to control levels [99].
Right now we do not have any reliable and easy to
follow stress-specific marker which could be used in
studies of human or animal exposure to different stres-
sors and their different intensity. Animal studies are
pointing to significant remodeling of adrenergic recep-
tors in heart and blood vessels in chronic stress, but
even in animal models we do not know how to prevent
them. Also, most animal studies are short-term, obser-
ving changes provoked after consecutive stress expo-
sure, while observations from human studies predict
more then a decade or two long progression of cardiac
pathology. We are looking not just for an animal mo-
del, but also for a study plan which would combine the
major risk factors and follow up data on vital functions
in a long term study.
Sex specific traits in the stress response and de-
velopment of heart failure. HPA response is a very
expensive effort for an organism and if overengaged
has potential consequences [100]. It is often raised in
the modern society even in the absence of physio-
logical challenge, driven by conditioning («memory»)
during anticipation of potential threat [69]. The autono-
mous nervous system has an interesting feature of iso-
lating some organs and/or recruiting some more than
others in general stress response. The heart is just one
of the target organs in the stress response, whose en-
gagement depends on individual heritable traits (inclu-
ding sex) and the environment as well.
The heart rhythm transcriptome genes encoding
adrenergic receptors, connexins, cadherins, plakophi-
lins, ankyrins, ion channels and transporters have signi-
ficant heart chamber sex differences observed in the rat
animal model [101]. Differences become particularly
prominent in knockout models challenged by physiolo-
gical ligand, agonist and antagonist of various recep-
tors participating in stress response [102].
Environmental and sex-specific genetic factors are
reflected on the pathology: prevalence of hypertension
in Western society is higher in men aged 30–45 years
than in women of similar age. On the other hand preva-
lence of hypertension in women after this age increases
to levels similar to or exceeds those in men [103–105].
Reverse man versus women epidemiology is observed
in vasomotor disorders like Raynaud’s disease, postu-
99
THE ROLE OF STRESS IN HEART FAILURE – GROUND FOR SEX SPECIFIC PATHOPHYSIOLOGY
ral orthostatic tachycardia syndrome and vasomotor
symptoms (hot flashes) of menopause and migraine
[106]. In both human and animal heart pathology diffe-
rences is connected with estrogen levels [107–109].
Because women develop manifestation of coronary
disease 10 years later then men, on average, and present
with myocardial infarction 20 years later [110], general
preconception is still how cardiovascular disease
(CVD) is not a leading cause of mortality in women.
The consequences of this misconception are numerous:
the two-thirds of women, who died suddenly, had unre-
cognized CVD symptoms, 35 % of heart attacks in
women are believed to go unnoticed or unreported, wo-
men present later and are more sick at the time of diag-
nosis, they are less likely to undergo interventional car-
diology, undergo cardiac rehabilitation and return to
work after the first heart attack – which they are less li-
kely to live through [111]. Women with acute coronary
disease are more likely to present atypical symptoms:
vomiting, abnormal pain location, nausea, dizziness
and fatigue. The pathophysiology of HF is also diffe-
rent in men and women: women more frequently deve-
lop diastolic HF with preserved left ventricular func-
tion and normal ejection fraction accompanied with
prolonged history of arterial hypertension and comor-
bidities [112, 113], men more frequently have systolic
HF because of coronary artery disease [114]. Pressure
overload, arterial hypertension, diabetes and aging it-
self initiate myocardial hypertrophy. The hypertrophy
generates alterations in cardiac geometry, referred as
ventricular remodeling, measured by transthoracic
echocardiography (two-dimensional or three-dimen-
sional) and expressed as left ventricular (LV) volume,
mass, sphericity index or LV mass/volume. The first
stage of hypertrophy is adaptive response to stress due
to increase of cardiomyocytes size and deposition of
extracellular matrix [115]. Further progression of hy-
pertrophy becomes maladaptive if accompanied with
fibrosis (involving collagen deposition) and apoptosis.
Male hearts develop more easily pathological hyper-
trophy, while female ventricular remodeling follows
the pattern of diastolic HF having a greater risk of ad-
verse outcome as baseline ejection fraction is decrea-
sing [113, 116].
Chronic hypertension induced ventricular hyper-
trophy, left ventricular fibrosis and action potential
prolongation is observed in animal models of both
aging male and female Spontaneosly Hypertensive
Rats (SHR) [117]. Male animals from 15 months of age
develop left ventricular thinning, systolic and diastolic
dysfunction, which is not present in females at the same
age. In the mouse model of pressure overload by trans-
verse aortic constriction, males show more hypertro-
phy than females and females develop concentric while
males develop eccentric hypertrophy [118]. Induction
of matrix-related genes and a repression of mitochond-
rial genes in maladaptive stress response are attenuated
in estrogen receptor β knockout mice pointing to mole-
cular mechanism of estrogen protection. Estrogen the-
rapy in male Gαq transgenic mice prevent HF by inhi-
bition of apoptosis-regulated signaling kinase-1 [119].
Women and men respond differently to chronic HF
therapies, tailored to better fit to male than female pa-
thology [120]. Women benefit more from angiotensin
receptor blockers, while men benefit more from angio-
tensin converting enzyme inhibitor [121]. Low dose of
estrogen attenuate structural and functional remodeling
in an animal model of HF [122]. Contrarily, estrogen
treated female rats have a greater postmyocardial in-
farction survival [123].
Also, estrogen did not improve ischemia and endo-
thelial function in randomized controlled trials in post-
menopausal women [124]. In survival studies, women
had advantage in advance HF if presented with non-
ischemic etiology [120].
The role of stress in CVD development is not fully
investigated. Sexual dismorphism in the stress respon-
se, especially its relation to female hormonal cycle, has
been observed in animal models and in humans [125,
126]. Stress induces different changes of adrenergic re-
ceptors and their signaling pathways. While all subty-
pes of α1-AR decrease in female mice, it happens just to
α1A-AR in a CRH gene knockout, suggesting the role of
CRH in down-regulation of others. However, β1-AR
decreases in male mice, but remains stable in female
mice. Also, while the ability of α2-AR agonist to inhibit
insulin secretion was attenuated in male insulin re-
ceptor substrate 2 knockout animals, female animal de-
veloped mild obesity and progressed less rapidly to dia-
betes under adrenergic stimulation [127]. Adrenergic
receptors and their down-stream signaling molecules
exert a variety of effects and these molecules are good
100
HEFFER M. ET AL.
candidate genes in gene polymorphism studies dealing
with sex-specific pathology. The polymorphism in the
nuclear receptor genes, like glucocorticoid receptor,
was documented as a significant sex specific factor in
rising stress response to psychosocial stimuli [128]. Al-
so, the sex specific pathway of cardioprotection me-
diated by estrogen receptors include transcription fac-
tor myocyte enhancer factor 2 and class II histone de-
acetylases, potential targets in sex specific therapy
[129]. Polymorphism in the β1-AR and β3-AR increases
cardiovascular risk in women, more to microvascular
pathology than to obstructive coronary disease [130].
Difference in stress-response reactions is noticed in
the peripheral and central nervous systems. Functional
brain imaging studies of central stress response circuit-
ry (amygdale, hypothalamus, hippocampus, brainstem,
orbitofrontal cortex, medial prefrontal cortex and ante-
rior cingulated gyrus) found the most prominent diffe-
rences between men and women during early follicular
phase [126]. Activation of central stress response cir-
cuitry somehow predisposed women for development
of more adverse effects; about twice as many women as
men would develop PTSD, under the same exposure to
trauma [131].
Also symptoms of further exacerbation are dife-
rent, while anxiety is better predictor of PTSD in men,
depression is found in women [132]. Psychosocial
variables were recently associated with morbidity and
mortality in CVD patients [133]. Psychosocial stress
and depression might have role in accelerated aging
[134]. Telomere length is a marker of biological aging
and presence of stressor. A telomerase deficient mouse
model is recently used in HF studies [135]. Emotio-
nal/cognitive symptom cluster composed of worrying,
feeling depressed and expressing cognitive problems
predicts a high risk for a cardiac event [136]. Insomnia
is a risk factor and symptom of stress, depression and
anxiety [137], highly prevalent in patients with chronic
heart disease [138].
Besides all indirect links between stress and cardiac
disease in humans, Tako-Tsubo syndrome, firstly de-
scribed by Sato et al in 1990 (Japan), directly links ex-
cessive sympathetic stimulation triggered by intense
psychological or physical stress and acute cardiomyo-
pathy in the absence of arterosclerotic coronary artery
disease [139, 140].
Stress is a multi organ disease. The heart is just one
organ affected after years, even decades of increased
sympathetic activity. Additional risk factors, genetic,
metabolic, socioeconomic and environmental bring a
different load on homeostatic mechanisms. The deve-
lopment of HF differs between male and female, this is
visible in the stress induced heart remodeling. Close
observation of the differences will bring us closer to
sex-specific therapy in the near future.
М. Хеф фер, Л. Зи бар, Б. Виль е тич, З. Ма ка ро вич
Роль стресу у сер цевій па то логії – осно ва міжстатевих
па тофізіологічгих розбіжнос тей
Ре зю ме
За останнє століття су час не суспільство за зна ло ба га то чи -
сельних змін у спо собі жит тя (звич ках, хар чу ванні, на ван та -
жен нях, фізичній ак тив ності), а та кож під впли вом чин ників
довкілля. Як біологічний вид ми не дуже доб ре адап ту ва ли ся до
нових умов. Вищі рівні гор монів стре су спри чи ня ють різні ефе-
кти, по сту по во змінюється чут ливість ад ре нергічних, глю ко-
корти кої дних і інсуліно вих ре цеп торів. Усі ці зміни взаємо-
пов’язані і за леж но від ге не тич них і еко логічних фак торів при -
зво дять до та ких ме та болічних син дромів, як ожиріння, цук -
ро вий діабет, сер це ва не дос татність тощо. Оскільки відпо-
відь на стрес за ле жить і від статі, потрібно вра хо ву ва ти
можливу різни цю у па тофізіології сер цевої не дос тат ності у
чоловіків і жінок. Про тя гом ба гать ох років функції ве ге та -
тив ної не рво вої сис те ми невірно трак ту ва ли ся су час ною ме -
ди ци ною, що відби ло ся на те рапії сер це вої не дос тат ності і гі-
пер тензії. Вплив стре су на сер це ву функцію у перід до і після
ме но па у зи різнить ся. У жінок у по стме но па узі знач но підви -
щується ри зик сер це во-су дин них за хво рю вань, який виз на ча-
ється зни жен ням за хис ної функції жіно чо го гор мо наль но го
цик лу. Глиб ше вив чен ня мо ле ку ляр них ме ханізмів дії ядерних ре -
цеп торів сте рої дних гор монів, фак торів транс крипції, які бе -
руть участь у ре мо де лю ванні сер ця, пе ре хресних ад ре нергіч-
них сиг наль них шляхів та їхніх ефек тор них мо ле кул при зве де до
поста нов ки но вих за дач для ген дер-спе цифічної те рапії.
Клю чові сло ва: сер це ва не дос татність, стрес, ад ре нергічні
ре цеп то ри, ста те ва спе цифічність.
М. Хеф фер, Л. Зи бар, Б. Виль е тич, З. Ма ка ро вич
Роль стрес са в сер деч ной па то ло гии – осно ва
па то фи зи о ло ги чес ких раз ли чий меж ду по ла ми
Ре зю ме
За по след нее сто ле тие со вре мен ное об щес тво пре тер пе ло
мно го чис лен ные из ме не ния в об ра зе жиз ни (при выч ках, спо со -
бе пи та нии, на груз ках, фи зи чес кой ак тив нос ти), а так же под
вли я ни ем фак то ров окру жа ю щей сре ды. Как би о ло ги чес кий
вид мы не очень хо ро шо адап ти ро ва лись к но вым усло ви ям. Бо -
лее вы со кие уров ни гор мо нов стрес са при во дят к раз лич ным
эф фек там, по сте пен но ме ня ет ся чу встви тель ность ад ре нер -
ги чес ких, глю ко кор ти ко ид ных и ин су ли но вых ре цеп то ров. Все
эти из ме не ния вза и мос вя за ны и в за ви си мос ти от ге не ти чес -
кой и эко ло ги чес ких фак то ров при во дят к та ким ме та бо ли -
101
THE ROLE OF STRESS IN HEART FAILURE – GROUND FOR SEX SPECIFIC PATHOPHYSIOLOGY
чес ким син дро мам, как ожи ре ние, са хар ный ди а бет, сер деч ная
не дос та точ ность и др. Пос коль ку от вет на стресс за ви сит и
от пола, нуж но учи ты вать воз мож ную раз ни цу в па то фи зи о -
ло гии сер деч ной не дос та точ нос ти у муж чин и жен щин. В те -
че ние мно гих лет функ ции ве ге та тив ной не рвной сис те мы
не вер но трак то ва лись со вре мен ной ме ди ци ной, что от ра зи -
лось на те ра пии сер деч ной не дос та точ нос ти и ги пер тен зии.
Вли я ние стрес са на сер деч ную функ цию в пе ри од до и по сле ме -
но па у зы раз ли ча ет ся. У жен щин в по стме но па у зе зна чи тель но
по вы ша ет ся риск сер деч но-со су дис тых за бо ле ва ний, опре де -
ля е мый сни же ни ем за щит ной функ ции жен ско го гор мо наль но -
го цик ла. Бо лее углуб лен ное из уче ние мо ле ку ляр ных ме ха низ мов
де йствия ядер ных ре цеп то ров сте ро ид ных гор мо нов, фак то -
ров транс крип ции, учас тву ю щих в ре мо де ли ро ва нии сер дца,
пе ре крес тных ад ре нер ги чес ких сиг наль ных пу тей и их эф фек -
тор ных мо ле кул при ве дет к по ста нов ке но вых за дач для ген -
дер-спе ци фи чес кой те ра пии.
Клю че вые сло ва: сер деч ная не дос та точ ность, стресс, ад -
ре нер ги чес кие ре цеп то ры, по ло вая спе ци фич ность.
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UDC 616.1 + 612.176
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