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ОБЗОРИ
REVIEWS
In 1985, David C. Flenely was the rst to use the
term “overlap syndrome” (OS) to characterize the
combination of chronic obstructive pulmonary disease
(COPD) and obstructive sleep apnea (OSA). Individu-
ally, the prevalence of COPD and OSA among patients
with heart failure is high, with studies also revealing a
high frequency of the combination of both conditions
[1, 2, 3]. Patients with OSA and COPD experience sig-
nicant oxygen desaturation during sleep, closely as-
sociated with a higher incidence of pulmonary hyper-
Г. Войнова¹, П. Калайджиев¹,², Р. Илиева¹,², Г. Николова1,3, Д. Марков¹,², С. Яков¹, Ц. Коцев¹,
Н. Георгиева¹, А. Христова¹,², Л. Шопов¹,², Е. Кинова¹,², А. Гудев¹,²
1Кардиологично отделение, УМБАЛ „Царица Йоанна – ИСУЛ“– София,
2Катедра по спешна медицина, 3Катедра по анестезиология и интензивно лечение МУ – София
G. Voynova¹, P. Kalaydzhiev¹,², R. Ilieva¹,², G. Nikolova1,3, D. Markov¹,², S. Yakov¹, Ts. Kotsev¹,
N. Georgieva¹, A. Hristova¹,², L. Shopov¹,², E. Kinova¹,², A. Goudev¹,²
1Cardiology Department, UMHAT “Tsaritsa Yoanna – ISUL” – Soa
2Department of Emergency Medicine, 3Department of Anesthesiology and Intensive Care, Medical University – Soa,
Резюме. Индивидуалния подход в лечението на сърдечната недостатъчност (СН) и персонализираната медицина са основна тема
през последните години на всички научни форуми. Съчетанието на хронична обструктивна белодробна болест (ХОББ)
и сънна апнея (СА) допълнително усложняват клиничната картина при пациентите със СН. Припокриването и на трите
заболявания изисква екип от специалисти и допълнителни терапевтични средства за по-добрия контрол и за подобряване
на прогнозата. Голяма част от патофизиологичните механизми на трите заболявания се припокриват. Новите терапии за
СН показват добри резултати, както при съсчтание с ХОББ, така и при СА. Неинвазивната вентилация при хоспитализация и
след това за дома е утвърден метод при отделните групи. В комбинация на трите заболявания все още липсват категорични
данни от рандомизирани проучвания.
Ключови думи: сърдечна недостатъчност; сънна апнея; хронична обструктивна белодробна болест; троен синдром на припокриването
Адрес за
кореспонденция: д-р Гергана Войнова, е-mail: gerivoinova@gmail.com
Abstract. The individual approach in the treatment of heart failure (HF) and personalized medicine have been the main topic in recent years in
all scientic forums. The combination of chronic obstructive pulmonary disease (COPD) and sleep apnea (SA) further complicates
the clinical presentation in patients with HF. The overlap of all three diseases requires a team of specialists and additional therapeutic
approach for better control and to improve the prognosis. A large number of the pathophysiological mechanisms of the three diseases
also overlap. The novel therapies for HF have shown good results, both in COPD and CA subgroups. Noninvasive ventilation during
hospitalization and at home is an established method in the individual groups. In a combination of the three diseases, denitive data
from randomized trials are still lacking.
Key words: heart failure; sleep apnea; chronic obstructive pulmonary disease; triple overlap syndrome
Address
for correspondence: Gergana Voynova, MD, е-mail: gerivoinova@gmail.com
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Г. Войнова и др.
tension and changes in the structure and function of
the right side of the heart compared to patients with
either OSA or COPD alone. The medication therapy for
COPD has no contraindications in patients with con-
gestive heart failure (CHF) and sleep apnoea. The new
medications for heart failure are benecial for all three
conditions. Treatment with positive airway pressure ef-
fectively benets individual patient groups. For patients
with OSA alone, continuous positive airway pressure
(CPAP) therapy is recommended for home use, while
for patients with COPD, bi-level positive airway pres-
sure (BiPAP) therapy is recommended, as ocially
outlined in the 2020 American Thoracic Society Clini-
cal Practice Guideline [4]. However, questions remain
open regarding patients with triple overlap syndrome.
OSA is characterized by repetitive and prolonged
interruptions (apneas) or reductions (hypopneas) in
airow by over 50% for more than 10 seconds during
sleep, accompanied by desaturation ≥ 4%, attributed to
upper airway obstruction [5]. Up to 81% of patients with
exacerbated heart failure are aected, as indicated by
a Bulgarian study on the subject [6]. The pathophysio-
logical mechanisms are well studied, with a pathological
cycle rapidly leading to the progression of heart failure
and higher rates of hospitalization and mortality. This is
illustrated in Figure 1. Regardless of the causative fac-
tors, the consequences involve variable levels of blood
oxygen and unstable carbon dioxide levels, along with
frequent arousals and signicant uctuations in chest
pressures. These uctuations cause disruptions in the
autonomic nervous system, leading to increased sym-
pathetic activity and decreased parasympathetic func-
tion, as well as disturbances in hypothalamic-pituitary
regulation. Variations in oxygen levels and subsequent
reoxygenation lead to the formation of free oxygen
radicals and oxidative stress, activating inammatory
mechanisms such as nuclear factor-kappa B (NF-kB)
and tumor necrosis factor-alpha (TNF-α). Finally, signi-
cant changes in intrathoracic pressure can cause atrial
stretching, changes in left ventricular wall pressure, and
increased oxygen demand by the cardiac muscle [7].
-
Continuous positive airway pressure (CPAP) therapy
is successfully used to treat OSA in patients with heart fail-
ure (HF), both acute [8] and chronic [9, 10, 11], with favor-
able benets for the cardiovascular system. An important
issue is the increased adrenergic activity in patients with
heart failure with preserved systolic function (Fig. 2).
In the literature many single-center studies add-
ing home CPAP therapy in HF patients show positive
results. Benets are noted regarding systolic function
and left ventricular ejection fraction, improvement in
diastolic function, and arterial pressure [12, 13, 14].
However, in one large study by McEvoy et al. involv-
ing over 1300 patients, no signicant dierence was
found in ejection fraction and systolic arterial pressure,
only a signicant dierence in diastolic arterial pres-
sure was noted [15]. Dierences in these studies may
be attributed to variations in follow-up periods ranging
from 6 months to 2 years and patient selection crite-
ria. Some studies include only patients with reduced
systolic function, while others, like ours, do not select
patients based on this parameter. Bulgarian authors
on the subject also demonstrated the benet of adding
Pathophysiological mechanisms of obstructive sleep apnea and heart failure
Застойна сърдечна недостатъчност...
automatic CPAP to standard home medication therapy
[16]. Individual parameters such as LVEF% (Fig. 3), body
mass index (BMI), systolic and diastolic arterial pressure
also inuence outcomes.
Following the data published by SERVE-HF in 2015
[17], Bradley TD et al. published the results of ADVENT-
HF [18] in 2023, where adaptive servo-ventilation (ASV)
was used in patients with reduced systolic function. No
benets were observed in terms of hospitalization and
mortality. These results practically exclude adaptive ser-
vo-ventilation as an option for non-invasive ventilation in
patients with reduced systolic function. There is a lack of
data from randomized trials regarding patients with pre-
served systolic function and sleep disorders for the use
of ASV.
These dierences in data necessitate large random-
ized trials with sham devices to conrm or refute the hy-
pothesis of the benet of CPAP therapy in HF patients.
The European Society of Car-
diology published its new recom-
mendations in 2021, and just 2
years later, in 2023, an update was
released [19, 20]. In 2021, the rec-
ommendations indicated sacubi-
tril/valsartan as a Class I, Level of
Evidence A medication for patients
with reduced systolic function due
to its ability to reduce overall mor-
tality, cardiovascular mortality, and
heart failure hospitalizations. This
change was based on the PARA-
DIGM-HF study involving 8442 pa-
tients with reduced left ventricular
systolic function [21]. Subsequent
analyses and studies explored the
eects of sacubitril/valsartan (SV)
on sleep apnea. Small prospec-
tive clinical trials reported improve-
ments in sleep apnea episodes in
patients on SV compared to those
on ACE inhibitors [22]. With the
2023 update, there is a high recom-
mendation for treating all classes of
heart failure with sodium-glucose
cotransporter-2 protein inhibitors
(SGLT2i). Analyses regarding their
impact on sleep apnea are also
ongoing. Xie L et al. conducted a
multicenter randomized clinical trial
comparing patients with obstructive
sleep apnea (OSA) and heart fail-
ure with added dapagliozin to standard therapy and a
control group, with a 3-month follow-up. Results showed
benets in sleep parameters, as well as improvement in
left ventricular systolic and diastolic function, NT-proBNP
levels, and left ventricular dimensions in patients receiv-
ing SGLT2i. It‘s worth noting that only 107 patients were
included, but it provides a good direction for larger ran-
domized trials [23]. Explaining the positive eects on
breathing during sleep, improvements in hemodynamics,
volume overload, and subsequently sympathetic activity
in these patients can be sought. The concept of shared
risk factors and pathophysiological mechanisms is sup-
ported by the fact that better treatment of heart failure also
inuences sleep apnea [24].
Heart failure (HF) and chronic obstructive pulmo-
nary disease (COPD) are signicant causes of mor-
Increased adrenergic activity in patients with heart failure with preserved ejection fraction
Change in left ventricular ejection
fraction during CPAP therapy
Г. Войнова и др.
bidity and mortality worldwide. The association between
the two diseases is common and characterized by higher
levels of mortality and morbidity than each disease alone.
Both conditions share common risk factors such as ad-
vanced age, smoking, and systemic inammation [25].
Obstructive syndrome is caused by chronically damaged
bronchi, with interstitial and submucosal edema and -
brotic remodeling that compress and obstruct the air-
ways. Destruction of lung tissue in alveolar walls, result-
ing in emphysematous bullae, leads to impaired function.
Individuals with stable COPD have low-grade, chronic
systemic inammation favoring systemic atherosclerosis
due to increased levels of C-reactive protein (CRP) and
tumor necrosis factor-alpha (TNF-α), leading to the de-
velopment of coronary artery disease [26]. On the other
hand, acute inammation has several cardiovascular ef-
fects: it increases neutrophil and brinogen levels, leading
to a procoagulant state and causing disturbances in the
autonomic nervous system that favor arrhythmias. COPD
is often associated with pulmonary arterial hypertension,
leading to right HF and eventually left HF over time.
COPD is characterized by persistent symptoms and
airow obstruction due respectively to damage to the air-
ways and alveoli, chronic bronchitis, and emphysema,
conrmed by spirometry with a post-bronchodilator test
showing FEV1 (forced expiratory volume in one second)/
FVC (forced vital capacity) < 70%. The severity of this
airow limitation is further classied based on post-bron-
chodilator FEV1 into GOLD stage 1 (FEV1 ≤ 80% predict-
ed), GOLD stage 2 (50-80%), GOLD stage 3 (30-50%),
GOLD 4 (FEV1 < 30%) [27].
Primary diagnosis is crucial. When HF is superim-
posed on COPD, it has a signicant adverse eect on
prognosis, while a secondary diagnosis of COPD in an
HF patient appears to have little impact [28]. Diagnosing
one from the other is a considerable clinical challenge,
even when using „gold standard“ diagnostic tests, but
timely identication and treatment of the underlying dis-
ease process have a signicant impact on symptoms,
quality of life, and, in the case of HF with reduced ejection
fraction (HFrEF), long-term outcomes. Once the diagno-
sis of HFrEF is established, early treatment with optimal
medical therapy is essential [30]. Increased attention is
recommended with beta-blockers, but comorbidity with
COPD should not be a reason to discontinue treatment. If
there are concerns about bronchoconstriction and thera-
py with non-selective beta-blockers like carvedilol, switch-
ing to a cardioselective betablocker such as bisoprolol is
recommended [30]. Note that most treatments for HFrEF,
including loop diuretics, may also have favorable aspects
in COPD in patients with both diagnoses. Subanalyses of
large drug trials that inhibit sodium-glucose cotransporter
proteins in the nephron (SGLT2i) also consider subgroups
with COPD. In DAPA-HF, one in eight patients with HFrEF
had concomitant COPD. Participants with COPD had a
higher risk of hospitalization and cardiovascular mortality.
The benet of dapagliozin was observed in both groups
of patients with and without COPD [31]. Drug interactions
are presented in Figure 4.
PAP has various eects on hemodynamics. Firstly,
PAP reduces systemic venous return and right cham-
ber preload by increasing intrathoracic pressure [32,
33, 34]. Secondly, PAP alters pulmonary vascular resis-
tance (PVR), a major factor in right chamber overload,
Various drug interactions
in HF and COPD treatment
Застойна сърдечна недостатъчност...
by alternating lung volume [35]. Additionally, reducing
right chamber preload and increasing right ventricular
afterload leads to decreased pulmonary venous return
and limitation of left chamber lling and preload. The
increased intrathoracic pressure compared to atmo-
spheric pressure creates a pressure dierence between
intrathoracic and extrathoracic cavities. Therefore, PAP
may reduce left chamber afterload. In patients without
HF, who are usually preload-dependent, reduced right
chamber preload and left chamber preload in addition
to increased right chamber afterload may result in a net
decrease in cardiac output, while reducing left chamber
afterload may result in increased cardiac output. Pa-
tients with HF are more sensitive to reduced afterload
and are mainly dependent on it. PAP therapy causes a
net increase in cardiac output by reducing right cham-
ber preload, left chamber preload, and afterload, while
increasing afterload may decrease cardiac output [36].
Bi-level PAP provides two xed levels of PAP: a
higher level of pressure during inspiration (inspiratory
positive airway pressure (IPAP)) and a lower level of
pressure during expiration – expiratory positive airway
pressure (EPAP). The level of pressure support is de-
termined as the dierence between IPAP and EPAP,
and the level of IPAP plays an important role in reliev-
ing respiratory muscles, reducing respiratory work,
controlling obstructive hypopnea or restricted ow,
maintaining alveolar ventilation, and reducing partial
pressure of carbon dioxide (PaCO2). EPAP has respi-
ratory and hemodynamic eects similar to those pro-
vided by CPAP. Additionally, BiPAP devices have sev-
eral backup ventilation modes, including spontaneous
breathing (S-mode), synchronized backup ventilation,
and spontaneous breathing with synchronized backup
ventilation (ST-mode) (Fig. 5) [37].
Studies demonstrate the ecacy of PAP therapy
during hospitalization for heart failure. In such cases,
BiPAP shows advantages over CPAP and better prog-
nosis, particularly in combination with sleep apnea and
COPD [38]. However, the situation regarding continu-
ation of home therapy is dierent. Large randomized
trials on post-discharge behavior of patients with over-
lapping triple syndrome are still lacking. Several retro-
spective studies show a clear link between cardiovas-
cular pathology and overlapping syndrome. Adle et al.
compared data from 14,300 patients with overlapping
syndrome, revealing a higher incidence of heart failure
and worse prognosis among these patients. Addition-
ally, there is a high prevalence of carotid stenosis and
strokes [39]. Adding BiPAP for acute decompensation
with carbon retention has entered the recommenda-
tions of Intensive Care Societies as a rst-line method
in several guidelines, including the European Respira-
tory Society [40].
Mokhlesi B et al. analyzed nearly 3000 patients who
received PAP without specifying the form of home therapy
after hospital discharge as empirical treatment. Interest-
ingly, every form of PAP improved the post-hospital period
and reduced mortality. The main inclusion criteria were
overweight and hypoventilation. The article also empha-
sizes the lack of randomized studies on the topic [41].
Based on available data on overlapping syndrome,
there seems to be a signicant link between heart fail-
ure, COPD, and OSA. The coexistence of all three con-
ditions can signicantly increase mortality. Compared
to groups with only COPD or only OSA, patients with
overlapping syndrome likely have worse diastolic func-
tion, right ventricular hypertrophy, more severe oxygen
desaturation, and more frequent decompensation of
heart failure. The main drug classes for both COPD
and HF have rather an additive eect. Positive pres-
sure therapy improves prog-
nosis, both with CPAP and Bi-
PAP, in various patient cohorts
with OSA and COPD. There is
insucient denitive data on
the benet of BiPAP in treating
patients with HF and overlap-
ping syndrome. Adding such
therapy after discharge would
be a non-pharmacological ap-
proach with an additional ef-
fect on standard heart failure
therapy.
Schematic presentation of Bi-level positive airway pressure
Г. Войнова и др.
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No conict of interest was declared
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