Circulation

IN DEPTH
Systemic Consequences of Pulmonary
Hypertension and Right-Sided Heart
Failure

ABSTRACT: Pulmonary hypertension (PH) is a feature of a variety of Stephan Rosenkranz, MD

diseases and continues to harbor high morbidity and mortality. The main Luke S. Howard, MD
consequence of PH is right-sided heart failure which causes a complex Mardi Gomberg-Maitland,
clinical syndrome affecting multiple organ systems including left heart, MD
brain, kidneys, liver, gastrointestinal tract, skeletal muscle, as well as Marius M. Hoeper, MD
the endocrine, immune, and autonomic systems. Interorgan crosstalk
and interdependent mechanisms include hemodynamic consequences
such as reduced organ perfusion and congestion as well as maladaptive
neurohormonal activation, oxidative stress, hormonal imbalance, and
abnormal immune cell signaling. These mechanisms, which may occur in
acute, chronic, or acute-on-chronic settings, are common and precipitate
adverse functional and structural changes in multiple organs which
Downloaded from http://ahajournals.org by on July 12, 2022

contribute to increased morbidity and mortality. While the systemic

character of PH and right-sided heart failure is often neglected or
underestimated, such consequences place additional burden on patients
and may represent treatable traits in addition to targeted therapy of
PH and underlying causes. Here, we highlight the current state-of-the-
art understanding of the systemic consequences of PH and right-sided
heart failure on multiple organ systems, focusing on self-perpetuating
pathophysiological mechanisms, aspects of increased susceptibility of
organ damage, and their reciprocal impact on the course of the disease.

P
ulmonary hypertension (PH) in its various forms affects ≈1% of the global
population, and up to 10% of individuals >65 years of age.1 PH is defined
by a mean pulmonary artery pressure ≥25 mm Hg at rest, although a lower
threshold (>20 mm Hg) was recently proposed during the 6th World Symposium
on PH.2 Based on left-sided filling pressure, measured as pulmonary arterial
wedge pressure (PAWP) or left ventricular end-diastolic pressure, PH is subclas-
sified into pre- (pulmonary arterial wedge pressure/ left ventricular end-diastolic
pressure ≤15 mm Hg) and postcapillary PH (pulmonary arterial wedge pressure/ Key Words:  cognitive function
left ventricular end-diastolic pressure >15 mm Hg).2,3 PH occurs as a common ◼ immune system ◼ kidney dysfunction
◼ liver dysfunction ◼ pulmonary
consequence of multiple underlying diseases including pulmonary vascular dis- hypertension ◼ right-sided heart failure
ease and thromboembolic disease, but is most commonly associated with left- ◼ sleep
sided heart disease and chronic lung disease, particularly in elderly individuals.1–3 Sources of Funding, see page 690
The clinical classification of PH distinguishes 5 groups: (1) Pulmonary arterial hy-
© 2020 American Heart Association, Inc.
pertension (PAH); (2) PH caused by left heart disease (LHD); (3) PH caused by lung
disease or hypoxia; (4) Chronic thromboembolic PH (CTEPH); and (5) PH with https://www.ahajournals.org/journal/circ

678 February 25, 2020 Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362

 Rosenkranz et al
unclear or multifactorial mechanisms.2 Although these
entities are distinct from a pathogenetic perspective,
they may all cause severe PH, representing an in-
creased right ventricular (RV) afterload and, as a com-
mon final path, eventually lead to right-sided heart
failure (HF), which aggravates symptoms and results
in a high mortality risk.3 Strikingly, deterioration in RV
structure and function greatly exceeded correspond-
ing changes in the left ventricle (LV) during long-term
follow-up in patients with left-sided HF with preserved
ejection fraction.4 In addition, PH and RV dysfunction
are often accompanied by hypoxemia, which can have
multiple, often co-existing causes, and affect multiple
organ systems (Figure 1). Interorgan crosstalk involves
circulating pro-inflammatory cytokines that act locally,
but may also affect other organ systems distant from
their origin (Figure 2). While the systemic character of
PH and right-sided HF is often neglected or underes-
timated, such consequences place additional burden
to patients and may represent treatable traits in addi-
tion to targeted therapy of PH and underlying causes.
Here, we highlight the systemic consequences of PH
and right-sided HF in multiple organ systems.
Downloaded from http://ahajournals.org by on July 12, 2022
Figure 1. Systemic consequences of pulmonary hypertension and right heart failure in multiple organ systems.
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
Systemic Consequences of PH and Right-Sided HF
LEFT VENTRICLE
STATE OF THE ART
Eccentric remodeling and contractile dysfunction of
the right heart in patients with PH or pulmonary arte-
rial hypertension (PAH) have an important impact on
the LV, as they may result in impairment of LV geom-
etry, structure, and function (Figure 3). Given the in-
terdependency of the left and right sides of the heart,
which is determined by shared myocardium (septum),
pericardial restraint and the serial nature of the circu-
latory system, right ventricular strain directly affects
the left ventricle. Increases in RV size and pressure
cause mechanical septal leftward shift leading to LV
compression,5 which is visualized by paradoxical sep-
tal movement, a “D-shaped” left ventricle, and an in-
creased LV eccentricity index. A low stroke volume and
cardiac output from RV dysfunction may contribute
to underfilling of the LV, particularly during exercise.6
Diastolic ventricular interaction is also important in PH/
RV failure, because right heart overload and pericar-
dial restraint may cause elevation in left heart filling
pressures even when LV preload is reduced and the LV
is underfilled.7,8
February 25, 2020 679
 Rosenkranz et al Systemic Consequences of PH and Right-Sided HF
STATE OF THE ART
Downloaded from http://ahajournals.org by on July 12, 2022

Figure 2. Systemic consequences of pulmonary hypertension (PH) and right-sided heart failure: Interdependent mechanisms, systemic inflamma-
tion, and interorgan cross-talk.
In PH or pulmonary arterial hypertension (PAH), elevated pulmonary artery pressure and pulmonary vascular resistance (PVR)—representing an increased right
ventricle (RV) afterload—lead to right heart strain and failure, which in turn also affects left heart function. Both impaired perfusion caused by systemic low
output and systemic congestion caused by impaired RV function cause insult to numerous organ systems. This leads to local liberation of soluble proinflammatory
mediators, and thus initiation of inflammatory cascades. This scenario is associated with systemic inflammation, where locally liberated circulating proinflamma-
tory cytokines act in a paracrine fashion, but also affect other targets.28,35 CVP indicates central venous pressure; GI, gastrointestinal; LMCS, left main compression
syndrome; PA, pulmonary artery; and RAP, right atrial pressure.

Because the heart muscle constantly adapts to its de-
mands, reduced work load and chronic underutilization
of the LV lead to deconditioning and atrophic remodel-
ing in PAH, characterized by reductions of LV end-dia-
stolic volume and LV mass by ≈10–20% and 5–15%,
respectively, and reductions in LV systolic strain, stroke
volume and ejection fraction.8–10
At the cellular and molecular level, the LV myocardi-
um of patients with end-stage PAH displays cardiomyo-
cyte atrophy and contractile dysfunction, as indicated
by substantial reductions in the cross-sectional area
and the maximal force-generating capacity of cardiac
myocytes by ≈30% and ≈25%, respectively, as well as
lower cellular content of the contractile protein myo-
sin, impaired phosphorylation of sarcomeric proteins
(cardiac troponin I, myosin-binding protein C), reduced
number of available myosin-based cross-bridges, and
a leftward shift in the force [Ca2+] relationship.11 The
latter indicates an increase in the [Ca2+] sensitivity of
force generation and may be viewed as a compensatory
mechanism for the reduced force-generating capacity,11
but may also provide an explanation for impaired LV
diastolic function in PAH.8
The importance of an atrophic and malfunctioning
LV becomes particularly evident in the context of lung
transplantation in end-stage PAH, where increased
postoperative filling and the inability to handle a nor-
malized preload may lead to LV failure.12 This temporary
phenomenon may effectively be bridged by veno-arte-
rial extracorporeal membrane oxygenation after lung
transplantation to allow the LV to adapt to normalized
hemodynamics.12
In addition to its consequences on LV myocardium,
severe PH may also affect coronary perfusion. Because
of the topographical proximity, pulmonary artery dila-
tion may occasionally cause compression of the left

680 February 25, 2020 Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362

 Rosenkranz et al
main coronary artery (left main compression syndrome),
and may trigger myocardial ischemia and arrhythmias.13
Indeed, a significant number of PAH patients die from
sudden death, and a pulmonary artery diameter ≥48
mm was associated with a 7.5-fold increased risk for
sudden unexplained death in patients with severe PAH
or CTEPH.14 As improved treatment options have led to
prolonged survival in PAH, physicians should be alert for
such emerging risk factors in long-term survivors.
LIVER
The liver of patients with PH and RV failure may be ex-
posed to decreased arterial perfusion, hypoxemia, and
venous congestion.15 Relatively little research has been
done on liver dysfunction in patients with PAH, while
Downloaded from http://ahajournals.org by on July 12, 2022
there is abundant literature on the effects of HF on liver
function in patients with underlying LHD. In the aggre-
gate, there is a strong body of evidence suggesting that
liver dysfunction in these patients is closely related to
right-sided HF rather than to LV dysfunction.
Acute right- or left-sided HF with shock and hepatic
hypoperfusion may result in ischemic hepatitis (Fig-
ure 4A, right). Its histological hallmark is centri-lobular
necrosis.15 Characteristic laboratory findings are rapid
increases in serum amino-transferases (>20 times the
upper level of normal) and lactate dehydrogenase. Se-
rum bilirubin is only mildly elevated, except for cases
that progress to liver failure or secondary ischemic
cholangiopathy. The majority of cases are reversible if
the underlying cause is resolved, although progressive
liver dysfunction and acute liver failure have been re-
ported. Pre-existing hepatic venous congestion caused
by right-sided HF seems to increase the risk of acute
ischemic hepatitis.16
Chronic congestive hepatopathy has commonly
been described in patients with underlying LHD, but
its degree is not related to LV dysfunction but to the
presence of PH and elevated right-sided filling pres-
sures.17,18 Chronic hepatic congestion may result in
liver fibrosis or, occasionally, in cardiac cirrhosis.19 In
patients with congestive HF, the extent of hepatic fi-
brosis was associated with right atrial pressure, right
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
Systemic Consequences of PH and Right-Sided HF
STATE OF THE ART
Figure 3. Impact of pulmonary hyperten-
sion and right heart failure on the left
heart.
Right ventricle (RV)–left ventricle (LV) interaction
is markedly influenced by volume management,
where IV fluid in the setting of marked LV com-
pression leads to increased RV wall tension and
further deterioration, whereas volume reduction
under careful monitoring decompresses the
RV, leads to improved RV function, and allows
better filling of the LV, improved coronary perfu-
sion, and increased cardiac output.
atrial dilatation, and right ventricular dilatation (Fig-
ure  4A, left).17 The authors concluded that hepatic
fibrosis correlated with the degree of right-sided HF,
irrespective of the cause. Consistently, in patients with
precapillary PH, elevated levels of liver fibrosis marker,
P4NP 7S (7S domain of collagen type IV), were associ-
ated with higher central venous pressure, right-sided
volume overload, and mortality.20
Patients who develop congestive hepatopathy are
typically those with severe and prolonged right-sided
HF. Presenting features include signs of systemic ve-
nous congestion such as enlarged and pulsating jugu-
lar veins and edema, as well as jaundice and ascites.
Larger amounts of ascites in the absence of edema
may indicate cardiac cirrhosis. Laboratory findings in-
clude elevated levels of yGT (y-glutamyl-transpepti-
dase), ALP (alkaline phosphatase) and bilirubin, and
normal or mildly elevated serum aminotransferases.15,19
Impaired synthetic liver function with reduced serum
albumin may be encountered in advanced cases,21
and hepatic drug metabolism may also be impaired.15
Characteristic changes in hepatic blood flow patterns
may be observed with ultrasound. Taniguchi et al re-
cently demonstrated that liver stiffness, as assessed by
elastography using a Fibroscan device correlated with
variables indicating right-sided HF, was associated to
the clinical severity of HF, and predicted clinical out-
comes.22 Elevated serum bilirubin levels are associated
with an increased mortality risk in patients with PAH, at
least in univariate analyses.23,24
KIDNEYS
Elevated serum creatinine concentrations and/or a
low estimated glomerular filtration rate are present in
12% to 29% of PAH patients and are associated with
poor outcome.25,26 In the REVEAL registry (Registry to
Evaluate the Early and Long-term Pulmonary Arterial
Hypertension Disease Management), a large US based
registry of PAH patients, an association between renal
insufficiency and death was found in both univariate
and multivariate analyses.24 Even slight abnormalities
are clinically significant,25 with both the absolute value
February 25, 2020 681
 Rosenkranz et al
STATE OF THE ART
Downloaded from http://ahajournals.org by on July 12, 2022
and a ≥10% decline in estimated glomerular filtration
rate from baseline over ≥1 year associated with an in-
creased risk of death in the REVEAL registry.27
In PH, the heart aims to accommodate increased
PVR by balancing pre- and afterload, which may be
accomplished by neurohormonal activation (eg, argi-
nine, vasopressin, endothelin-1). This however leads to
water and salt retention, venous congestion, and re-
duced cardiac output. In states of diminished cardiac
output or impaired contractile reserve, renal dysfunc-
tion is traditionally thought to occur secondary to renal
hypoperfusion (Figure 4B, right).28,29 Accordingly, mark-
ers of low cardiac output or tissue hypoxia, including
uric acid, correlate with disease severity and mortality
in PAH.31 However, chronic venous congestion resulting
from right-sided HF also appears to play a central role in
distant organ malfunction including acute and chronic
kidney injury, and central venous pressure has been
found to be one of the most important hemodynamic
682 February 25, 2020
Systemic Consequences of PH and Right-Sided HF
Figure 4. The liver and kidney in pulmonary
hypertension and right heart failure.
A, Acute ischemic hepatitis and congestive
hepatopathy. Right inset, Centrilobular necrosis
in ischemic hepatitis (from reference 15). Left in-
set, Chronic hepatic congestion with sinusoidal
dilatation and portal fibrosis (from reference 17).
B, Congestive nephropathy. Right inset, Low
perfusion kidney injury caused by hypoperfu-
sion and ischemia, demonstrating fibosis (*),
necrotic cells (arrowhead), and intraluminal
debris (from reference 30). Left inset, Conges-
tive nephropathy, characterized by interstitial
edema, swollen tubule cells, and tubular com-
pression (from reference 33). ALAT indicates ala-
nine transaminase; AP, arterial pressure; ASAT,
aspartate aminotransferase; CVP, central venous
pressure; LDH, lactic acid dehydrogenase; and
yGT, gamma-glutamyl transpeptidase.
determinants of worsening renal function in both PAH
and HF.26,32 In PAH patients, both decreased cardiac in-
dex and increased right atrial pressure were indepen-
dent determinants of reduced estimated glomerular
filtration rate over time.26
Renal congestion results from backward transmission
of elevated central venous pressure as a consequence
of right-sided HF and is characterized by renal edema,
increased interstitial pressure, tubular compression, and
intracapsular tamponade, which may further aggravate
back pressure and thus decrease renal perfusion pres-
sure and glomerular filtration rate (Figure  4B, left). A
recent Doppler ultrasonography study in HF patients re-
vealed that intrarenal venous flow patterns, rather than
arterial resistance index, related to central venous pres-
sure and strongly correlated with clinical outcomes.34
Furthermore, activation of venous endothelium acts as
a stimulus for release of inflammatory mediators, which
in turn may act locally (causing structural glomerular
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
 Rosenkranz et al
and interstitial damage, sclerosis/fibrosis as well as
functional abnormalities such as diminished tubular re-
absorption, proteinuria, and retention of salt and wa-
ter)28,29 or affect distant organ systems (Figure  2), in-
cluding the lung.35
During the course of PH progression, it is likely that
repetitive episodes of subclinical acute kidney injury oc-
cur, which depict a slow progressive degenerative pro-
cess and predispose to the development of subsequent
chronic kidney disease.36 Sensitive markers of early
kidney injury include L-FABP (L-type fatty acid-binding
protein), NGAL (neutrophil gelatinase-associated lipo-
calin, and KIM-1 (kidney injury molecule-1).37,38 Even
mild proteinuria indicates endothelial dysfunction, and
tubulo-interstitial fibrosis best correlates with the devel-
opment of chronic kidney disease.
In the setting of decompensated PH, RV failure,
and acute kidney injury, deterioration of either organ
function may result in a vicious circle leading to refrac-
tory congestive right-sided HF. Patients with acute-on-
chronic renal injury have a narrow window for fluid
management of venous congestion and are at high risk
of worsening cardiorenal function and death. However,
in the setting of acute decompensated HF with worsen-
ing renal function, it is important to note that although
intensive volume removal initially resulted in worsen-
ing of creatinine and a rise in tubular injury biomarkers
(NAG, KIM-1, NGAL), renal function recovery over time
was superior, suggesting that the benefits of deconges-
Downloaded from http://ahajournals.org by on July 12, 2022
tion may outweigh any modest or transient increases in
serum creatinine or tubular injury markers.39
Notably, there is crosstalk between the pulmonary
vasculature, the (right) heart, and the kidney.28 While
the kidney is dependent on blood flow and perfusion
pressure generated by the heart, the heart is directly
dependent on the regulation of fluid homeostasis and
the body´s salt and water content by the kidney. Fur-
thermore, renal dysfunction itself may aggravate PH,
because circulatory factors have been implicated in the
pathogenesis of pulmonary inflammation after renal in-
jury, which may aggravate pathomechanisms of PH.28
Few data are available on the impact of targeted PAH
therapies on renal function. In a post hoc analysis of
the SUPER-1 study (Sildenafil Use in Pulmonary Arterial
Hypertension-1), treatment with the phosphodiesterase
type 5 inhibitor sildenafil was associated with improved
kidney function.40 The impact of other targeted PAH
therapies on renal function merits further investigation.
GUT AND BOWEL
Altered gut permeability resulting in bacterial transloca-
tion and endotoxinemia was described in patients with
congestive HF and has been linked to impaired arterial
perfusion and venous congestion.41 Similar mechanisms
are to be expected in patients with PH and right-sided
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
Systemic Consequences of PH and Right-Sided HF
HF. Mechanistically, bacterial translocation occurs when
the edematous or ischemic gut mucosa loses its bar-
STATE OF THE ART
rier function. Bacteria and toxins penetrate through the
intestinal epithelium and are carried by lymphatic drain-
age to mesenteric lymph nodes from where they reach
other organs and the blood stream.42
Niebauer and coworkers have shown that in patients
with congestive HF and edema, elevated endotoxin lev-
els could be normalized with diuretic treatment,43 sug-
gesting that venous congestion of the bowel wall was
the main cause of a leaky bowel. Bacterial translocation
from the bowel may also explain, at least partly, why
nonpneumogenic sepsis and sepsis-like illness without
documented bacteremia were relatively frequent causes
(15%) of intensive care unit admissions in patients with
PAH.44 Furthermore, C-reactive protein levels were el-
evated in the vast majority of PAH patients admitted to
the intensive care unit, in particular in patients who did
not survive.44 Although speculative, it is possible that a
leaky bowel may have been a main source of inflamma-
tion in these patients.
Recently, Ranchoux et al proposed a gut-lung con-
nection in PAH where intestinal leakiness and endo-
toxinemia, potentially occurring as a consequence of
right-sided HF and intestinal congestion, may promote
exacerbated inflammation and pulmonary vascular re-
modeling,45 thus contributing to a self-perpetuating
process. Specifically, they showed that lipopolysac-
charide translocation from gut lumen to bloodstream
activated pulmonary and systemic TLR4 (Toll-like recep-
tor 4), the main receptor for lipopolysaccharide, which
was associated with increased levels of soluble CD14
(cluster of differentiation 14 lipopolysaccharide-binding
protein), a marker of macrophage activation. The blood
levels of lipopolysaccharide, TLR4 and soluble CD14
were markedly elevated in patients with idiopathic PAH
(IPAH) or heritable PAH, supporting that both bacte-
rial translocation and macrophage activation occur in
PAH.45 Furthermore, lipopolysaccharide serum levels
were substantially lower in treated versus untreated
PAH patients, and TLR4 deficiency completely protected
against experimental PH. Interference with gut micro-
biota or TLR4 may thus be effective in disrupting this
vicious circle.
Bowel dysfunction in patients with HF has been
linked to the development of cachexia, which again
seems to be closely associated with the presence of RV
rather than LV dysfunction.46 In a recent study among
patients with left-sided HF, the presence of cachexia
was related to bowel wall thickness, elevated right
atrial pressures and RV dysfunction, but not LV ejection
fraction.47 Bowel wall thickness, in turn, correlated with
C-reactive protein levels, suggesting a link between el-
evated right-sided filling pressures, bowel congestion,
and systemic inflammation. In patients with intestinal
congestion and cachexia, gut microbiota may also
February 25, 2020 683
 Rosenkranz et al
contribute to progression of the HF syndrome and mor-
tality.48 While data on cachexia have been generated
STATE OF THE ART
primarily from patients with PH-LHD, similar mecha-
nisms likely apply to other forms of PH.
IRON HOMEOSTASIS
Iron deficiency (ID) is common in patients with idiopath-
ic PAH, with prevalence ranging from 30% to 63%,49,50
and occurring independently of anticoagulation status.
In a study where the prevalence of ID was 30%, pa-
tients with mutations in BMPR2 (bone morphogenetic
protein receptor type 2) appeared to have the highest
point prevalence of ID at 60%.50 In the same study,
patients with CTEPH had lower point prevalence of ID
than idiopathic PAH despite higher rates of anticoagu-
lation and being older.50 While not entirely consistent
across studies, ID appears to be associated with worse
World Health Organization Functional Class, lower ex-
ercise capacity, worse hemodynamics, and higher se-
rum NT-proBNP (N-terminal pro-B-type natriuretic pep-
tide) levels in idiopathic PAH.49,50 In addition, ID (defined
as soluble transferrin receptor levels >28.1 nmol/l or by
the soluble transferrin receptor index) was associated
with increased mortality.49
Enteric iron absorption is negatively regulated by
hepcidin, which is released from the liver in the pres-
ence of iron loading. Hepcidin levels were inappropri-
Downloaded from http://ahajournals.org by on July 12, 2022
ately elevated in patients with IPAH, which may contrib-
ute to ID49 and explain the poor response to oral iron
replacement, through presumed decreased gut absorp-
tion.51 The inappropriate elevation of hepcidin in idio-
pathic PAH appears to be independent of IL-6.49 When
BMPR-2 is knocked down in HepG2 cells (hepatoma
cell line G2), BMP-6–mediated hepcidin expression is
further increased,49 possibly providing a connection be-
tween altered BMP signaling in PAH and ID.
It has not yet been established whether ID is sim-
ply a bystander (risk marker) or disease-modifying risk
factor in PAH. In humans, there are fairly compelling
data that iron is a significant regulator of pulmonary
vascular tone. Otherwise healthy individuals with ID
have exaggerated hypoxic vasoconstrictive response
which can be corrected with intravenous iron replace-
ment.52 In addition to its effects on pulmonary vas-
cular tone, ID may also affect vascular remodeling,
although this is less clear.
ID may thus be mimicking a pseudohypoxic stimulus
to the pulmonary vasculature. Iron is a cofactor in the
prolyl hydroxylation of hypoxia-inducible factor (HIF) 1α
and 2α, which targets it for ubiquitination and degra-
dation. Thus, ID leads to stabilization of HIFs and in-
creased HIF-dependent transcription. Conversely, in the
presence of ID, depletion of iron-sulphur clusters allows
iron-regulatory protein-1 to bind to cis-regulatory iron
response elements, leading to translational repression
684 February 25, 2020
Systemic Consequences of PH and Right-Sided HF
of HIF2α, which prevents expression of erythropoietin.53
In addition to direct effects on the pulmonary vascula-
ture, ID is associated with reduced myoglobin, impaired
mitochondrial oxidative capacity, and anemia, limiting
the aerobic capacity of muscle tissue, and may also af-
fect myocardial metabolic substrate use through mito-
chondrial dysfunction.54
Two open-label studies of intravenous iron replace-
ment in patients with ID and PAH have demonstrated
improved exercise capacity and delayed time to the an-
aerobic threshold.55,56 No changes were seen in right
ventricular function, yet skeletal muscle biopsy samples
showed improved oxygen handling through increased
myoglobin and mitochondrial oxidative capacity, sug-
gesting that the benefits of iron repletion may not be
acting only through changes in central cardiopulmo-
nary hemodynamics.56
SKELETAL MUSCLES AND DIAPHRAGM
Reduced cardiac function with impaired oxygen deliv-
ery to skeletal muscles during exercise is the predomi-
nant mechanism by which exercise is impaired in PH.
Yet, skeletal muscle function, including that of respi-
ratory muscles,57 may be affected in PAH independent
of cardiac output. Maximal volitional and nonvolitional
strength of the skeletal muscle is not dependent upon
blood flow and is therefore an independent indicator of
muscle function. In PAH, both the quadriceps and inspi-
ratory muscles have impaired strength which correlates
with exercise capacity.
Studies investigating the mechanisms involved have
yielded inconsistent findings, although overall, there is
a tendency towards decreased maximal tension, but
with variable findings of muscle fiber size, fiber subtype,
and capillary density.57 Diaphragm samples obtained
at the time of pulmonary endarterectomy in patients
with CTEPH showed that slow twitch fibers displayed
decreased maximal force generation, which correlated
with maximal inspiratory pressure.58 No difference was
seen in fiber cross-sectional area between patients and
controls undergoing elective surgery, but calcium sensi-
tivity of force generation was reduced in fast twitch fi-
bers, which could be restored with troponin activation.
Mechanisms leading to muscle dysfunction are not
fully understood but may be both systemic and local in
origin. Circulatory pro-inflammatory cytokines are pos-
tulated to lead to muscle fiber atrophy and impaired
contractile function through proteolysis.59 More specifi-
cally, increased circulating GDF-15 (growth differentia-
tion factor-15) correlates with muscle fiber diameter and
strength, which may be mediated through phosphory-
lation of TAK1 (TGFβ-activated kinase 1) and reversed
by TAK1 inhibition.60 Reduced physical activity in PH but
increased ventilatory demand may be expected to lead
to relative protection of respiratory muscle function
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
 Rosenkranz et al
compared with peripheral muscles, but in turn, this may
make them more vulnerable because of increased pro-
tein turnover and thus susceptible to systemic factors.57
Deconditioning of peripheral muscles is associated with
reductions in capillary density, and systemic factors such
as iron deficiency and reduced cardiac output/oxygen
delivery further contribute to impaired aerobic capacity
of muscle tissue.
ENDOCRINE SYSTEM
Thyroid Disease
Patients with PAH have a high prevalence of thyroid
disease of ≈20%,61 and thyroid disease is a predictor
of poor prognosis in PH. A recent registry analysis of
1756 patients with various forms of PH determined
that untreated hypo- or hyperthyroidism measured by
thyroid stimulating hormone levels predicted mortality
in IPAH patients.62 Patients with treated thyroid disease
had a better survival and reduced free triiodothyroine
levels predicted death in PAH and CTEPH patients with
untreated thyroid disease.62 Even subclinical hyper- or
hypothyroidism are associated with an increased risk of
incident atrial fibrillation,63 which is detrimental in PH.
Hypothyroidism
The prevalence of hypothyroidism in IPAH is 10% to
Downloaded from http://ahajournals.org by on July 12, 2022
24%.64 Despite data on its association beginning over
2 decades ago, information about the direct relation-
ship of hypothyroidism and the pulmonary circulation
remains limited. One observational study of 63 patients
with PAH found that ≈50% had concomitant autoim-
mune thyroid disease.61 Notably, patients with PAH
have an increased prevalence of both antithyroglobulin
and antithyroperoxidase antibodies.61
Hyperthyroidism
The development of hyperthyroidism itself can lead to
arrhythmias and worsening right-sided HF and is mag-
nified in PH patients. Thyroid hormone directly affects
the heart, and the peripheral and pulmonary vascular
systems. Besides increasing myocardial inotropy and
heart rate, a low peripheral vascular resistance may
be the direct result of thyroid hormone on arteriolar
smooth muscle tone, as it enhances the signaling path-
way related to PI3K/akt (phosphatidylinositol 3-kinase/
protein kinase B) thus increasing 3 nitric oxide synthase
isoforms in endothelial and muscular cells.65 A high car-
diac output state in the setting of hyperthyroidism may
aggravate PH and exacerbate RV dysfunction, which
may result in cardiac decompensation. In addition, hy-
perthyroidism may also exert direct remodeling or func-
tional effects on the pulmonary vasculature and heart.65
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
Systemic Consequences of PH and Right-Sided HF
Possible mechanisms include enhanced catecholamine
sensitivity, increased metabolism of intrinsic pulmonary
STATE OF THE ART
vasodilators, and decreased metabolism of vasocon-
strictors. In patients with hyperthyroidism, Grave’s dis-
ease antibody levels directly correlated with pulmonary
artery pressure.
Metabolic Syndrome and Diabetes
Mellitus
The metabolic syndrome is highly associated with PH-
LHD.66 Loss of myocardial compliance because of meta-
bolic derangements of cardiac muscle and increased LV
mass lead to increased afterload and resultant postcap-
illary PH. Patients with PAH and metabolic syndrome
associated comorbidities did worse in the REVEAL reg-
istry, including reduced exercise capacity (hypertension,
diabetes mellitus, obesity), higher functional class (obe-
sity), and higher mortality (diabetes mellitus).66
Registry data indicate a higher than expected preva-
lence of diabetes mellitus in PAH patients.67 Older pa-
tients are more likely to have diabetes mellitus, and the
combination of diabetes mellitus and PAH is associated
with a higher mortality.67 While epidemiologic data in-
dicate an association, they cannot show that diabetes
mellitus itself leads to PAH or accelerates the disease, or
vice versa. Research however indicates that the effects
of hyperglycemia and insulin resistance on pulmonary
microcirculation, and perhaps the RV, may modify the
course of PH.68
Insulin resistance is linked to deficiency of the nu-
clear receptor PPARγ (peroxisome proliferator-activated
receptor gamma), which is also reduced in human PAH
and is involved in growth and apoptosis regulation of
endothelial cells and smooth muscle cells.69 Accord-
ingly, targeted deletion of PPARγ in smooth muscle
cells led to development of PH in animal models, and
treatment with PPARγ activators halted the progression
of experimental PH,70 and prevented right HF via fatty
acid oxidation.71 Furthermore, hyperglycemia inhibits
endothelial NO synthase and promotes the liberation of
reactive oxygen species and activation of protein kinase
C, leading to vasoconstriction and inflammation.68
In addition to its impact on the pulmonary vascula-
ture, the role of diabetes mellitus in RV fibrosis and isch-
emia also likely influences disease course and prognosis
of PAH patients. As in the microcirculation, local hyper-
glycemia in the RV stimulates the expression of growth
factors such as endothelin-1, platelet-derived growth
factor and TGF-β, resulting in fibrosis and inflamma-
tion.68 Likewise, insulin resistance in the heart upreg-
ulates the diabetic marker microRNA miR-29 family,
causing cardiac fibroblasts to increase collagen produc-
tion and myocardial fibrosis.72 Although not specifically
shown for the RV, the impact of diabetes mellitus on
microvessels promoting ischemia in numerous vascular
February 25, 2020 685
 Rosenkranz et al
beds is well established. Given the impact of diabetes
mellitus on RV fibrosis and the microvasculature, the
STATE OF THE ART
diabetic milieu in the right heart likely deteriorates the
adaptation of the RV to an increased afterload, and
thus RV/pulmonary artery coupling in PAH.
INFLAMMATION AND IMMUNE
SYSTEM, COAGULATION DISORDERS,
AND PLATELETS
Inflammation and Immune System
Inflammation is involved in PAH pathobiology and may
occur as a consequence of PAH in the lungs and various
other organ systems. There is systemic interaction be-
tween lungs, heart, and kidney, where soluble inflam-
matory mediators and regulators of innate and adaptive
immunity are secreted in response to PH-associated RV
hypertrophy/dilation and kidney injury, which may act
locally or affect distant organs.28 Consequently, patients
with PAH have elevated circulating levels of inflamma-
tory mediators in the blood and lungs, which are predic-
tive for survival.73 Classic severe PAH lesions contain pul-
monary perivascular inflammatory infiltrates composed
of T and B lymphocytes, mast cells, dendritic cells, and
macrophages.74 The pulmonary vasculature responds
to circulating inflammatory stimuli by increased prolif-
eration or migration and apoptotic-resistant phenotype
Downloaded from http://ahajournals.org by on July 12, 2022
producing smooth muscle cell hyperplasia, adventitial
remodeling, and endothelial dysfunction.74 Both B cells
and T cells contribute to the pro-inflammatory environ-
ment. The increased production of interleukin-1 and in-
terleukin-6 promotes activation, proliferation, and dif-
ferentiation of B lymphocytes.73 Regulatory T-cells are
dysfunctional in various forms of PAH, which occurs in
a leptin-dependent manner in idiopathic and connec-
tive tissue disease-associated PAH, but irrespective to
leptin levels in heritable PAH.75 Circulating autoantibod-
ies against endothelial cells and smooth muscle cells,
which alter different components of the vascular wall
in various tissues, have been described in patients with
IPAH and scleroderma-associated PAH.74,76 Whether
immune dysregulation may represent the cause or the
effect of PAH is not entirely known, but the systemic
character of circulating inflammatory mediators and or-
gan interaction should be recognized.28,74
Coagulation System
Increased plasma concentrations or plasma activities,
respectively, of procoagulatory factors such as fibrino-
gen, von Willebrand factor, and plasminogen-activator
inhibitor-1 have been described in patients with PAH
and CTEPH.77 Some patients with high pulmonary shear
stress conditions may develop an acquired von Wil-
lebrand syndrome.78 On the other hand, thrombi are
686 February 25, 2020
Systemic Consequences of PH and Right-Sided HF
commonly detected in the small pulmonary arteries in
IPAH.79 While anticoagulation was previously recom-
mended in all patients with idiopathic, heritable, and
anorexigen associated PAH, the overall level of evidence
to support this is weak, and current guidelines now rec-
ommend that this decision be made on a case by case
basis for the above subgroups, and recommend against
routine anticoagulation for other PAH subgroups.80 In
contrast, lifelong anticoagulation is strongly recom-
mended for CTEPH.
Thrombocytopenia
Thrombocytopenia (ie, platelet count <150 × 109/L) has
been reported in up to 20% of patients with idiopath-
ic PAH and seems to be related to disease severity.81
Thrombocytopenia is also commonly found in patients
with portopulmonary hypertension as a result of hyper-
splenism. The mechanisms causing thrombocytopenia
in IPAH are enigmatic. However, the observation that
it is almost exclusively found in patients with severe
disease may suggest a pulmonary thrombotic microan-
giopathy in these patients. There is no evidence that
other forms of PH are also associated with thrombocy-
topenia, except for some hematological conditions and
PAH patients with Eisenmenger syndrome who have a
higher platelet size, mean platelet volume, thrombo-
cytopenia, and platelet dysfunction, all of which may
contribute to the higher risk of thrombosis and bleed-
ing seen in these patients.82 Chronic platelet activation
as evidenced by higher plasma P-selectin, β-thrombo-
globulin, and platelet factor-4 may play a role in Eisen-
menger patients with erythrocytosis.83
COGNITIVE FUNCTION, DEPRESSION,
AND ANXIETY
As is the case in many chronic disorders, anxiety and
depression are common in PH and are associated with
disease severity;84 however, impairment of cognitive
function has also been noted in PH.85 One study of 46
patients with PAH demonstrated cognitive sequelae in
58% of patients. Moderate-to-severe depression and
anxiety were also present in 26% and 19% of patients,
respectively.86 A lower quality of life was not seen in
patients with worse cognitive function, although qual-
ity of life was associated with working memory. There
were no clear differences in disease severity between
those with and without cognitive impairment.
It has been suggested that cognitive impairment
may relate to impaired cerebral tissue oxygenation. In
an interventional study examining the impact of PAH
therapies on cognitive function, baseline cerebral tissue
oxygenation as measured by near-infrared spectros-
copy and 6-minute walk distance were the two inde-
pendent predictors of cognitive function and cerebral
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
 Rosenkranz et al
tissue oxygenation on multiple regression analysis.86
After the introduction of PAH therapies there was a
significant improvement in cognitive function on an ar-
ray of tests, but no change in cerebral tissue oxygen-
ation, and indeed there was no correlation between
change in cerebral tissue oxygenation and improve-
ment in cognitive function.
Pulmonary endarterectomy in CTEPH patients in-
volves deep hypothermic circulatory arrest and there
have been concerns that this may result in cognitive
impairment. A randomized trial was conducted to com-
pare deep hypothermic circulatory arrest with ante-
grade cerebral perfusion, which showed no difference
between the two techniques in terms of impact on cog-
nitive function.87 Rather, there was an improvement in
both groups by 12 weeks after surgery, possibly linking
cardiovascular with cognitive function.
EYES
Ocular involvement in patients with PH has not been
systematically studied. Several case reports have de-
scribed open-angle glaucoma, retinal detachment,
venous stasis retinopathy, ciliary detachment, and cen-
tral retinal vein occlusion in patients with PAH, most
of whom presented with elevated right-sided cardiac
filling pressures.88,89 It is conceivable that not PH itself,
but systemic venous congestion affects the eyes, in par-
Downloaded from http://ahajournals.org by on July 12, 2022
ticular by causing choroidal and retinal venous stasis.
However, the frequency and clinical relevance of such
findings are unknown.
AUTONOMIC FUNCTION AND
PERIPHERAL ENDOTHELIAL FUNCTION
While PAH is primarily recognized as a pulmonary vas-
cular disease imposing hemodynamic stress on the RV,
the course of the disease may be subject to variation by
circulating neurohormonal mediators (eg, sympathetic
nervous system, renin-angiotensin-aldosterone system)
and autonomic dysfunction which may act as disease
modifiers.90 In PAH, as well as in other forms of PH,
there is compelling evidence for both sympathetic and
parasympathetic abnormalities that are not restricted to
advanced stages of RV failure but also occur in early
stages. For instance, elevated circulating levels of nor-
epinephrine are found in IPAH and associated forms of
PAH, which act systemically and represent an indepen-
dent predictor of clinical deterioration.90
Altered autonomic function in PH thus has several
important consequences: (1) Adrenoceptor (α1, β1,
D1-5) downregulation and desensitization, caused by
adrenergic overspill and mediated through GRK2 (G-
protein-coupled receptor kinase-2), represent hallmarks
of maladaptive RV remodeling and may explain the
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
Systemic Consequences of PH and Right-Sided HF
poor long-term response of the failing RV to inotro-
pes;90 (2) Impairment of autonomous control reduces
STATE OF THE ART
heart rate variability in right HF, which correlates with
pulmonary artery pressure in patients with IPAH and has
prognostic significance in various cardiac diseases;91 (3)
Lower adrenergic baroreflex sensitivity in PAH patients
is associated with a greater susceptibility to systemic
(orthostatic) hypotension, cerebral hypoperfusion, and
syncope, which is also indicative of poor outcome;92 (4)
It was recently shown in animal models that sympathet-
ic overactivity and electrophysiological cellular remodel-
ing in experimental PH were linked to an increased vul-
nerability to atrial fibrillation and atrial flutter,93 which
are associated with poor outcome in human PAH;94 (5)
There is also a link between immune dysregulation, au-
tonomic dysfunction, and endothelial dysfunction in
PAH.74 Several studies have shown that patients with
PAH display impaired peripheral endothelial function as
assessed by measurement of brachial artery flow-medi-
ated dilation or the peripheral arterial tone ratio.95
Although several recent studies have investigated
a potential role of pharmacological (β-adrenoceptor
blockade [95]) or interventional approaches (pulmonary
artery denervation, renal denervation)96 to modify auto-
nomic function in PAH, such approaches may be detri-
mental and are yet to be properly assessed.
SLEEP AND HYPOXEMIA
Patients with PH frequently report poor sleep quality
which associates with worse functional status, exercise
capacity, quality of life, and psychological disorders.97,98
Sleep-disordered breathing is common in patients with
various forms of PH. Wide variations in the rates of
central and obstructive sleep apnea have been report-
ed,97,98 with rates of obstructive sleep apnea varying
from 10% to 50%. Furthermore, because of the un-
derlying gas exchange disturbances in PH, hypoxemia
may occur or worsen at night, and daytime measure-
ments may underestimate nocturnal oxygen desatura-
tions.99 In a cohort of 46 patients with PAH and CTEPH,
nocturnal hypoxemia was observed in 83% of patients,
with the major mechanisms being ventilation-perfusion
mismatch in 76%, obstructive sleep apnea in 66%, and
overlap in 45%.97 The degree of nocturnal hypoxemia
correlated with worse daytime PaO2 and distal airways
narrowing (FEV25-75). No significant differences were
found between patients desaturating and those not
desaturating in terms of PH severity, however, numbers
were small, and multivariate logistic regression showed
that a higher pulmonary artery pressure and lower
FEV25-75 predicted overnight hypoxemia.
There are insufficient data to evaluate whether
sleep-disordered breathing or nocturnal hypoxemia
adversely affects long-term outcomes. However,
nocturnal oxygen therapy over 1 week improved
February 25, 2020 687
 Rosenkranz et al
6-minute walking distance, nocturnal heart rate, and
corrected QT interval in patients with precapillary PH
STATE OF THE ART
and isolated nocturnal hypoxemia or >10 oxygen dips
per hour.100
TREATABLE TRAITS: TOWARDS
PRECISION MEDICINE IN PH
Recognizing PH as a disease with various systemic
implications leads to the identification of treatable
traits in individual patients and to a personalized
treatment approach. Assessments and interventions
most strongly recommended in current PH guidelines
include routine measurement of renal function, ane-
mia, and thyroid function, and periodic assessment
Downloaded from http://ahajournals.org by on July 12, 2022
Figure 5. Treatable traits in pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH).
Frequent consequences and factors contributing to disease progression and clinical deterioration. In addition to targeted therapies, the disease course may be
influenced by pharmacological/interventional approaches or supportive care.
688 February 25, 2020
Systemic Consequences of PH and Right-Sided HF
of oxygen saturation during both the day and night.
Treatment should include correction of hypoxemia if
present, use of diuretics in patients with fluid reten-
tion from right heart failure, and supervised exercise
training in patients with deconditioning.80 Other inter-
ventions may be considered on a case by case basis, as
shown in Figure 5.
CONCLUSIONS
Although a large body of evidence indicates that sys-
temic consequences of PH and right-sided HF place ad-
ditional burden on patients and contribute to adverse
outcome, this is often underestimated. Regardless of
the underlying cause of PH, the common final path is
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
 Rosenkranz et al Systemic Consequences of PH and Right-Sided HF

Table.  Consequences of Right-Sided HF and PH in Various Organ Systems

STATE OF THE ART

Organ System Consequence of Right-Sided HF Type of PH/HF in Which Gaps in Knowledge and
Affected and PH Evidence was Obtained Needs for Further Study Refs.
Left heart LV compression or underfilling; PAH Relevance of secondary LV dysfunction for 5-11
cardiomyocyte atrophy outcome
Interdependence between RV and Mainly HFpEF, (PAH) Further studies needed for better pathophysiological 5-8
LV; (RA and LA) understanding (rest and exercise)
Disparity between RV hypertrophy PAH, PH-LHD, HFpEF Incompletely understood; data are not entirely 9-11
and LV atrophy consistent; needs further study
Left main compression syndrome PAH Prevalence and impact on outcome? 13
(LMCS)
Liver Ischemic hepatitis Acute/chronic HF (with shock) Relevance of preexisting RV dysfunction/ 15,16
congestion for low-perfusion liver injury?
Congestive hepatopathy Chronic LHD/HF; closely Prevalence of liver dysfunction in PAH, and impact 17-21
related to RV (rather than LV) on outcome
dysfunction
Kidneys Low perfusion renal injury Congestive HF (HFrEF) Impact of systemic flow/perfusion vs. venous 28,29,31
congestion on renal function in PAH
Chronic congestive nephropathy Chronic LHD/HF; closely Precise diagnostic evaluation of renal congestion 28,29
related to RV (rather than LV) in P(A)H and HF 27,32
dysfunction (PAH) 34-40
Correlation between RV (vs. LV) dysfunction and
kidney function
Prediction on need for renal replacement therapy
in PAH or PH-LHD
Impact of renal dysfunction on outcome in PAH or
other PH groups
Impact of PAH therapies on kidney function
Interorgan cross-talk and pathogenic role
of kidney-derived, circulatory inflammatory
mediators
Downloaded from http://ahajournals.org by on July 12, 2022

Gut/Bowel “leaky bowel syndrome”; bacterial Congestive HF, venous Impact of “leaky bowel” and bacterial 42,43
translocation congestion translocation in PAH and other PH groups
Gut microbiota, endotoxinemia, PAH Further mechanistic insights 44,45
inflammation (LPS/TLR4)
Cachexia HF (HFrEF); related to RV Mechanisms and impact of cachexia in PAH and 46-48
dysfunction other forms of PH
Iron homeostasis Iron deficiency HF (HFrEF), preliminary Impact of iron supplementation on exercise 49-56
evidence in PAH capacity and morbidity/mortality in PAH; RCT
needed
Altered hepcidin levels; connection PAH Further mechanistic studies needed for better 49,52,53
to BMPR2 mutations and hypoxia under-standing; role of congestion?
Skeletal muscle Muscle dysfunction/weakness/ PAH, CTEPH Further mechanistic insights needed 57-60
deconditioning (fiber size/atrophy,
Establish interventions to maintain/improve
contractile dysfunction, calcium
skeletal muscle function
sensitivity)
Endocrine system Thyroid disease (hypo-/ PAH, CTEPH (PH-LHD, PH-CLD) Precise mechanisms and prognostic relevance not 61-65
hyperthyroidism) entirely clear; needs further study
Metabolic syndrome PH-LHD, PH-CLD (COPD) Relation between P(A)H and MS/DM needs to 66
be further established (cause/consequence of
pulmonary vascular disease, RV dysfunction)
Diabetes mellitus PAH, PH-LHD 67-72
Inflammation and Increased circulating inflammatory PAH, PH-LHD Further characterization of inflammatory 28,73-75
immunity mediators; inter-organ cross-talk mechanisms
Perivascular inflammatory infiltrates PAH, PH-LHD Assessment of anti-inflammatory therapies 74
Coagulation system Hypercoagulatory state PAH, CTEPH Not clear whether cause or consequence of PH; 77-79
(Fibrinogen, vWF, PAI-1) Role of anticoagulation not established (except
for CTEPH)
Thrombocytopenia Severe IPAH Mechanism(s) enigmatic 81-83
(Continued )

Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362 February 25, 2020 689

 Rosenkranz et al Systemic Consequences of PH and Right-Sided HF

Table. Continued
STATE OF THE ART

Organ System Consequence of Right-Sided HF Type of PH/HF in Which Gaps in Knowledge and
Affected and PH Evidence was Obtained Needs for Further Study Refs.
Central nervous Impaired cognitive function HF, PH No clear correlation with disease severity of PH 85-87
system
Depression/anxiety HF, PH 84

Eyes Several ocular disorders
(open-angle glaucoma, retinal
detachment, venous stasis
retinopathy, ciliary detachment,
central retinal vein occlusion)
Skin Prurigo simplex
Autonomic function Sympathetic/parasympa-thetic
dysregulation
Reduced heart rate variability
Lowered adrenergic baroreflex
sensitivity
Increased susceptibility of atrial
flutter/fibrillation
Enhanced postganglionic
peripheral muscle sympathetic
nerve activity
Endothelial dysfunction
Sleep/Hypoxia Sleep disturbances, poor sleep
quality
Sleep-disordered breathing
(central/obstructive sleep apnea),
nocturnal hypoxemia
Daytime hypoxemia
Downloaded from http://ahajournals.org by on July 12, 2022
PAH, systemic venous
congestion
(severe PH, advanced right
heart failure)
PAH, other forms of PH
PAH; right heart failure
Experimental PH; Association
with poor outcome in PAH
PAH
HF, PAH
Several PH groups including
PAH and PH-LHD
PAH, CTEPH, HF
IPAH/HPAH
Clinical relevance and frequency need to be 88,89
systematically studied
Author´s experience, evidence and mechanisms —
need to be established
Not a target of current therapies 90-95
Potential assessment of PA denervation; renal 91,92
denervation; RCTs needed
Impact of rhythm control/interventional therapy 93,94
on hemodynamics, RV function and outcome in
PAH and PH-LHD; RCTs needed
Impact of targeted therapies and/or exercise 90
95
Impact on QoL and outcome 97,98
Insufficient data on impact on long-term 97-100
outcomes
Prognostic impact unclear 100

CLD indicates chronic lung disease; COPD, chronic obstructive pulmonary disease; CTEPH, chronic thromboembolic pulmonary hypertension; DM, diabetes
mellitus; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HPAH, heritable PAH; IPAH,
idiopathic PAH; LA, left arterial; LHD, left heart disease; LV, left ventricle; MS, metabolic syndrome; PA, pulmonary artery; PAH, pulmonary arterial hypertension; P(A)
H, PH or PAH; PAI-1, plasminogen activator inhibitor-1; PH, pulmonary hypertension; RA, right arterial; RV, right ventricle; and vWF, von Willebrand factor.

right-sided HF. As a consequence, both systemic ve-

nous congestion caused by RV dysfunction and im-
paired peripheral perfusion caused by right-left heart
interaction and diminished systemic output contribute
to insult to multiple organ systems and interorgan
crosstalk, which may result in a systemic inflammatory
state that needs to be further characterized. It should
be pointed out that many of the available evidence on
secondary organ damage (particularly on liver and kid-
ney impairment) is primarily related to left HF, whereas
the consequences of isolated right-sided HF caused by
PAH or other forms of precapillary PH are far less well
studied and require further research (Table). However,
when summarizing the available evidence, it becomes
clear that even in patients with LHD, right-sided rath-
er than left-sided HF is the main driver of secondary
organ dysfunction. The important role of the right
heart in this context is frequently underestimated in
‍‍ARTICLE INFORMATION
Correspondence
Stephan Rosenkranz, MD, Klinik III für Innere Medizin, Center for Molecular
Medicine Cologne (CMMC) and Cologne Cardiovascular Research Center
(CCRC), Herzzentrum der Universität zu Köln, Kerpener Str. 62, 50937 Köln,
Germany. Email stephan.rosenkranz@uk-koeln.de
Affiliations
Clinic III for Internal Medicine (Cardiology) and Cologne Cardiovascular Re-
search Center (CCRC), Heart Center at the University of Cologne, Germany
(S.R.). Center for Molecular Medicine Cologne (CMMC), University of Cologne,
Germany (S.R.). National Pulmonary Hypertension Service, Imperial College
Healthcare NHS Trust, London, United Kingdom (L.S.H.). Department of Medi-
cine, George Washington University, Washington, DC (M.G.M.). Department of
Respiratory Medicine, Hannover Medical School, Germany (M.M.H.). German
Center for Lung Research (DZL), Hannover, Germany (M.M.H.).
Sources of Funding
This work was supported in part by the Deutsche Forschungsgemeinschaft
(GRK-2407 to Dr Rosenkranz).

clinical practice and needs to be further studied. This

knowledge is key to the understanding and treating
of secondary organ dysfunction in patients with left
heart disease as well as other forms of PH leading to
right-sided HF.
Disclosures
Dr Rosenkranz has received remunerations for lectures or consultancy from Ab-
bot, Actelion, Arena, Bayer, Gilead, GSK, Merck, Novartis, Pfizer, and United
Therapeutics. His institution has received research grants from Actelion, Bayer,
Novartis, Pfizer, and United Therapeutics. Dr Howard has received fees for

690 February 25, 2020 Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362

 Rosenkranz et al
lectures or consultancy from Actelion, Bayer, GSK, and Merck. His institution
has received research grants from Bayer. Dr Gomberg-Maitland served as a
consultant and as a member of steering committees and DSMB/event commit-
tees for Actelion, Bayer, Gilead, Medtronic, UCB, Bellerophon (formerly known
as Ikaria), and United Therapeutics. She has received honoraria for CME from
Medscape and ABComm. Actelion, Bayer, Gilead, Medtronic, Lung Biotechnol-
ogy, and Reata have provided funding to the University of Chicago during the
last year to support her conduct of clinical trials. She is a member of the PCORI
Advisory Panel on Rare Diseases and a Special Government Employee for the
FDA Cardio-Renal division. Dr Hoeper has received fees for lectures or consul-
tancy from Actelion, Bayer, Gilead, GSK, Merck, and Pfizer.
REFERENCES
1. Hoeper MM, Humbert M, Souza R, Idrees M, Kawut SM, Sliwa-Hahnle K,
Jing ZC, Gibbs JS. A global view of pulmonary hypertension. Lancet Respir
Med. 2016;4:306–322. doi: 10.1016/S2213-2600(15)00543-3
2. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA,
Krowka M, Williams PG, Souza R. Haemodynamic definitions and updated
clinical classification of pulmonary hypertension. Eur Respir J 2019;53:doi:
10.1183 / 13993003.01913-2018.
3. Rosenkranz S, Gibbs JS, Wachter R, De Marco T, Vonk-Noordegraaf A,
Vachiéry JL. Left ventricular heart failure and pulmonary hypertension. Eur
Heart J. 2016;37:942–954. doi: 10.1093/eurheartj/ehv512
4. Obokata M, Reddy YNV, Melenovsky V, Pislaru S, Borlaug BA. Deteriora-
tion in right ventricular structure and function over time in patients with
heart failure and preserved ejection fraction. Eur Heart J. 2019;40:689–
697. doi: 10.1093/eurheartj/ehy809
5. Gan C, Lankhaar JW, Marcus JT, Westerhof N, Marques KM, Bronzwaer JG,
Boonstra A, Postmus PE, Vonk-Noordegraaf A. Impaired left ventricular fill-
ing due to right-to-left ventricular interaction in patients with pulmonary
arterial hypertension. Am J Physiol Heart Circ Physiol. 2006;290:H1528–
H1533. doi: 10.1152/ajpheart.01031.2005
6. Gorter TM, Obokata M, Reddy YNV, Melenovsky V, Borlaug BA. Exer-
cise unmasks distinct pathophysiologic features in heart failure with
preserved ejection fraction and pulmonary vascular disease. Eur Heart J.
Downloaded from http://ahajournals.org by on July 12, 2022
2018;39:2825–2835. doi: 10.1093/eurheartj/ehy331
7. Moore TD, Frenneaux MP, Sas R, Atherton JJ, Morris-Thurgood JA,
Smith ER, Tyberg JV, Belenkie I. Ventricular interaction and external
constraint account for decreased stroke work during volume loading
in CHF. Am J Physiol Heart Circ Physiol. 2001;281:H2385–H2391. doi:
10.1152/ajpheart.2001.281.6.H2385
8. Tonelli AR, Plana JC, Heresi GA, Dweik RA. Prevalence and prognostic
value of left ventricular diastolic dysfunction in idiopathic and heritable
pulmonary arterial hypertension. Chest. 2012;141:1457–1465. doi:
10.1378/chest.11-1903
9. Hardziyenka M, Campian ME, Reesink HJ, Surie S, Bouma BJ, Groenink M,
Klemens CA, Beekman L, Remme CA, Bresser P, et al. Right ventricular
failure following chronic pressure overload is associated with reduction in
left ventricular mass: evidence for atrophic remodeling. J Am Coll Cardiol.
2011;57:921–928. doi: 10.1016/j.jacc.2010.08.648
10. Kishiki K, Singh A, Narang A, Gomberg-Maitland M, Goyal N, Maffessanti F,
Besser SA, Mor-Avi V, Lang RM, Addetia K. Impact of severe pulmonary ar-
terial hypertension on the left heart and prognostic implications. J Am Soc
Echocardiogr. 2019;32:1128–1137. doi: 10.1016/j.echo.2019.05.008
11. Manders E, Bogaard HJ, Handoko ML, van de Veerdonk MC, Keogh A,
Westerhof N, Stienen GJ, Dos Remedios CG, Humbert M, Dorfmüller P,
et al. Contractile dysfunction of left ventricular cardiomyocytes in patients
with pulmonary arterial hypertension. J Am Coll Cardiol. 2014;64:28–37.
doi: 10.1016/j.jacc.2014.04.031
12. Tudorache I, Sommer W, Kühn C, Wiesner O, Hadem J, Fühner T, Ius F,
Avsar M, Schwerk N, Böthig D, et al. Lung transplantation for severe pul-
monary hypertension–awake extracorporeal membrane oxygenation for
postoperative left ventricular remodelling. Transplantation. 2015;99:451–
458. doi: 10.1097/TP.0000000000000348
13. Galiè N, Saia F, Palazzini M, Manes A, Russo V, Bacchi Reggiani ML,
Dall’Ara G, Monti E, Dardi F, Albini A, et al. Left main coronary artery
compression in patients with pulmonary arterial hypertension and angina.
J Am Coll Cardiol. 2017;69:2808–2817. doi: 10.1016/j.jacc.2017.03.597
14. Żyłkowska J, Kurzyna M, Florczyk M, Burakowska B, Grzegorczyk F,
Burakowski J, Wieteska M, Oniszh K, Biederman A, Wawrzyńska L, et al.
Pulmonary artery dilatation correlates with the risk of unexpected death
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
Systemic Consequences of PH and Right-Sided HF
in chronic arterial or thromboembolic pulmonary hypertension. Chest.
2012;142:1406–1416. doi: 10.1378/chest.11-2794
STATE OF THE ART
15. Samsky MD, Patel CB, DeWald TA, Smith AD, Felker GM, Rogers JG,
Hernandez AF. Cardiohepatic interactions in heart failure: an overview
and clinical implications. J Am Coll Cardiol. 2013;61:2397–2405. doi:
10.1016/j.jacc.2013.03.042
16. Fuhrmann V, Kneidinger N, Herkner H, Heinz G, Nikfardjam M,
Bojic A, Schellongowski P, Angermayr B, Kitzberger R, Warszawska J, et
al. Hypoxic hepatitis: underlying conditions and risk factors for mortal-
ity in critically ill patients. Intensive Care Med. 2009;35:1397–1405. doi:
10.1007/s00134-009-1508-2
17. Dai DF, Swanson PE, Krieger EV, Liou IW, Carithers RL, Yeh MM. Conges-
tive hepatic fibrosis score: a novel histologic assessment of clinical severity.
Mod Pathol. 2014;27:1552–1558. doi: 10.1038/modpathol.2014.79
18. Nikolaou M, Parissis J, Yilmaz MB, Seronde MF, Kivikko M, Laribi S,
Paugam-Burtz C, Cai D, Pohjanjousi P, Laterre PF, et al. Liver function ab-
normalities, clinical profile, and outcome in acute decompensated heart
failure. Eur Heart J. 2013;34:742–749. doi: 10.1093/eurheartj/ehs332
19. Louie CY, Pham MX, Daugherty TJ, Kambham N, Higgins JP. The liver in
heart failure: a biopsy and explant series of the histopathologic and labo-
ratory findings with a particular focus on pre-cardiac transplant evalua-
tion. Mod Pathol. 2015;28:932–943. doi: 10.1038/modpathol.2015.40
20. Yoshihisa A, Kimishima Y, Kiko T, Sato Y, Watanabe S, Kanno Y, Abe S,
Miyata-Tatsumi M, Sato T, Suzuki S, et al. Liver fibrosis marker, 7S domain
of collagen type IV, in patients with pre-capillary pulmonary hypertension.
Int J Cardiol. 2018;258:269–274. doi: 10.1016/j.ijcard.2018.01.138
21. Biegus J, Hillege HL, Postmus D, Valente MA, Bloomfield DM, Cleland JG,
Cotter G, Davison BA, Dittrich HC, Fiuzat M, et al. Abnormal liver function
tests in acute heart failure: relationship with clinical characteristics and
outcome in the PROTECT study. Eur J Heart Fail. 2016;18:830–839. doi:
10.1002/ejhf.532
22. Taniguchi T, Ohtani T, Kioka H, Tsukamoto Y, Onishi T, Nakamoto K,
Katsimichas T, Sengoku K, Chimura M, Hashimoto H, et al. Liver stiff-
ness reflecting right-sided filling pressure can predict adverse outcomes in
patients with heart failure. JACC Cardiovasc Imaging. 2019;12:955–964.
doi: 10.1016/j.jcmg.2017.10.022
23. Takeda Y, Takeda Y, Tomimoto S, Tani T, Narita H, Kimura G. Bilirubin as a
prognostic marker in patients with pulmonary arterial hypertension. BMC
Pulm Med. 2010;10:22. doi: 10.1186/1471-2466-10-22
24. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ,
Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, et al. Predicting
survival in pulmonary arterial hypertension: insights from the Regis-
try to Evaluate Early and Long-Term Pulmonary Arterial Hypertension
Disease Management (REVEAL). Circulation. 2010;122:164–172. doi:
10.1161/CIRCULATIONAHA.109.898122
25. Shah SJ, Thenappan T, Rich S, Tian L, Archer SL, Gomberg-Maitland M.
Association of serum creatinine with abnormal hemodynamics and mor-
tality in pulmonary arterial hypertension. Circulation. 2008;117:2475–
2483. doi: 10.1161/CIRCULATIONAHA.107.719500
26. Bitker L, Sens F, Payet C, Turquier S, Duclos A, Cottin V, Juillard L. Pres-
ence of kidney disease as an outcome predictor in patients with pul-
monary arterial hypertension. Am J Nephrol. 2018;47:134–143. doi:
10.1159/000487198
27. Chakinala MM, Coyne DW, Benza RL, Frost AE, McGoon MD,
Hartline BK, Frantz RP, Selej M, Zhao C, Mink DR, et al. Impact of de-
clining renal function on outcomes in pulmonary arterial hypertension:
A REVEAL registry analysis. J Heart Lung Transplant. 2018;37:696–705.
doi: 10.1016/j.healun.2017.10.028
28. Husain-Syed F, McCullough PA, Birk HW, Renker M, Brocca A, Seeger W,
Ronco C. Cardio-pulmonary-renal interactions: a multidisciplinary ap-
proach. J Am Coll Cardiol. 2015;65:2433–2448. doi: 10.1016/j.jacc.
2015.04.024
29. Schefold JC, Filippatos G, Hasenfuss G, Anker SD, von Haehling S. Heart
failure and kidney dysfunction: epidemiology, mechanisms and manage-
ment. Nat Rev Nephrol. 2016;12:610–623. doi: 10.1038/nrneph.2016.113
30. Le Clef N, Verhulst A, D’Haese PC, Vervaet BA. Unilateral renal ischemia-
reperfusion as a robust model for acute to chronic kidney injury in mice.
PLoS One. 2016;11:e0152153. doi: 10.1371/journal.pone.0152153
31. Nagaya N, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N,
Yamagishi M, Kunieda T, Miyatake K. Serum uric acid levels correlate with the
severity and the mortality of primary pulmonary hypertension. Am J Respir
Crit Care Med. 1999;160:487–492. doi: 10.1164/ajrccm.160.2.9812078
32. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC,
Young JB, Tang WHW. Importance of venous congestion for worsening
February 25, 2020 691
 Rosenkranz et al
of renal function in advanced decompensated heart failure. J Am Coll
Cardiol. 2009;53:589–596. doi: 10.1016/j.jacc.2008.05.068
STATE OF THE ART
33. Hemmi S, Matsumoto N, Jike T, Obana Y, Nakanishi Y, Soma M, Hemmi A.
Proximal tubule morphology in rats with renal congestion: a study involv-
ing the in vivo cryotechnique. Med Mol Morphol. 2015;48:92–103. doi:
10.1007/s00795-014-0084-x
34. Iida N, Seo Y, Sai S, Machino-Ohtsuka T, Yamamoto M, Ishizu T,
Kawakami Y, Aonuma K. Clinical implications of intrarenal hemodynamic
evaluation by doppler ultrasonography in heart failure. JACC Heart Fail.
2016;4:674–682. doi: 10.1016/j.jchf.2016.03.016
35. Faubel S, Edelstein CL. Mechanisms and mediators of lung injury
after acute kidney injury. Nat Rev Nephrol. 2016;12:48–60. doi:
10.1038/nrneph.2015.158
36. Haase M, Kellum JA, Ronco C. Subclinical AKI–an emerging syndrome
with important consequences. Nat Rev Nephrol. 2012;8:735–739. doi:
10.1038/nrneph.2012.197
37. Torregrosa I, Montoliu C, Urios A, Andrés-Costa MJ, Giménez-Garzó C,
Juan I, Puchades MJ, Blasco ML, Carratalá A, Sanjuán R, et al. Urinary
KIM-1, NGAL and L-FABP for the diagnosis of AKI in patients with acute
coronary syndrome or heart failure undergoing coronary angiography.
Heart Vessels. 2015;30:703–711. doi: 10.1007/s00380-014-0538-z
38. Ko GJ, Grigoryev DN, Linfert D, Jang HR, Watkins T, Cheadle C,
Racusen L, Rabb H. Transcriptional analysis of kidneys during repair from
AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-
CKD transition. Am J Physiol Renal Physiol. 2010;298:F1472–F1483. doi:
10.1152/ajprenal.00619.2009
39. Rao VS, Ahmad T, Brisco-Bacik MA, Bonventre JV, Wilson FP, Siew ED,
Felker GM, Anstrom KK, Mahoney DD, Bart BA, et al. Renal effects
of intensive volume removal in heart failure patients with preexist-
ing worsening renal function. Circ Heart Fail. 2019;12:e005552. doi:
10.1161/CIRCHEARTFAILURE.118.005552
40. Webb DJ, Vachiery JL, Hwang LJ, Maurey JO. Sildenafil improves renal
function in patients with pulmonary arterial hypertension. Br J Clin Phar-
macol. 2015;80:235–241. doi: 10.1111/bcp.12616
41. Sundaram V, Fang JC. Gastrointestinal and liver issues in heart failure. Circula-
tion. 2016;133:1696–1703. doi: 10.1161/CIRCULATIONAHA.115.020894
42. Sedman PC, Macfie J, Sagar P, Mitchell CJ, May J, Mancey-Jones B,
Johnstone D. The prevalence of gut translocation in humans. Gastroen-
Downloaded from http://ahajournals.org by on July 12, 2022
terology. 1994;107:643–649. doi: 10.1016/0016-5085(94)90110-4
43. Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR,
Rauchhaus M, Poole-Wilson PA, Coats AJ, Anker SD. Endotoxin and im-
mune activation in chronic heart failure: a prospective cohort study. Lan-
cet. 1999;353:1838–1842. doi: 10.1016/S0140-6736(98)09286-1
44. Sztrymf B, Souza R, Bertoletti L, Jaïs X, Sitbon O, Price LC, Simonneau G,
Humbert M. Prognostic factors of acute heart failure in patients with
pulmonary arterial hypertension. Eur Respir J. 2010;35:1286–1293. doi:
10.1183/09031936.00070209
45. Ranchoux B, Bigorgne A, Hautefort A, Girerd B, Sitbon O, Montani D,
Humbert M, Tcherakian C, Perros F. Gut-lung connection in pulmonary
arterial hypertension. Am J Respir Cell Mol Biol. 2017;56:402–405. doi:
10.1165/rcmb.2015-0404LE
46. Melenovsky V, Kotrc M, Borlaug BA, Marek T, Kovar J, Malek I, Kautzner J.
Relationships between right ventricular function, body composition, and
prognosis in advanced heart failure. J Am Coll Cardiol. 2013;62:1660–
1670. doi: 10.1016/j.jacc.2013.06.046
47. Valentova M, von Haehling S, Bauditz J, Doehner W, Ebner N, Bekfani T,
Elsner S, Sliziuk V, Scherbakov N, Murín J, et al. Intestinal congestion and
right ventricular dysfunction: a link with appetite loss, inflammation, and
cachexia in chronic heart failure. Eur Heart J. 2016;37:1684–1691. doi:
10.1093/eurheartj/ehw008
48. Tang WH, Wang Z, Fan Y, Levison B, Hazen JE, Donahue LM, Wu Y,
Hazen SL. Prognostic value of elevated levels of intestinal microbe-gen-
erated metabolite trimethylamine-N-oxide in patients with heart failure:
refining the gut hypothesis. J Am Coll Cardiol 2014;64:1908-1914. doi:
10.1016/j.jacc.2014.02.617
49. Rhodes CJ, Howard LS, Busbridge M, Ashby D, Kondili E, Gibbs JS,
Wharton J, Wilkins MR. Iron deficiency and raised hepcidin in idio-
pathic pulmonary arterial hypertension: clinical prevalence, outcomes,
and mechanistic insights. J Am Coll Cardiol. 2011;58:300–309. doi:
10.1016/j.jacc.2011.02.057
50. Soon E, Treacy CM, Toshner MR, MacKenzie-Ross R, Manglam V,
Busbridge M, Sinclair-McGarvie M, Arnold J, Sheares KK, Morrell NW, et al.
Unexplained iron deficiency in idiopathic and heritable pulmonary arterial
hypertension. Thorax. 2011;66:326–332. doi: 10.1136/thx.2010.147272
692 February 25, 2020
Systemic Consequences of PH and Right-Sided HF
51. Bregman DB, Morris D, Koch TA, He A, Goodnough LT. Hepcidin levels
predict nonresponsiveness to oral iron therapy in patients with iron defi-
ciency anemia. Am J Hematol. 2013;88:97–101. doi: 10.1002/ajh.23354
52. Frise MC, Cheng HY, Nickol AH, Curtis MK, Pollard KA, Roberts DJ,
Ratcliffe PJ, Dorrington KL, Robbins PA. Clinical iron deficiency disturbs
normal human responses to hypoxia. J Clin Invest. 2016;126:2139–2150.
doi: 10.1172/JCI85715
53. Robinson JC, Graham BB, Rouault TC, Tuder RM. The crossroads of iron
with hypoxia and cellular metabolism: implications in the pathobiology of
pulmonary hypertension. Am J Respir Cell Mol Biol. 2014;51:721–729.
doi: 10.1165/rcmb.2014-0021TR
54. Melenovsky V, Petrak J, Mracek T, Benes J, Borlaug BA, Nuskova H,
Pluhacek T, Spatenka J, Kovalcikova J, Drahota Z, et al. Myocardial iron
content and mitochondrial function in human heart failure: a direct tissue
analysis. Eur J Heart Fail. 2017;19:522–530. doi: 10.1002/ejhf.640
55. Viethen T, Gerhardt F, Dumitrescu D, Knoop-Busch S, ten Freyhaus H,
Rudolph TK, Baldus S, Rosenkranz S. Ferric carboxymaltose improves ex-
ercise capacity and quality of life in patients with pulmonary arterial hy-
pertension and iron deficiency: a pilot study. Int J Cardiol. 2014;175:233–
239. doi: 10.1016/j.ijcard.2014.04.233
56. Ruiter G, Manders E, Happé CM, Schalij I, Groepenhoff H, Howard LS,
Wilkins MR, Bogaard HJ, Westerhof N, van der Laarse WJ, et al. Intravenous
iron therapy in patients with idiopathic pulmonary arterial hypertension
and iron deficiency. Pulm Circ. 2015;5:466–472. doi: 10.1086/682217
57. Manders E, Rain S, Bogaard HJ, Handoko ML, Stienen GJ, Vonk-
Noordegraaf A, Ottenheijm CA, de Man FS. The striated muscles in pul-
monary arterial hypertension: adaptations beyond the right ventricle. Eur
Respir J. 2015;46:832–842. doi: 10.1183/13993003.02052-2014
58. Manders E, Bonta PI, Kloek JJ, Symersky P, Bogaard HJ, Hooijman PE,
Jasper JR, Malik FI, Stienen GJ, Vonk-Noordegraaf A, et al. Reduced force
of diaphragm muscle fibers in patients with chronic thromboembolic pul-
monary hypertension. Am J Physiol Lung Cell Mol Physiol. 2016;311:L20–
L28. doi: 10.1152/ajplung.00113.2016
59. de Man FS, van Hees HW, Handoko ML, Niessen HW, Schalij I, Humbert M,
Dorfmüller P, Mercier O, Bogaard HJ, Postmus PE, et al. Diaphragm muscle
fiber weakness in pulmonary hypertension. Am J Respir Crit Care Med.
2011;183:1411–1418. doi: 10.1164/rccm.201003-0354OC
60. Garfield BE, Crosby A, Shao D, Yang P, Read C, Sawiak S, Moore S, Parfitt L,
Harries C, Rice M, et al. Growth/differentiation factor 15 causes TGFβ-
activated kinase 1-dependent muscle atrophy in pulmonary arterial hyper-
tension. Thorax. 2019;74:164–176. doi: 10.1136/thoraxjnl-2017-211440
61. Chu JW, Kao PN, Faul JL, Doyle RL. High prevalence of autoimmune thy-
roid disease in pulmonary arterial hypertension. Chest. 2002;122:1668–
1673. doi: 10.1378/chest.122.5.1668
62. Richter MJ, Sommer N, Schermuly R, Grimminger B, Seeger W, Tello K,
Ghofrani HA, Gall H. The prognostic impact of thyroid function in pul-
monary hypertension. J Heart Lung Transplant. 2016;35:1427–1434. doi:
10.1016/j.healun.2016.05.022
63. Baumgartner C, da Costa BR, Collet TH, Feller M, Floriani C, Bauer DC,
Cappola AR, Heckbert SR, Ceresini G, Gussekloo J, et al; Thyroid Studies
Collaboration. Thyroid function within the normal range, subclinical hypo-
thyroidism, and the risk of atrial fibrillation. Circulation. 2017;136:2100–
2116. doi: 10.1161/CIRCULATIONAHA.117.028753
64. Curnock AL, Dweik RA, Higgins BH, Saadi HF, Arroliga AC. High prevalence
of hypothyroidism in patients with primary pulmonary hypertension. Am J
Med Sci. 1999;318:289–292. doi: 10.1097/00000441-199911000-00001
65. Osmak-Tizon L, Poussier M, Cottin Y, Rochette L. Non-genomic ac-
tions of thyroid hormones: Molecular aspects. Arch Cardiovasc Dis.
2014;107:207–211. doi: 10.1016/j.acvd.2014.02.001
66. Poms AD, Turner M, Farber HW, Meltzer LA, McGoon MD. Comorbid
conditions and outcomes in patients with pulmonary arterial hyper-
tension: a REVEAL registry analysis. Chest. 2013;144:169–176. doi:
10.1378/chest.11-3241
67. Pugh ME, Robbins IM, Rice TW, West J, Newman JH, Hemnes AR. Un-
recognized glucose intolerance is common in pulmonary arterial hy-
pertension. J Heart Lung Transplant. 2011;30:904–911. doi: 10.1016/j.
healun.2011.02.016
68. Grinnan D, Farr G, Fox A, Sweeney L. The role of hyperglycemia and
insulin resistance in the development and progression of pulmo-
nary arterial hypertension. J Diabetes Res. 2016;2016:2481659. doi:
10.1155/2016/2481659
69. Ameshima S, Golpon H, Cool CD, Chan D, Vandivier RW, Gardai SJ,
Wick M, Nemenoff RA, Geraci MW, Voelkel NF. Peroxisome prolifera-
tor-activated receptor gamma (PPARgamma) expression is decreased in
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
 Rosenkranz et al
pulmonary hypertension and affects endothelial cell growth. Circ Res.
2003;92:1162–1169. doi: 10.1161/01.RES.0000073585.50092.14
70. Hansmann G, Wagner RA, Schellong S, Perez VA, Urashima T, Wang L,
Sheikh AY, Suen RS, Stewart DJ, Rabinovitch M. Pulmonary arterial hyper-
tension is linked to insulin resistance and reversed by peroxisome prolif-
erator-activated receptor-gamma activation. Circulation. 2007;115:1275–
1284. doi: 10.1161/CIRCULATIONAHA.106.663120
71. Legchenko E, Chouvarine P, Borchert P, Fernandez-Gonzalez A, Snay E,
Meier M, Maegel L, Mitsialis SA, Rog-Zielinska EA, Kourembanas S, et al.
PPARγ agonist pioglitazone reverses pulmonary hypertension and prevents
right heart failure via fatty acid oxidation. Sci Transl Med 2018;10(438).
pii: eaao0303. doi: 10.1126/scitranslmed.aao0303
72. Arnold N, Koppula PR, Gul R, Luck C, Pulakat L. Regulation of car-
diac expression of the diabetic marker microRNA miR-29. PLoS One.
2014;9:e103284. doi: 10.1371/journal.pone.0103284
73. Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado
RD, Trembath RC, Jennings S, Barker L, Nicklin P, et al. Elevated levels
of inflammatory cytokines predict survival in idiopathic and familial
pulmonary arterial hypertension. Circulation. 2010;122:920–927. doi:
10.1161/CIRCULATIONAHA.109.933762
74. Huertas A, Perros F, Tu L, Cohen-Kaminsky S, Montani D, Dorfmüller P,
Guignabert C, Humbert M. Immune dysregulation and endothelial dys-
function in pulmonary arterial hypertension: a complex interplay. Circula-
tion. 2014;129:1332–1340. doi: 10.1161/CIRCULATIONAHA.113.004555
75. Huertas A, Phan C, Bordenave J, Tu L, Thuillet R, Le Hiress M, Avouac J,
Tamura Y, Allanore Y, Jovan R, et al. Regulatory T cell dysfunction in idio-
pathic, heritable and connective tissue-associated pulmonary arterial hyper-
tension. Chest. 2016;149:1482–1493. doi: 10.1016/j.chest.2016.01.004
76. Becker MO, Kill A, Kutsche M, Guenther J, Rose A, Tabeling C,
Witzenrath M, Kühl AA, Heidecke H, Ghofrani HA, et al. Vascular recep-
tor autoantibodies in pulmonary arterial hypertension associated with
systemic sclerosis. Am J Respir Crit Care Med. 2014;190:808–817. doi:
10.1164/rccm.201403-0442OC
77. Huber K, Beckmann R, Frank H, Kneussl M, Mlczoch J, Binder BR. Fi-
brinogen, t-PA, and PAI-1 plasma levels in patients with pulmonary
hypertension. Am J Respir Crit Care Med. 1994;150:929–933. doi:
10.1164/ajrccm.150.4.7921465
78. Pelland-Marcotte MC, Humpl T, James PD, Rand ML, Bouskill V, Reyes JT,
Downloaded from http://ahajournals.org by on July 12, 2022
Bowman ML, Carcao MD. Idiopathic pulmonary arterial hypertension - a
unrecognized cause of high-shear high-flow haemostatic defects (other-
wise referred to as acquired von Willebrand syndrome) in children. Br J
Haematol. 2018;183:267–275. doi: 10.1111/bjh.15530
79. Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD,
McLaughlin VV, Jessup M, Grizzle WE, Aldred MA, Cool CD, et al. Modern
age pathology of pulmonary arterial hypertension. Am J Respir Crit Care
Med. 2012;186:261–272. doi: 10.1164/rccm.201201-0164OC
80. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G,
Peacock A, Vonk-Noordegraaf A, Beghetti M, et al; ESC Scientific Docu-
ment Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment
of pulmonary hypertension: the Joint Task Force for the Diagnosis and
Treatment of Pulmonary Hypertension of the European Society of Car-
diology (ESC) and the European Respiratory Society (ERS): Endorsed by:
Association for European Paediatric and Congenital Cardiology (AEPC),
International Society for Heart and Lung Transplantation (ISHLT). Eur Heart
J. 2016;37:67–119. doi: 10.1093/eurheartj/ehv317
81. Mojadidi MK, Goodman-Meza D, Eshtehardi P, Pamerla M, Msaouel P,
Roberts SC, Winoker JS, Jadeja NM, Zolty R. Thrombocytopenia is an in-
dependent predictor of mortality in pulmonary hypertension. Heart Lung.
2014;43:569–573. doi: 10.1016/j.hrtlng.2014.07.006
82. Remková A, Šimková I, Valkovičová T, Kaldarárová M. Platelet abnormali-
ties in adults with severe pulmonary arterial hypertension related to con-
genital heart defects (Eisenmenger syndrome). Blood Coagul Fibrinolysis.
2016;27:925–929. doi: 10.1097/MBC.0000000000000523
83. Horigome H, Murakami T, Isobe T, Nagasawa T, Matsui A. Soluble P-
selectin and thrombomodulin-protein C-Protein S pathway in cyanotic
congenital heart disease with secondary erythrocytosis. Thromb Res.
2003;112:223–227. doi: 10.1016/j.thromres.2003.12.011
84. Harzheim D, Klose H, Pinado FP, Ehlken N, Nagel C, Fischer C, Ghofrani A,
Rosenkranz S, Seyfarth HJ, Halank M, et al. Anxiety and depression disor-
ders in patients with pulmonary arterial hypertension and chronic throm-
boembolic pulmonary hypertension. Respir Res. 2013;14:104. doi:
10.1186/1465-9921-14-104
Circulation. 2020;141:678–693. DOI: 10.1161/CIRCULATIONAHA.116.022362
Systemic Consequences of PH and Right-Sided HF
85. White J, Hopkins RO, Glissmeyer EW, Kitterman N, Elliott CG. Cognitive,
emotional, and quality of life outcomes in patients with pulmonary
STATE OF THE ART
arterial hypertension. Respir Res. 2006;7:55. doi: 10.1186/1465-
9921-7-55
86. Somaini G, Stamm A, Müller-Mottet S, Hasler E, Keusch S, Hildenbrand
FF, Furian M, Speich R, Bloch KE, Ulrich S. Disease-targeted treat-
ment improves cognitive function in patients with precapillary pul-
monary hypertension. Respiration. 2015;90:376–383. doi: 10.1159/
000439227
87. Vuylsteke A, Sharples L, Charman G, Kneeshaw J, Tsui S, Dunning J,
Wheaton E, Klein A, Arrowsmith J, Hall R, et al. Circulatory arrest versus
cerebral perfusion during pulmonary endarterectomy surgery (PEACOG):
a randomised controlled trial. Lancet. 2011;378:1379–1387. doi:
10.1016/S0140-6736(11)61144-6
88. Yang S, Jeong J, Kim JG, Yoon YH. Progressive venous stasis retinopa-
thy and open-angle glaucoma associated with primary pulmonary hy-
pertension. Ophthalmic Surg Lasers Imaging. 2006;37:230–233. doi:
10.3928/15428877-20060501-08
89. Feng Z, Dong L, Cao J, Bai J, Yang MM, Zheng Y, Lin D. A case study of cil-
iary detachment with primary pulmonary hypertension. Int Ophthalmol.
2018;38:375–379. doi: 10.1007/s10792-017-0443-4
90. Maron BA, Leopold JA. Emerging concepts in the molecular basis of pul-
monary arterial hypertension: part ii: neurohormonal signaling contrib-
utes to the pulmonary vascular and right ventricular pathophenotype of
pulmonary arterial hypertension. Circulation. 2015;131:2079–2091. doi:
10.1161/CIRCULATIONAHA.114.006980
91. Yi HT, Hsieh YC, Wu TJ, Huang JL, Lin WW, Liang KW, Su CS, Tsai WJ,
Wang KY. Heart rate variability parameters and ventricular arrhythmia
correlate with pulmonary arterial pressure in adult patients with  idio-
pathic pulmonary arterial hypertension. Heart Lung. 2014;43:534–540.
doi: 10.1016/j.hrtlng.2014.05.010
92. Mar PL, Nwazue V, Black BK, Biaggioni I, Diedrich A, Paranjape SY,
Loyd JE, Hemnes AR, Robbins IM, Robertson D, et al. Valsalva maneu-
ver in pulmonary arterial hypertension: susceptibility to syncope and
autonomic dysfunction. Chest. 2016;149:1252–1260. doi: 10.1016/j.
chest.2015.11.015
93. Zhao Q, Deng H, Jiang X, Dai Z, Wang X, Wang X, Guo Z, Hu W, Yu S,
Yang B, et al. Effects of intrinsic and extrinsic cardiac nerves on atrial ar-
rhythmia in experimental pulmonary artery hypertension. Hypertension.
2015;66:1042–1049. doi: 10.1161/HYPERTENSIONAHA.115.05846
94. Olsson KM, Nickel NP, Tongers J, Hoeper MM. Atrial flutter and fibrillation
in patients with pulmonary hypertension. Int J Cardiol. 2013;167:2300–
2305. doi: 10.1016/j.ijcard.2012.06.024
95. Perros F, Ranchoux B, Izikki M, Bentebbal S, Happé C, Antigny F,
Jourdon P, Dorfmüller P, Lecerf F, Fadel E, et al. Nebivolol for improving
endothelial dysfunction, pulmonary vascular remodeling, and right heart
function in pulmonary hypertension. J Am Coll Cardiol. 2015;65:668–
680. doi: 10.1016/j.jacc.2014.11.050
96. Chen SL, Zhang FF, Xu J, Xie DJ, Zhou L, Nguyen T, Stone GW.
Pulmonary artery denervation to treat pulmonary arterial hyperten-
sion: the single-center, prospective, first-in-man PADN-1 study (first-in-
man pulmonary artery denervation for treatment of pulmonary artery
hypertension). J Am Coll Cardiol. 2013;62:1092–1100. doi: 10.1016/j.
jacc.2013.05.075
97. Jilwan FN, Escourrou P, Garcia G, Jaïs X, Humbert M, Roisman G. High
occurrence of hypoxemic sleep respiratory disorders in precapillary pul-
monary hypertension and mechanisms. Chest. 2013;143:47–55. doi:
10.1378/chest.11-3124
98. Orr JE, Auger WR, DeYoung PN, Kim NH, Malhotra A, Owens RL.
Usefulness of low cardiac index to predict sleep-disordered breathing
in chronic thromboembolic pulmonary hypertension. Am J Cardiol.
2016;117:1001–1005. doi: 10.1016/j.amjcard.2015.12.035
99. Hildenbrand FF, Bloch KE, Speich R, Ulrich S. Daytime measurements
underestimate nocturnal oxygen desaturations in pulmonary arte-
rial and chronic thromboembolic pulmonary hypertension. Respiration.
2012;84:477–484. doi: 10.1159/000341182
100. Ulrich S, Keusch S, Hildenbrand FF, Lo Cascio C, Huber LC, Tanner FC,
Speich R, Bloch KE. Effect of nocturnal oxygen and acetazolamide
on exercise performance in patients with pre-capillary pulmonary
hypertension and sleep-disturbed breathing: randomized, dou-
ble-blind, cross-over trial. Eur Heart J. 2015;36:615–623. doi:
10.1093/eurheartj/eht540
February 25, 2020 693