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Circ Res. Author manuscript; available in PMC 2015 June 20.
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Circ Res. 2014 June 20; 115(1): 176–188. doi:10.1161/CIRCRESAHA.113.301129.
The Right Ventricle in Pulmonary Arterial Hypertension:

Disorders of metabolism, angiogenesis and adrenergic signaling
in right ventricular failure
John J Ryan, MB BCh1 and Stephen L Archer, MD2
1Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City,
UT
2Department of Medicine, Queen's University, Queen’s University, Kingston, ON
Abstract
The right ventricle (RV) is the major determinant of functional state and prognosis in pulmonary
arterial hypertension (PAH). RV hypertrophy (RVH) triggered by pressure overload is initially

compensatory but often leads to RV failure. Despite similar RV afterload and mass some patients
develop adaptive RVH (concentric with retained RV function), whilst others develop maladaptive
RVH, characterized by dilatation, fibrosis and RV failure. The differentiation of adaptive versus
maladaptive RVH is imprecise but adaptive RVH is associated with better functional capacity and
survival. At the molecular level, maladaptive RVH displays greater impairment of angiogenesis,
adrenergic signaling and metabolism than adaptive RVH and these derangements often involve the
left ventricle. Clinically, maladaptive RVH is characterized by increased NT-proBNP levels,
troponin release, elevated catecholamine levels, RV dilatation and late gadolinium-enhancement
on magnetic resonance imaging, increased 18fluorodeoxyglucose uptake on positron emission
tomography and QTc prolongation on the electrocardiogram. In maladaptive RVH there is reduced
inotrope responsiveness due to G-protein receptor kinase (GRK2)-mediated downregulation,
desensitization and uncoupling of β-adrenoreceptors. RV ischemia may result from capillary
rarefaction and/or decreased right coronary artery perfusion pressure. Maladaptive RVH shares
metabolic abnormalities with cancer including aerobic glycolysis (resulting from a FOXO1-
mediated transcriptional upregulation of pyruvate dehydrogenase kinase, PDK), and

glutaminolysis (reflecting ischemia-induced cMyc activation). Augmentation of glucose oxidation
is beneficial in experimental RVH and can be achieved by inhibition of PDK, fatty acid oxidation,
or glutaminolysis. Therapeutic targets in RV failure include chamber-specific abnormalities of
metabolism, angiogenesis, adrenergic signaling and phosphodiesterase-5 expression. The ability to
restore RV function in experimental models challenges the dogma that RV failure is irreversible
without regression of pulmonary vascular disease.
Address for correspondence: Stephen L. Archer MD. FRCP(C), FAHA, FACC, Professor and Head, Department of Medicine,
Queen's University, Etherington Hall, Room 3041, 94 Stuart St. Kingston, Ontario, Canada, K7L 3N6, [email protected],
Telephone: 613 533-6327; Fax: 613 533-6695.
Disclosures:
None.
Ryan and Archer Page 2
Keywords
Right ventricular failure (RVF); aerobic glycolysis; glutaminolysis; G protein receptor kinase 2
(GRK2); Forkhead box protein O1 (FOXO1); adrenoreceptors; pyruvate dehydrogenase (PDH);

glutaminolysis; microvascular ischemia; Congenital Heart Disease; fluorodeoxyglucose positron
emission tomography (FDG-PET); cardiac magnetic resonance imaging (CMR)
Introduction
The right ventricle (RV) and left ventricle (LV)have discrete embryological origins. The LV
develops first, originating from the primary heart field; subsequently the RV develops from
precursors cells in the secondary heart field1. The transcriptional regulation of myoblast
differentiation also differs between the RV and LV. RV myocytes are directed in their
development by chamber-specific transcription factors, such as dHAND and MEF2C2, 3. In
contrast, LV myocyte development is guided by Nkx2.5 and eHAND1. The RV’s unique
embryology foreshadows differences in its response to pressure and volume overload.
Right ventricular anatomy

The fetal/neonatal RV is a thick-walled chamber that ejects blood at relatively high pressure
into a high resistance vascular bed. The wall thickness of both ventricles increases in parallel
to ~3.5 mm at term4. Postnatally the pulmonary circulation transitions to a low-pressure
circuit and the RV wall thickness remains ~4 mm whilst the LV, faced with 4-times greater
afterload, increases in thickness to ~11 mm.
The RV’s crescentic geometry is distinct from the cone-shaped LV. The RV can be divided
into 3 segments, including: (1) the inlet, comprised of the tricuspid valve, chordae tendineae,
and papillary muscles (2) the trabeculated apical myocardium and (3) the outflow region
(called the conus or infundibulum), which has a smooth myocardial surface5. RV
contraction starts at the inflow section and progresses towards the outflow tract. A
superficial, circumferential layer of RV myocardial fibers is in continuity with the LV fibers,
accounting for the systolic motion of the RV free wall toward the interventricular septum. A
deeper layer of vertically arranged RV fibers mediates RV systolic shortening. This
longitudinal shortening is exploited in echocardiography to measure RV function using the
M-mode measurement, tricuspid annular plane systolic excursion (TAPSE). TAPSE predicts
RV function and prognosis in adults with Pulmonary Arterial Hypertension (PAH). A
TAPSE <18mm indicates a poor prognosis6.
Right ventricular function

After birth, with closure of the ductus arteriosus and foramen ovale, the RV conveys the
same cardiac output as the LV, but at ~20% of the LV’s pressure. The RV ejection fraction
(EF) in normal children is 53% while the LVEF is 68%7. However, cardiac output is
essentially identical, because the RV has slightly larger volumes. In adults the normal RVEF
is 62% compared to a normal LVEF of 65%8. RVEF is reduced by half in adults with WHO
Group 1 PH (to a mean of 34±10%)9.

The Multi-Ethnic Study of Atherosclerosis (MESA) study used magnetic resonance imaging
(MRI) to determine normal values for RV size and function in 4123 normal adults, age
61.5±10.1 years (47.5% males)10. Normal values for RV mass in females and males were
19.2±3.6g and 23.1±4.4g, respectively. Normal values for RV end-diastolic volume in

females and males were 108.9±23.2mL and 140.9±29.7mL, respectively. Males had 4%
lower RVEF than females. Age was associated with lower RV mass but higher RVEF.
The RV in normal individuals increases cardiac output during exercise. However, at rest, the
cardiac output can be maintained at near normal levels without a functional RV, provided
that the LV function is normal and there is no pulmonary vascular disease. This is illustrated
by two surgical studies in which the RV is removed from the circulation. First, in normal
dogs replacement of the RV with a noncontractile Dacron patch reduces cardiac output by
only 25%and many animals survive without heart failure. The Dacron patch is pulled toward
the septum by the LV and the septum bulges into the RV cavity in systole, creating
sufficient force to eject blood into the normal pulmonary circulation11. The second example
is the Fontan procedure, performed in patients with tricuspid or pulmonic valve atresia. In
the Fontan procedure, all caval flow bypasses the RV and enters directly into the pulmonary
circulation. Cardiac output and functional capacity is maintained in these patients, provided
there is no pulmonary vascular disease. If performed before age 5-years these patients
maintain normal resting cardiac output more than a decade later, although maximal exercise
capacity is reduced12.
Rationale for study of the RV

RV function is a major determinant of functional capacity and prognosis when RV afterload
is elevated, as in WHO Group 1 PH (PAH)13 or congenital heart diseases, such as pulmonic
stenosis14. RV failure (RVF) in PAH differs from LV failure (LVF) in etiology (being more
related to increased afterload), prognosis (having higher mortality rates during acute
decompensation) and therapy (benefiting from different approved therapies). Compared to
LVF the following features are more common in PAH-associated RVF:1) compression of
the LV by the enlarged RV, reflecting ventricular interdependence, 2) decreased RV
perfusion due to microvascular ischemia and/or reduced epicardial coronary artery perfusion
pressure and 3) a high, fixed transpulmonary gradient15. These changes are uncommon in
most types of LVF. In adult PAH patients, RV failure requiring inotropic support and
admission to an intensive care unit has an inpatient mortality rate over 40%16, 17, far higher
than the 13–14% mortality for patients admitted to hospital with LVF requiring inotropes18.
A National Heart Lung and Blood Institute-sponsored working group recently highlighted
the need to develop a robust basic understanding of the RV’s unique properties, and apply
this to advance the understanding of etiology and design of therapies for RV hypertrophy
(RVH) and RVF19.
Although the RV is somewhat unique, there are lessons about RVH and RVF to learn from
LV hypertrophy (LVH) and LVF. Although the RV has poorer tolerance to sustained
afterload than the LV, both ventricles respond to increased afterload with β-receptor
downregulation20, 21, increased glycolysis22, 23, and decreased capillary density15, 24. In
LVH, proto-oncogenes, such as c-Myc, reactivate fetal gene expression25, including the β-

isoform of myosin heavy chain, α-skeletal muscle actin, and atrial natriuretic factor. RVH is
also associated with reactivation of the fetal gene package, with activation of c-Myc and a
switch to the fetal isoforms of myosin and actin26.
The right ventricle in pulmonary hypertension

Chronic pressure overload, as occurs in World Health Organization (WHO) Categories 1-5
pulmonary hypertension (PH)27, stimulates RVH. RVH can compensate for the increased
afterload and maintain cardiac output. However, RVH is rarely fully compensatory and may
create RV ischemia and lead to RV failure28.
The ideal means of regressing RVH is reduction in afterload. Unfortunately, approved PH

therapies cause only modest reductions in mean pulmonary artery pressure and pulmonary
vascular resistance (PVR). There are two circumstances where substantial reductions in
PVR demonstrate the expected regression of RVH in response to effective therapy. In a
small study of 12 patients with PAH who underwent lung transplantation, there was modest
decrease in RV volume after 3 months29. However these changes observed in RVH and
RVF after lung transplant for PAH, pale in comparison to that seen in, chronic
thromboembolic pulmonary hypertension (CTEPH), where RV function typically returns to
normal within weeks after pulmonary endarterectomy (PEA)30. This likely reflects a much
more multi-faceted disease process in PAH compared with CTEPH, but also may reflect
distinct patterns of the development of RVH. The pattern of recovery seen after PEA for
CTEPH and in some PAH patients post-lung transplant indicates that the RV dysfunction is
triggered by increased afterload but does not explore the possibility that cardiac-targeted
therapies, such as modulators of adrenergic signaling, angiogenesis, fibrosis or metabolism,
might serve as a bridge to definitive afterload reduction. This review focuses on identifying
pathophysiologic mechanisms that might be exploited to optimize RV function in conditions
where RV afterload cannot be corrected,
RV Failure
Clinically, RVF reflects inability of the RV to perfuse the lung circulation adequately to
maintain LV filling at low venous/diastolic pressures. Although there is no standard
hemodynamic definition, RVF can be characterized by a reduced cardiac index (<2.5
L/min/m2) and increased RV filling pressures (right atrial pressure > 8 mmHg31). The
normal values for RV hemodynamics in humans and rodents are contrasted with those
observed in PAH in Table 1 & Table 2, respectively. On physical examination, RVF is
manifest as an elevation in jugular venous pressure (JVP), reflecting elevated right atrial
pressure. Appreciation of an RV lift on palpation of the precordium indicates RV
enlargement. A right-sided third heart sound on auscultation indicates a noncompliant and
failing RV. In patients with RV dysfunction that are rendered euvolemic on medical therapy
the exam may be unremarkable at rest but signs of impaired RV reserve can be elicited by
maneuvers that increase venous return to the RV. Kussmaul’s sign (a paradoxical increase in
JVP with inspiration) and hepatojugular reflux (a rise in JVP upon pressure over the liver/
abdomen) are features of impaired RV reserve. In addition, RVF frequently results in
peripheral edema and hepatic congestion on physical examination.

Although elevated afterload, due to pulmonary vascular disease, initiates RVH in PAH, it is
the decline in RV function (manifest as reduced RVEF and RV dilatation)that best predicts
adverse prognosis. Consistent with this, impaired RVEF predicts clinical worsening in PAH
more accurately than elevated PVR32. In fact, the RV response to therapy is the key
determinant of clinical outcomes in PAH. Even though PAH therapies target pulmonary
vasoconstriction, survival has been shown to be significantly associated with changes in
RVEF, whereas therapeutic changes in PVR or CO demonstrated little relationship to
survival. 5-year survival exceeds 90% in PAH patients with a stable or increased RVEF and
an accompanying fall in PVR. However, in some patients, despite a demonstrable
therapeutic decrease in afterload, there is continued deterioration in RV function and
increased RV dimensions. Increases in RV end-systolic and end-diastolic volumes correlate
with mortality, an association which may be related to the Law of Laplace (higher wall
tension related to chamber dilatation) combined with increased intraluminal pressure33.
Thus, the RV may ultimately decompensate because of persistently elevated wall stress. The
variability in RV response between patients may suggest intrinsic genetic or epigenetic
differences in susceptibility to decompensation. Ventricular interdependence is also
important when considering the status of the RV in PAH. Inadequate RV perfusion and
impingement of the pressure and volume overloaded RV on the LV, leads to LV under-
filling, which reduces cardiac output. The resulting phenotype, a small LV and a dilated RV,
portends poor prognosis34. In severe RVF, low cardiac output can reduce pulmonary artery
pressure, which portends a worsening prognosis35. Reduction in RVEF and/or late
gadolinium enhancement (LGE) at the RV-LV septal hinge points on MRI predicts clinical
worsening in PAH36.
Adaptive versus Maladaptive RVH

There is heterogeneity in RVH in terms of its effects on cardiac output and the likelihood of
progression to RVF that is not explained by differences in RV mass or RV pressure
overload. Some patients have maladaptive forms of RVH and rapidly decompensate whilst
others remain stable for decades, despite similar elevations in RV pressure and RVH22
(Figure 1A). Within the WHO classification there is subclass heterogeneity in the
predilection to RVF, even within the relatively homogenous Group 1 patients. RVF is much
less prevalent and occurs later in those with congenital heart disease (i.e. Eisenmenger’s
syndrome37) versus in those with scleroderma-associated PAH38, 39. Patients with RV
pressure overload without pulmonary vascular disease, such as those with pulmonic stenosis,
retain concentrically hypertrophied, contractile RVs for decades40–42.
Animal models of RVH recapitulate this separation into adaptive and maladaptive
categories, as judged by their exercise performance and survival20. RVH in rats post
pulmonary artery banding (PAB), which models pulmonic stenosis, is better tolerated, than
RVH induced by endothelial toxins, such as monocrotaline or the vascular endothelial
growth factor receptor (VEGF-R) antagonist, Sugen 5416, plus chronic hypoxia (CH+SU)43.
That RV failure is more prevalent in PAH models with endothelial injury, suggests a
potential role for endothelial dysfunction in the coronary vasculature of the RV itself.

Using monocrotaline rats, Sutendra et al have studied the transition period between adaptive
and maladaptive RVH44. In this work, the transition to maladaptive RVH is associated with
a decrease in RV HIF1α, a decline in angiogenesis, a fall in glucose uptake and a reversion
towards normal metabolism. The authors argue that metabolic shift observed in the RV is
not sustained throughout the progression of RV failure. A rise in mitochondrial-derived ROS
potentially results in HIF1α inhibition, thereby suppressing angiogenesis. The resultant
ischemia from the decrease in angiogenesis may contribute to the rapid deterioration of RV
function in maladaptive RVH.
Although this is an elegant theory, the time course over which this maladaptive metabolism
regresses in undefined and the clinical relevance is unclear. In the limited data available
patients with advanced PAH manifest persistent glycolytic shift on FDG-PET22, 45.
Moreover, there is disagreement regarding the predominant transcription factor involved in
aerobic glycolysis in the heart. HIF1α is not consistently upregulated in our rodent RVH
experiments and HIF1α is not known to upregulate transcription of PDK4, the predominant
cardiac form of PDK that leads to aerobic glycolysis. In contrast to the heart, HIF1α is
upregulated in the lung in PAH models46 (relating to epigenetic silencing of SOD247). In the
lung vasculature, HIF1α appears to account for aerobic glycolysis; in contrast, the metabolic
remodeling in the RV appears to be more related to pathologic activation of FOXO1 and c-

Myc26, 48. Emerging concepts regarding the molecular basis for these adaptive and
maladaptive RVH phenotypes and their therapeutic implications are discussed subsequently.
There are many factors that determine whether RVH will be well tolerated, such as the
presence and severity of RV fibrosis, ischemia, autonomic dysregulation, and metabolic
changes (Figure 1B). Adaptive RVH is provisionally defined by preservation of normal
cardiac output, RVEF, RV filling pressures and exercise capacity. It is usually characterized
by concentric hypertrophy with minimal RV dilatation or fibrosis. Conversely, the
maladaptive phenotype can be defined by significant reductions in cardiac output, RVEF
with elevation of RV filling pressures and reduced exercise capacity. Maladaptive RVH
commonly displays RV fibrosis and dilatation (Figure 1C). While these definitions are
imprecise, there is progress towards more rigorous, molecular fingerprints of these RVH
phenotypes. Several abnormalities appear common to maladaptive RVH, including RV
ischemia49 and two forms of cancer metabolism, aerobic glycolysis22, 45, 50 and
glutaminolysis26. In addition maladaptive RVH shows greater impairment of angiogenesis,
manifest as capillary rarefaction and decreased expression of angiogenic genes (VEGF,

IGF-1, apelin and angiopoeitin-1). There is also greater dysregulation of the autonomic
nervous system in maladaptive RVH with a broad downregulation and sensitization of α, β
and dopaminergic receptors in the RV myocytes45, 50–52. Finally, in maladaptive RVH
changes in RV perfusion, angiogenesis, adrenergic signaling and metabolism tend to involve
the LV whereas they tend to be confined to the RV in adaptive RVH. Although these
changes have yet to shape clinical practice, they do offer opportunities for research and
suggests new therapeutic strategies (Figure 2).

Right Ventricular ischemia

RV dysfunction in PAH may reflect chronic reduction in RV perfusion in the presence of
viable myocardium, representing a form of myocardial hibernation. Evidence of RV

ischemia in PAH includes angina-like chest pain, ischemia on nuclear perfusion stress
imaging53, and increased RV uptake of 18fluorodeoxyglucose on positron emission
tomography (FDG-PET)45, 54. Evidence of ischemia, such as elevation of troponin levels,
indicates poor prognosis49, 55. Ischemia is also relevant to RVF in congenital heart disease.
Late failure of the systemic RV after the Mustard repair of transposition of the great arteries
is associated with impaired myocardial flow reserve56–58. Nuclear perfusion scans
commonly demonstrate perfusion defects with concordant regional wall motion
abnormalities after repair of transposition of the great arteries56.
RV ischemia may reflect reduced right coronary artery (RCA) perfusion pressure, and/or
decreased coronary flow reserve59. The low RV systolic pressure (RVSP) in normal
individuals permits filling of the RCA during both systole and diastole. In RV pressure
overload, the systolic perfusion gradient (Aortic pressuresystole-RVSP)may be eliminated
and the diastolic RCA perfusion pressure (Aortic pressurediastole-RV end diastolic pressure)
be reduced, thereby impairing RCA flow60, 61. RV contractile function remains constant
until RCA perfusion pressures fall below 50 mmHg62.
It has been suggested that an additional cause of ischemia contributes to RVF in PAH,
namely capillary rarefaction, defined as a reduction in the density of capillaries and small
intramyocardial arterioles in the RV15. RV capillary density is reduced in CH+SU and
monocrotaline RV with little change in PAB RVs15, 26 (Figure 3). RV capillary rarefaction
may occur in PAH patients, particularly those with scleroderma PAH26. Since CH+SU and
monocrotaline rats have similar elevation in RVSP and similar RVH as PAB rats, their
reduced functional capacity and greater mortality suggests that ischemia cannot be explained
solely by diminished RCA perfusion pressure50.
Correctly identifying the cause of RV ischemia in RVH has therapeutic ramifications. If

RVF were initiated primarily by a drop in coronary perfusion pressure then strategies such
as infusion of phenylephrine to increase the aortic-RV pressure gradient to drive coronary
perfusion might be rational. However, if capillary rarefaction contributes to RV ischemia it
would be more logical to treat RV failure by pharmacologically changing metabolism to “do

more with less” or by enhancing RV angiogenesis. In rodent models capillary rarefaction
observed in PAH rats appears to be reversible with β-blockers63. It is likely that ischemia
precipitates many of the metabolic changes that occur in RVH.
Metabolism of the right ventricle in PAH

Aerobic Glycolysis
In the fetal heart, where circulating fatty acid levels are low, glycolysis and glucose
oxidation are the major sources of ATP production64. In the adult heart fatty acid oxidation
(FAO) becomes the predominant energy source (60–90%) but glucose metabolism continues
to contribute 10%-40% of ATP production65.

In RVH the metabolic fate of glucose is altered because mitochondrial metabolism is

actively (although reversibly) suppressed66. Glucose metabolism starts with cytosolic
glycolysis, which ultimately converts glucose to pyruvate. In the normal adult RV myocyte,
pyruvate is transferred to the mitochondria where it serves as substrate for pyruvate

dehydrogenase (PDH).If the PDH complex in mitochondria is active, pyruvate is converted
to acetyl CoA, fueling Krebs cycle and providing electron donors (NADH and FADH) for
the electron transport chain and ATP generation67.
Pyruvate dehydrogenase kinase (PDK), a key inhibitory regulator of PDH (and thus of
glucose oxidation), is transcriptionally upregulated in RVH (Figure 1B). All 4 PDK
isoforms inhibit PDH by phosphorylating its E1-∝ subunit. The predominant cardiac PDK
isoforms in the RV are PDK2 and PDK448. When PDH is inhibited, supply of electron
donors to Krebs’ cycle is limited, which reduces energy production68. This PDK-mediated
metabolic switch is associated with decreased RV contractility and reduced cardiac output50.
The shift to aerobic glycolysis in RVH has several consequences (Figure 4A). First, lactate
is produced, resulting in acidosis, which impairs RV function. Second, only 2 ATP
molecules/glucose are obtained per mole of glucose, compared to the 32 ATP generated
during glucose oxidation50. To support the increased glycolysis required to maintain energy
homeostasis there is marked upregulation of glucose uptake, which can be detected by FDG-
PET scans in RVH45, 54, 66 (Figure 1C).
Increased RV glucose uptake, reflective of increased glycolysis, has been shown in a small
series of PAH patients undergoing FDG-PET45, 54. Moreover, there is some evidence that
effective reduction of afterload reduces RV uptake of FDG45. Likewise, in experimental
RVH, there is increased RV glycolysis, evidenced by direct measurement of metabolism in
isolated RV working heart and increased uptake of FDG-PET in vivo45.
In a case report comparing a long-term PAH survivor with an individual who rapidly
decompensated from RV failure, the markers of aerobic glycolysis (the glucose transporter,
glut 1, and PDK4) were less elevated in the adaptive versus the maladaptive RVH patient22.
Perhaps the hypokinetic RV in maladaptive RVH reflects a form of myocardial hibernation,
precipitated by impaired RV perfusion and metabolic shifts in the RV myocytes22 (Figure
2).
In rodents, PDH is inhibited more in maladaptive monocrotaline RVH than in adaptive PAB
RVH22. Dichloroacetate (DCA), a PDK inhibitor, reduces PDH phosphorylation and
partially restores RV contractility in rodent models of PAH50, 69,70 (Figure 5). The
possibility that RV function can be improved by metabolically targeted therapies, even
without reducing the afterload, is intriguing. There is a similar metabolic shift towards
aerobic glycolysis in the lung vasculature in PAH66, 71. Thus a PDK inhibitor might be
expected to have beneficial effects on both the RV and lung circulation54, 66, 69. A
therapeutic strategy of enhancing glucose oxidation has the potential to dramatically change
the treatment paradigms of PAH patients with RV failure. DCA has been used safely in
children with lactic acidosis72 and in adults with glioblastoma multiforme73, with the main
toxicity being reversible peripheral neuropathy. A phase 1 clinical trial is currently assessing

DCA in PAH (Dichloroacetate (DCA) for the Treatment of Pulmonary Arterial

Hypertension; NCT01083524)74.
Pathologic activation of transcription factors in the RV in PAH (e.g. HIF1α, and FOXO1)
leads to changes in metabolism, notably activation of PDK2 and PDK4. This decreases
expression of repolarizing voltage-gated potassium channels (Kv), such as Kv1.5, in cardiac
myocytes. In rodent models of RVH this ionic remodeling results in prolongation of the
RV’s monophasic action potential duration and mild QTc interval prolongation on the
surface electrocardiogram. Therapy with the PDK inhibitor DCA restores oxidative glucose
metabolism and restores Kv channel expression leading to normalization of QTc intervals
(Figure 5D, 5E)75. In PAH patients QTc intervals are also prolonged compared with normal
subjects (454.8±29 ms vs. 429.8±18 ms) and the QTc interval correlates directly with
increasing RV end-diastolic volume and mass and inversely with RVEF. QTc interval is
thus a potential simple biomarker of RVH. Prognostically, a QTc interval >480 ms portends
decreased survival in PAH76.
Fatty Acid Oxidation and the Randle Cycle

There is a reciprocal relationship between the two major oxidative metabolic pathways, such
that inhibiting FAO increases the glucose oxidation. This is called the Randle cycle77
(Figure 4B). A therapeutic strategy of enhancing glucose oxidation by inhibiting FAO might
be beneficial in RVH since FAO uses 12% more oxygen than glucose oxidation to generate
the same amount of ATP78. FAO’s demand for oxygen may be difficult to sustain in the
presence of RV ischemia. Partial inhibitors of fatty acid oxidation (pFOXi) are approved for
human use for several cardiovascular indications. Trimetazidine, a long-chain 3-ketoacyl
coenzyme A thiolase, is used in Europe to treat refractory ischemia in patients with coronary
artery disease79–82. Another pFOXi, ranolazine, is approved for refractory ischemia in
America83–85 (although there is some controversy whether it works through inhibition of
FAO and activation of PDH86–88).
The reciprocal relationship between FAO and glucose oxidation reflects (in part) citrate
production during FAO. Citrate inhibits phosphofructokinase (PFK), causing accumulation
of glucose-6-phosphate, which inhibits hexokinase and glucose oxidation. In addition, acetyl
CoA, generated from FAO, inhibits PDH. FAO inhibition can reduce these inhibitory
mechanisms and enhance glucose oxidation. A study of trimetazidine and ranolazine in rats
with PAB-induced RVH showed that pFOXi increased cardiac output and treadmill exercise
capacity, suggesting that the increased FAO in PAB-RVH is maladaptive75. FAO inhibitors
elevated RV ATP and increased glucose oxidation, reflecting activation of the Randle
cycle75. Like PDK inhibitors, pFOXi also partially regressed RVH and increased cardiac
output75. The beneficial effect of trimetazidine has also been shown in monocrotaline-
induced RVH89. In this model, trimetazidine enhanced cardiac mitochondrial function and
increased oxygen consumption, while reducing the formation of oxygen free radicals90.
PET studies have shown that in patients with idiopathic dilated cardiomyopathy,
trimetazidine decreases FAO and causes a compensatory increase in glucose oxidation91.
Whether combining PDK inhibitors and pFOXi would have additive or synergistic benefit in

RVH has not been studied. It should also be noted that FAO is not increased in all models of
RVH48.
Glutaminolysis
The Warburg phenomenon (aerobic glycolysis) and glutaminolysis are metabolic pathways
that are common in cancer and permit rapid cell growth without apoptosis92. Perhaps in
maladaptive RVH these cancer metabolic pathways permit inappropriate myocyte
enlargement. We recently examined the possibility that glutaminolysis might also occur in
RVH. In comparisons of monocrotaline-RVH and PAB-RVH we noted the monocrotaline
model had greater ischemia as determined by larger reductions in RV VEGFα expression,
greater reduction in coronary blood flow and reduced RV microvascular density. Consistent
with increased glutaminolysis in monocrotaline-RVH, RV expression of glutamine
transporters (SLC1A5 and SLC7A5) and mitochondrial malic enzyme were elevated. This is
analogous to the upregulation of glut-1 transporter that is seen in aerobic glycolysis50. In
both scenarios, transporter upregulation ensures that substrate provision is not a limiting
factor in metabolic capacity. Direct measurement of metabolism in the RV working heart
model, using a dual isotope technique, demonstrated a 6-fold increase in 14C-glutamine
metabolism in monocrotaline-RVH, which was not seen in PAB. As with aerobic glycolysis,
glutaminolysis appears to be maladaptive.In vivo, the glutamine antagonist,6-Diazo-5-oxo-
L-norleucine (DON), at doses that inhibited glutaminolysis, increased glucose oxidation and
elevated cardiac output. Longer-term therapy with DON restored PDH activity, reduced
RVH and increased cardiac output. The transcriptional basis for this RV metabolic pathway
appears to be activation of the cMyc-Max pathway, perhaps as a consequence of RV
ischemia. Glutaminolysis may be a therapeutic target in maladaptive RVH, although DON
has nonspecific systemic toxicity (Figure 4C).
Right Ventricular Sympathetic activation in PAH

Dopamine and dobutamine are commonly used as inotropic agents to treat acute RVH in
PAH patients. Some centers also use the pure α-adrenergic agonist, phenylephrine, as a
vasopressor, to increase coronary perfusion pressure. Dobutamine and dopamine primarily
exert their inotropic effects by stimulating β1-adrenergic receptors (β1-AR) but dopamine
has some reliance on α-adrenergic receptors (α-AR) at higher doses (10–20 µg/Kg/min).
However, the choice of inotropes for RVF is highly variable amongst practitioners, even at a
single institution, and inotrope use is also associated with extremely high mortality17. This
may reflect the dire condition of PAH patients that suggests the need for inotropic support
but should provoke the question whether catecholamines might actually worsen prognosis in
RV failure. The latter interpretation is possible, since the adrenergic system is arguably
maximally activated in RV failure in PAH20. PAH patients with RVF have high circulating
catecholamine levels and lose the normal ability to augment catecholamine levels with
exercise93. Autonomic activation, loss of inotropy to β-AR agonists and downregulation of
β1-AR expression also occurs in maladaptive rat PAH models94, 95.
In a canine RVF model, which combined PAB and tricuspid valve avulsion, downregulation
of the β-AR was confined to the RV and resulted in chamber specific reduction of

isoproterenol-induced cAMP production96. In humans with PAH and RVF, RV β-AR

density is decreased and the response to inotropes is similarly impaired97. However, whereas
Bristow et al found no impairment of LV β-AR signaling in human RVF associated with
PAH, β-AR density decreases in the non-hypertrophied LV in monocrotaline RVH98, a

finding that was recently reproduced20.
We recently discovered a broad downregulation of adrenoreceptors in rodent RVH,

including α1, β1 and dopamine (1–5) receptors20. While changes occurred in all forms of
RVH, the adrenoreceptor downregulation was more severe in maladaptive RVH, and
extended to the LV. The cause of this broad downregulation of adrenergic receptor
expression and function was activation of G protein receptor kinase (GRK2) (also called β-
adrenergic receptor kinase 1 (BARK1)). Interestingly, GRK2 activity was as high in RVH at
baseline as could be stimulated by catecholamines in normal RVs. This suggests a near
maximal receptor downregulation and desensitization occurs in RVH.
β1-receptor uncoupling and downregulation reduced the RV response to all inotropes in

RVH, perhaps indicating why patients with PAH and RVF respond poorly to inotrope
infusion. In rodent models, dobutamine was superior to dopamine in terms of its ability to
increase RV contractility in RV Langendorff models and in vivo. Dobutamine’s superiority

was associated with its superior coupling to adenylyl cyclase (evident as a greater increase
in cAMP levels). Interrupting Gβγ-signaling, using gallein, inhibits GRK2 activity and
improved cardiac function when administered chronically in vivo20.
In left heart failure, β-blockers improve survival and LV function99. However, β-blockers
are not used clinically in PAH and concerns about their safety exist. However, the α/β
blocker carvedilol and the β-blocker propranolol have been shown to regress RVH and
lower RVSP in experimental models of chronic hypoxic pulmonary hypertension and in the
CH+SU model100. Small clinical trials have demonstrated that β-blockade with carvedilol
can improve RV systolic function101and a clinical trial of β-blockers for RVH in WHO
Group 1 PH is underway102.
Phosphodiesterase-5 and Endothelinin RVH

In the normal heart quantitative differences in expression of many pumps and transporters
exists between the RV versus LV103. This is a reminder that there may be other chamber-
selective therapeutic targets in RVH. Sildenafil, a phosphodiesterase (PDE) 5 inhibitor has

been found to have a direct RV inotropic effect104, 105. Interestingly PDE5 is not present in
the normal RV myocytes but is induced during RVH, both in rodents and humans104. By
inhibiting PDE5, sildenafil increases cGMP levels, which then inhibits PDE3. Sildenafil’s
modest inotropic effects are due (in part) to this indirect inhibition of PDE3. Thus there are
mechanistic similarities between sildenafil’s actions in RVH and the more potent direct
PDE3 inhibitor of milrinone105. This de novo appearance of a selective RV target accounts
in part for sildenafil’s ability to increase cardiac output in PAH105.
Patients with PAH also have up-regulation of the RV myocardial endothelin axis, which
may be a compensatory mechanism to increase contractility and cardiac output in the setting
of the increased afterload observed. In the working heart model, endothelin receptor

antagonists (ERAs) decrease contractility106. This is of interest because of the published

trials failing to show a benefit of ERAs in left heart failure107 although ERAs have
demonstrated an established clinical improvement in PAH108, 109.
Both the effects of PDE5 inhibitors and ERAs on the RV were unanticipated by PAH trials
which focused on the effects of these drugs on the pulmonary vasculature. Future trials
should directly examine the effects of putative PAH therapies on the RV, to detect both
benefit and harm110.
Right ventricular fibrosis

In adult patients with PAH, late gadolinium-enhancement on MRI at the RV insertion points
is likely evidence of localized fibrosis and is associated with worsened prognosis111. In
children with congenital heart disease, fibrosis may also be an important determinant of
RVF.
Whether trials should be performed to reduce RV fibrosis is unclear. There are several
potential means by which fibrosis could be inhibited, such as using inhibitors of the renin-
angiotensin-aldosterone system, including angiotensin receptor blockers or
mineralocorticoid antagonists112. A study in patients with congenital heart disease and a

systemic RV tested the ability of the angiotensin receptor blocker, losartan, to improve
cardiac function. In this study, losartan failed to improve hemodynamics or exercise
capacity113. In PAH, the aldosterone pathway has been identified as a potential therapeutic
target114.
Conclusions
Although a cure for PAH will require regression of pulmonary vascular lesions or
transplantation, substantial improvement in longevity and functional state might be achieved
by an effective treatment for RV failure. Hopefully an increased understanding of
adrenergic, angiogenic, fibrotic and metabolic derangements in the RV in PAH will offer
new therapeutic targets to enhance RV function (Figure 2).
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
We apologize to colleagues whose work could not be cited due to space limitations.
Funding Sources:
This work is supported by NIH-RO1-HL071115 and 1RC1HL099462 (SLA).
Non-standard Abbreviations and Acronyms
CH+SU Chronic hypoxia plus Sugen 5416

CTEPH Chronic Thromboembolic Pulmonary Hypertension

DCA Dichloroacetate
EF Ejection fraction
ERA Endothelin receptor antagonist
FAO Fatty acid oxidation
FDG-PET 18fluorodeoxyglucose positron emission tomography
GRK2 G protein receptor kinase
HIF1α Hypoxia-inducible factor 1 alpha
LGE Late gadolinium enhancement
LV Left ventricle
LVF Left ventricular failure
LVH Left ventricular failure
MRI Magnetic Resonance Imaging

PAH Pulmonary Arterial Hypertension
PDE Phosphodiesterase
PDH Pyruvate dehydrogenase
PDK Pyruvate dehydrogenase kinase
PEA Pulmonary Endarterectomy
PH Pulmonary Hypertension
PVR Pulmonary vascular resistance
RCA Right coronary artery
RV Right ventricle
RVF Right ventricular failure
RVH Right ventricular hypertrophy
TAPSE Tricuspid annular plane systolic excursion

VEGF Vascular endothelial growth factor receptor;
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A Patient Asks Questions…

I met this patient in the PAH group meeting… She has lower pulmonary artery
pressures than I do, but she is much sicker….What does that mean; how is it
possible?
At first, this appears to be a paradox; one would assume that higher lung blood pressure
would mean more advanced disease and more symptoms. However, as it was discussed
in the first paper in this collection, the symptoms in PAH (i.e. shortness of breath) are not
caused by the pressure in the arteries of the lungs, but by the function of the right
chambers of the heart (right ventricle). At some point the muscle of the right ventricle
starts getting exhausted due to pumping against higher than normal pressures. Its
contractile strength is suppressed, causing a decrease in the amount of blood ejected with
each contraction; and thus decrease in the amount of blood (and thus oxygen) that
reaches the organs of the body, generating the sensation of shortness of breath. However,
as the contractile power of the heart muscle decreases, so does the pressure of the blood
that it ejects; in other words, the pressure in the lung blood vessels decreases. This is
similar to the decrease in the pressure of the water at a water hose, not because there is
narrowing of the hose lumen but because the pressure in the water pump feeding the hose
is decreasing.
This is a very important realization that sometimes may even confuse physicians. For
example, let’s say that a therapy is initiated to treat PAH aiming to decrease the
narrowing of lung blood vessels. Let’s assume that this therapy may also unexpectedly
suppress the function of the heart muscle in the right ventricle. Such unexpected effects
(sometimes called “off target effects”) are much more common than we assume in
Medicine. In this case, the pressures in the lung arteries will decrease not because the
therapy improved the function of the blood vessels, but because it adversely decreased
the contractile power of the heart. While the pressures in tests (for example, an
echocardiogram) may appear to be decreasing, the patient will actually feel worse. If the
patient does not communicate well with the treating physician and if the treating
physician does not look at the “big picture”, he/she may actually prescribe an increase in
the dose of the therapy, rather than stopping it. This would obviously make things even
worse.
This is why it is important to approach the right ventricle in parallel to the lung vessels in
PAH, an idea that is changing the way that we approach PAH. This article discusses
many mechanisms that may explain why the right ventricle may worsen and perhaps why
it may worsen in one patient but not another. In our patient’s question, the one with lower
pressures was feeling worse because she has worse right ventricular function. What
makes the right ventricle start deteriorating at some point and why this happens earlier in
some patients, is one of the most critical questions that we need to answer in PAH.
Understanding this concept may also help the patients to better understand their
symptoms and their response to standard or investigative therapies.

Figure 1.
Increased glycolysis in the right ventricle (RV) in right ventricular hypertrophy (RVH) in
PAH patients. (A) The cross sections of RVs from patients with adaptive versus maladaptive
RVH. RV chambers are enlarged in both patients however adaptive RVH is concentric with
less dilatation and fibrosis. (B) Immunostaining shows up-regulation of Glut1 and PDK4
expression in RV myocytes and is less profound in the PAH patient with adaptive RVH. (C)
Imaging modalities showing RV dilatation in MRI, RV fibrosis in MRI and increased FDG
uptake in PET scan. The figure is partially adapted from references22, 36, 45with permission.

Figure 2.
Vicious cycle of right ventricular failure including metabolic changes and RV ischemia.

Figure 3.
Decreased capillary density in animal models of maladaptive PAH but not in adaptive PAH.

Figure 4.
A: Mechanism of impaired glucose oxidation and enhanced glycolysis in RVH. In RVH,
activation of various transcription factors, including FOXO1, cMyc and HIF-1α upregulates
expression of many glycolytic gene. A common finding in RVH is increased PDK
expression, which inhibits PDH and reduces mitochondrial respiration. PDK activation also
occurs in the lung in PAH, although the transcriptional regulation and isoform specificity
may differ than that seen in the RV. Dichloroacetate inhibits PDK and thereby promotes
glucose oxidation and inhibits glycolysis. ETC = electron transport chain, HK = hexokinase,
H2O2 = hydrogen peroxide, LDHA = lactate dehydrogrenase A, PFK =
phosphofructokinase. Adapted from 50
B: The Randle cycle in RVH The inhibition of β-FAO by trimetazidine and ranolazine
increases PDH activity and improves GO. This reciprocal relationship between GO and
FAO is referred to as the Randle cycle. Adapted with permission from 75.
C: Proposed mechanism of glutaminolysis in RVH. RV ischemia and capillary rarefaction
activate cMyc and Max, which increases glutamine uptake and production of α-
ketoglutarate (α-KG). α-KG enters Krebs’ cycle leading to production of malate. Krebs’
cycle-derived malate generates cytosolic pyruvate, which is converted by lactate

dehydrogenase A (LDHA) to lactate. In conditions of high glutaminolysis GO is inhibited.

Reproduced from 26 (Illustration Credit: Ben Smith).


Figure 5.
(A)DCA Reduces Glut-1 expression in RV in monocrotaline-PAH. (B) DCA Reduces FDG
uptake on in RV on PET scan in monocrotaline-PAH. (C) DCA Improves RV function in
monocrotaline-PAH.(D)Representative traces and mean data showing MAPD20 and
MAPD90 are significantly prolonged in the monocrotaline (MCT) group vscontrol (CTR)
and that repolarization is improved by DCA. (E) Representative traces and mean data of
lead II surface ECG. DCA reduces the QTc prolongation in RVH. Red highlighted arrows
indicate QTc intervals. Adapted with permission from 50, 75

Table 1
Normal pressure ranges and vascular resistance in humans (adapted from 115 and 116). PAH range is derived
from patients with severe Group 1 PH, reference116. In this patient population, 74% of patients were NYHA
functional class III and 26% were NYHA functional class IV. This study is chosen because it represents a
modern untreated cohort.
Hemodynamics Normal Range PAH Range (mmHg)

Right atrium - Mean (mmHg) 1–5 11–13
Pulmonary Artery - Mean (mmHg) 9–20 57–61
Pulmonary Capillary Wedge - End-expiratory (mmHg) 4–12 9–11
Systemic artery pressure - Mean (mmHg) 90–96 87–91
Heart beat (bpm) 60–90 84–88
Cardiac index (L/min/m2) 2.6–4.2 1.9–2.3
Pulmonary vascular resistance (dynes sec cm−5) 20–130 (0.25–1.625 Wood Units) 1200–1360 (15–17 Wood Units)
Systemic vascular resistance (dynes sec cm−5) 700–1600 (9–20 Wood Units) 1840–2000 (23–25 Wood Units)

Table 2
Normal pressure ranges and vascular resistance in rodents (adapted from 20, 117** represents statistical
significance)
Hemodynamics Normal rats Monocrotaline rats
Pulmonary artery systolic pressure (mmHg) 25±1 60±5**
Pulmonary artery diastolic pressure (mmHg) 3±1 13±2**
Systemic artery mean pressure (mmHg) 110±8 95±6
Heart rate (bpm) 320±7 294±5**
CO (ml/min) 110±5 76±5**
Pulmonary vascular resistance (dynesseccm−5) 0.07±0.01 0.44±0.08**
Systemic vascular resistance (dynesseccm−5) 0.85±0.12 1.01±0.6


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Circ Res. 2014 June 20; 115(1): 176–188. doi:10.1161/CIRCRESAHA.113.301129.

The Right Ventricle in Pulmonary Arterial Hypertension:

arterial hypertension (PAH). RV hypertrophy (RVH) triggered by pressure overload is initially

mediated transcriptional upregulation of pyruvate dehydrogenase kinase, PDK), and

(GRK2); Forkhead box protein O1 (FOXO1); adrenoreceptors; pyruvate dehydrogenase (PDH);

Right ventricular anatomy

Right ventricular function

Circ Res. Author manuscript; available in PMC 2015 June 20.

19.2±3.6g and 23.1±4.4g, respectively. Normal values for RV end-diastolic volume in

Rationale for study of the RV

Circ Res. Author manuscript; available in PMC 2015 June 20.

The right ventricle in pulmonary hypertension

The ideal means of regressing RVH is reduction in afterload. Unfortunately, approved PH

Circ Res. Author manuscript; available in PMC 2015 June 20.

Adaptive versus Maladaptive RVH

Circ Res. Author manuscript; available in PMC 2015 June 20.

remodeling in the RV appears to be more related to pathologic activation of FOXO1 and c-

manifest as capillary rarefaction and decreased expression of angiogenic genes (VEGF,

Circ Res. Author manuscript; available in PMC 2015 June 20.

Right Ventricular ischemia

viable myocardium, representing a form of myocardial hibernation. Evidence of RV

until RCA perfusion pressures fall below 50 mmHg62.

Correctly identifying the cause of RV ischemia in RVH has therapeutic ramifications. If

would be more logical to treat RV failure by pharmacologically changing metabolism to “do

Metabolism of the right ventricle in PAH

Circ Res. Author manuscript; available in PMC 2015 June 20.

In RVH the metabolic fate of glucose is altered because mitochondrial metabolism is

pyruvate is transferred to the mitochondria where it serves as substrate for pyruvate

Circ Res. Author manuscript; available in PMC 2015 June 20.

DCA in PAH (Dichloroacetate (DCA) for the Treatment of Pulmonary Arterial

Fatty Acid Oxidation and the Randle Cycle

Circ Res. Author manuscript; available in PMC 2015 June 20.

Right Ventricular Sympathetic activation in PAH

Circ Res. Author manuscript; available in PMC 2015 June 20.

isoproterenol-induced cAMP production96. In humans with PAH and RVF, RV β-AR

PAH, β-AR density decreases in the non-hypertrophied LV in monocrotaline RVH98, a

We recently discovered a broad downregulation of adrenoreceptors in rodent RVH,

β1-receptor uncoupling and downregulation reduced the RV response to all inotropes in

increase RV contractility in RV Langendorff models and in vivo. Dobutamine’s superiority

Phosphodiesterase-5 and Endothelinin RVH

selective therapeutic targets in RVH. Sildenafil, a phosphodiesterase (PDE) 5 inhibitor has

Circ Res. Author manuscript; available in PMC 2015 June 20.

antagonists (ERAs) decrease contractility106. This is of interest because of the published

Right ventricular fibrosis

mineralocorticoid antagonists112. A study in patients with congenital heart disease and a

Refer to Web version on PubMed Central for supplementary material.

This work is supported by NIH-RO1-HL071115 and 1RC1HL099462 (SLA).

Non-standard Abbreviations and Acronyms

CH+SU Chronic hypoxia plus Sugen 5416

Circ Res. Author manuscript; available in PMC 2015 June 20.

CTEPH Chronic Thromboembolic Pulmonary Hypertension

MRI Magnetic Resonance Imaging

TAPSE Tricuspid annular plane systolic excursion

Circ Res. Author manuscript; available in PMC 2015 June 20.

Pediatr Crit Care Med. 2010; 11:S15–S22. [PubMed: 20216156]

11. Sawatani S, Mandell G, Kusaba E, Schraut W, Cascade P, Wajszczuk WJ, Kantrowitz A.

pulmonary arterial hypertension. Eur Respir J. 2011; 38:359–367. [PubMed: 21310884]

Circ Res. Author manuscript; available in PMC 2015 June 20.