Journal of Cardiothoracic and Vascular Anesthesia 37 (2023) 20732086

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Journal of Cardiothoracic and Vascular Anesthesia

journal homepage: www.jcvaonline.com

Review Article

Mechanisms of Acute Right Ventricular Injury

in Cardiothoracic Surgical and Critical Care Settings:
Part 1
Vasileios Zochios, MD*,y 1, Benjamin Shelley, MDz,x,
,

Marta Velia Antonini, CCP||,{, Sanchit Chawla, MD#,

Ryota Sato, MD**, Siddharth Dugar, MD#,yy,
Kamen Valchanov, MDzz, Andrew Roscoe, MB ChBzz,xx,
Jeffrey Scott, DO||||, Mansoor N. Bangash, PhD{{,##,***,
Waqas Akhtar, BMBChyyy, Alex Rosenberg, MBBSyyy,
Ioannis Dimarakis, MDzzz, Maziar Khorsandi, MDzzz,
Hakeem Yusuff, MBBS*,xxx, for Protecting the Right Ventricle
Network (PRORVnet)
*
Department of Cardiothoracic Critical Care Medicine and ECMO Unit, Glenfield Hospital,
University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
y
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
z
Department of Cardiothoracic Anesthesia and Intensive Care, Golden Jubilee National Hospital,
Clydebank, United Kingdom
x
Anesthesia, Perioperative Medicine and Critical Care research group, University of Glasgow, Glasgow,
United Kingdom
||
Anesthesia and Intensive Care Unit, Bufalini Hospital, AUSL della Romagna, Cesena, Italy
{
Department of Biomedical, Metabolic and Neural Sciences, University of Modena & Reggio Emilia,
Modena, Italy
#
Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH
**
Division of Critical Care Medicine, Department of Medicine, The Queen’s Medical Center, Honolulu, HI
yy
Cleveland Clinic Lerner College of Medicine, Case Western University Reserve University, Cleveland, OH
zz
Department of Anesthesia and Perioperative Medicine, Singapore General Hospital, Singapore
xx
Department of Anesthesiology, Singapore General Hospital, National Heart Center, Singapore
||||
Jackson Health System, Miami Transplant Institute, Miami, FL
{{
Liver Intensive Care Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
##
Birmingham Liver Failure Research Group, Institute of Inflammation and Ageing, College of Medical and
Dental sciences, University of Birmingham, Birmingham, United Kingdom
***
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, College of Medical and
Dental sciences, University of Birmingham, Birmingham, United Kingdom
yyy
Royal Brompton and Harefield Hospitals, Part of Guys and St. Thomas’s National Health System Founda-
tion Trust, London, United Kingdom
zzz
Division of Cardiothoracic Surgery, University of Washington Medical Center, Seattle, WA
xxx
Department of Respiratory Sciences, University of Leicester, Leicester, United Kingdom

1
Address correspondence to Vasileios Zochios MD, Department of Cardiothoracic Critical Care Medicine and ECMO Unit, Glenfield Hospital, University Hos-
pitals of Leicester NHS Trust, Leicester, UK, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
E-mail address: vasileioszochios@doctors.org.uk (V. Zochios).
DOI of original article: http://dx.doi.org/10.1053/j.jvca.2023.07.018.

https://doi.org/10.1053/j.jvca.2023.06.014
1053-0770/Ó 2023 Elsevier Inc. All rights reserved.
2074 V. Zochios et al. / Journal of Cardiothoracic and Vascular Anesthesia 37 (2023) 20732086
Keywords: right ventricular failure; right ventricular injury; heart failure; right ventricular dysfunction; cardiothoracic surgery
Right ventricular (RV) biomechanics play a key role in
maintaining cardiovascular homeostasis in cardiothoracic sur-
gical settings. The interplay between the RV and pulmonary
vasculature, the so-called "ventriculoarterial coupling", deter-
mines the response of the RV to different loading conditions
and its interaction with the left ventricle in order to meet flow
demand. There is a lack of universal RV injury (RVI) defini-
tion since it represents a range of abnormal RV biomechanics
and phenotypes—from diastolic dysfunction to RV failure and
shock. Understanding the mechanisms of uncoupling between
the RV and pulmonary circulation, as well as primary RV
insult, may inform future research, particularly phenotyping of
RVI, which may aid in individualizing RV-targeted therapies.
In this narrative review, the authors discuss the mechanisms of
RVI in cardiac and thoracic surgical settings and its implica-
tions for practice.
A VARIETY of disease states can adversely affect the bio-
mechanics of the right ventricle (RV) and the interplay
between the RV and the pulmonary vasculature. Diagnosing
acute RV injury (RVI) is more complex than simply assessing
RV performance since there is no universally accepted RVI
definition. Most of the currently accepted definitions refer to
RV failure, which represents advanced-stage RVI.1,2 RV fail-
ure has been previously defined as a state in which the RV is
unable to meet blood flow demands without excessive use of
the Frank-Starling mechanism, whereby sarcomeres become
overstretched at high RV end-diastolic volumes and the RV
fails to increase its contractility.3 RVI can be viewed as a het-
erogeneous clinical syndrome that is associated with adverse
outcomes in perioperative and critical care settings.4-9 The
syndrome comprises different clinical phenotypes, from RV
diastolic dysfunction to RV failure and shock.4-9 It should be
noted that the different RVI phenotypes (eg, isolated RV dila-
tation, RV dilatation with impaired function meeting flow
demand, RV dilatation with impaired function not meeting
flow demand) do not remain static and may overlap depending
upon the stage and timing of RVI development.2,10
A clear understanding of the specific etiology underlying
RVI in terms of pressure overload, volume overload, or pri-
mary myocardial process is necessary in order to make appro-
priate preemptive decisions and implement RV-targeted
therapies aiming to mitigate advanced RVI and shock.11 The
aim of this narrative review is to discuss the mechanisms of
RVI in cardiothoracic perioperative settings and highlight
implications for practice and research gaps that should be
overcome in the future.
Right Ventricle-Pulmonary Artery Uncoupling
A key concept in understanding RVI, especially in the con-
text of elevated RV afterload, is the RV coupling to pulmonary
arterial (PA) circulation, the so-called "RV-PA coupling".12
RV-PA coupling refers to the relationship between RV con-
tractility and RV afterload.12 RV contractility is measured by
end-systolic elastance (Ees), and RV afterload is measured by
PA elastance (Ea).12 The latter is a load-dependent measure of
both pulsatile and resistive components of ventricular afterload
represented by PA compliance and pulmonary vascular resis-
tance (PVR), respectively.12 The ratio Ees-to-Ea determines
the mechanoenergetic relationship between the RV and PA.
The system is coupled when Ees-to-Ea >1, indicating ade-
quate RV stroke work and right coronary arterial blood
flow.12,13 The Ees-to-Ea ratio can be measured invasively or
noninvasively. Invasive methods include catheter-based
measurements using RV pressure-volume loops to derive
end-systolic/arterial elastance and RV diastolic stiffness.14
Surrogate echocardiography markers, such as the ratio of
tricuspid annular plane systolic excursion (TAPSE) and PA
systolic pressure (PASP), may be utilized to measure RV-
PA coupling noninvasively.14 A TAPSE-to-PASP ratio
<0.31 mm-to-mmHg has been shown to predict mortality
in patients with severe pulmonary hypertension.15 Pending
validation in large cohorts of cardiac surgical patients,
assessment of TAPSE-to-PASP ratio, could potentially be
incorporated into clinical practice to aid in risk stratifica-
tion, patient selection, and implementation of certain peri-
operative RV-protective strategies.
In acute pulmonary hypertensive states, there is an
increase in intrinsic RV contractile force in order to com-
pensate for the elevated RV afterload.12,13 The phase of
RV systolic adaptation is known as "homeometric
adaptation".12,13 When the RV systolic function adaptation
fails, RV-PA uncoupling occurs via Frank-Starling’s het-
erometric adaptation, with acute RV dilatation to preserve
systemic blood flow.12,13 A subsequent reduction in Ees-to-
Ea ratio (<1) due to Ea-Ees mismatch results in a negative
interaction between the RV and the left ventricle (LV). RV
dilatation causes a shift of the interventricular septum
toward the left, altering LV geometry and increasing peri-
cardial constraint. The phenomenon whereby dysfunction
of 1 ventricle affects the function of the other is known as
"ventricular interdependence".12-14 Tricuspid regurgitation
may ensue, along with the negative systolic and diastolic
interaction between the 2 ventricles, causing further RV
overload, systemic venous congestion, coronary ischemia,
and an inability of the RV to meet flow demand.12,13
Cardiac Surgery
Clinically significant RVI occurs in 2.9% of cardiac surgical
patients, and is associated with adverse outcomes, including
stroke, reintubation, prolonged intensive care unit stay, and
mortality.4 The mechanisms behind this dysfunction are multi-
factorial and addressed below (Fig 1).
 V. Zochios et al. / Journal of Cardiothoracic and Vascular Anesthesia 37 (2023) 20732086 2075

Fig 1. Potential mechanisms of perioperative RVI associated with all general cardiac surgical procedures and cardiopulmonary bypass, including heart and lung
transplantation, and specific procedures, such as pulmonary endarterectomy and LVAD implantation.16-87 *Indicates pulmonary endarterectomy in the manage-
ment of chronic thromboembolic pulmonary hypertension. CABG, coronary artery bypass graft; CPB, cardiopulmonary bypass; CPS, cardioplegic solution; CSS,
cold static storage; DHCA, deep hypothermic circulatory arrest; DND, donation after neurologic determination of death; EVLW, extravascular lung water; EVMP,
ex-vivo machine perfusion; LAD, left anterior descending coronary artery; LV, left ventricle; LVAD, left ventricular assist device; NO, nitric oxide; PA, pulmo-
nary artery; PAPs, pulmonary arterial pressures; PE, pulmonary embolism; PVR, pulmonary vascular resistance; RA, right atrium; RV, right ventricle; RVI, right
ventricular injury; RVOT, right ventricular outflow tract; SIRS, systemic inflammatory response syndrome; SVR, systemic vascular resistance.
2076 V. Zochios et al. / Journal of Cardiothoracic and Vascular Anesthesia 37 (2023) 20732086
Cardiopulmonary Bypass and Myocardial Protection
Cardiopulmonary bypass (CPB) has been associated with
impaired biventricular filling patterns and depressed RV func-
tion following valvular and coronary artery bypass grafting
(CABG) surgery.16,17 Patients with normal global echocardio-
graphic indices of RV function, such as RV ejection fraction
(RVEF), RV fractional area change, and global longitudinal
strain, may have severe loss of RV longitudinal contraction
after CPB, as evidenced by reduced TAPSE and lateral tricus-
pid annulus peak systolic velocity.18 Korshin et al demon-
strated that RV longitudinal function was consistently reduced
after uncomplicated CABG19; echocardiographic assessment
performed at various time points intraoperatively showed that
the reduction took place mainly after weaning from CPB,
which is highly suggestive of conformational change of the
RV.
During CPB, the myocardium is protected by the injection
of cardioplegic solutions into the coronary circulation.20-22
This can be achieved through an antegrade injection through
the coronary arteries or retrograde through the coronary sinus.
Limited evidence suggests that retrograde cardioplegia alone
may not provide adequate RV myocardial protection, as evi-
denced by contrast echocardiography, poor coronary ostial
drainage, and metabolic analyses.20 This observation could
potentially be explained by cardiac venous anatomy; in partic-
ular, the absence of the small cardiac vein, which is the right
coronary vein that drains parts of the right atrium and RV and
can be absent in up to 75% of patients. This results in RV
drainage limited to thebesian veins that drain directly into the
ventricle, making retrograde perfusion to the RV free wall
technically difficult or even impossible.20 A recent meta-anal-
ysis has shown that there is no significant outcome difference
between cold versus warm cardioplegia, which had previously
been thought to be related to RVI.21 The type of cardioplegia
that may confer the highest level of RV myocardial protection
is currently unknown. A network meta-analysis of 18 random-
ized controlled trials and 49 observational cohort studies
(n = 18,191) that compared different types of commonly used
well-defined cardioplegia solutions (crystalloid materials and
mixtures of crystalloids and blood products), demonstrated
that the use of a 4:1 mixture of crystalloid solution and blood
products (del Nido cardioplegia) might be associated with
lower perioperative mortality.23 Mitigation of leukocyte-
induced myocardial inflammation and calcium overload due to
low levels of leukocytes and calcium ions contained in the
solution could theoretically explain the outcome benefit shown
in the meta-analysis.23 This notion, however, should be further
examined in large prospective studies.
Factors Affecting Right Ventricle (RV) Afterload
RV afterload comprises a static or resistive component and a
pulsatile component.12 PVR represents the resistive compo-
nent determined by the small distal pulmonary arteries, and
accounts for 75% of the RV afterload.12,24 The pulsatile com-
ponent contributes 25% of the RV pulmonary vascular load,
and represents the energy required to overcome elevated sys-
tolic pressure during ejection.24 Elevated RV afterload in the
perioperative period can overwhelm a normal thin-walled
RV.3,4 A rise in PA pressure (PAP) can be attributed to ventila-
tory changes, with atelectasis from lung deflation in surgery
and reperfusion injury after CPB.3,4 The management of venti-
lation to adequately rerecruit lungs avoiding extremes of lung
volumes is essential to prevent acute pulmonary hyperten-
sion.25 Pulmonary embolism postcardiac surgery can be
related to standard venous thromboembolism risk factors, as
well as directly due to types of cardiac surgical procedures
affecting the pulmonary vasculature.26 Indeed, incidental pul-
monary emboli have been found in 6% of patients undergoing
CABG.26 These emboli could conceivably be adding to the
milieu of raised PAPs and RV afterload that lead to RV-PA
uncoupling and RVI.
RV afterload can also rise with pharmacologic effects.
Examples include protamine administration and high doses of
catecholaminergic and noncatecholaminergic vasopressors,
such as norepinephrine and phenylephrine, respectively.25
Protamine-associated acute pulmonary vasoconstriction is
rare, and its true incidence is not known. Pulmonary vasocon-
striction associated with protamine use occurs only in the pres-
ence of heparin; it can be immunologic and nonimmunologic,
and implicated mediators include interleukin-6, interleukin-8,
and thromboxane.27,28 High doses of norepinephrine increase
PVR and, potentially, the ratio of PVR-to-systemic vascular
resistance through alpha-1 agonism, leading to decreased coro-
nary perfusion.25 Phenylephrine, a direct alpha-agonist, may
also cause a rise in PVR.25 Vasopressin, a nonsympathomi-
metic pressor, however, has been shown to reduce PVR and
the PVR:systemic vascular resistance ratio through a nitric
oxide-dependent mechanism via V1 receptors.25,29
CPB use has been associated with a rise in PVR in the periop-
erative period.30,31 The potential mechanisms of elevated PVR
due to CPB are related to inflammation, pulmonary vasomotor
dysfunction, oxidative stress, and impaired thromboxane A2 and
nitric oxide pathways.30,32,33 In particular, ischemia-reperfusion
has been linked to impaired microvascular endothelial dilator
function, leading to imbalance between endothelium-derived con-
strictive and relaxing substances.34 A rise in oxygen-derived free
radicals following reperfusion causes degradation of nitric oxide
and PA vasoconstriction.30,32,34,35 The resultant oxidative stress,
neutrophil, and complement activation may also impair endothe-
lial nitric oxide release, causing a further increase in PVR.34
There is also further consideration for RVI from volume
overload in the postoperative period, as well as RV outflow
tract obstruction, which can occur with excess positive ino-
tropy and volume depletion.36
Surgical Procedure
The type of surgery also influences the potential for RVI.
Following sternotomy and subsequent pericardiotomy, the
contractile patterns and contributions of the septum to blood
ejection change. Loss of pericardial support has been shown to
have immediate effects on RV geometry and function.37 It has
 V. Zochios et al. / Journal of Cardiothoracic and Vascular Anesthesia 37 (2023) 20732086
been demonstrated that irrespective of underlying pathology
and type of cardiac surgery, full pericardial incision causes a
reduction in longitudinal RV tissue Doppler velocities in the
postoperative period.38 Pericardiectomy for constrictive peri-
carditis has also been associated with postoperative RVI.39
RVI in this context could be explained by myocardial atrophy
due to chronic constriction and postoperative RV dilatation, or
myocardial injury secondary to an acute increase in RV wall
tension and impaired coronary blood flow.39 In a randomized
study comparing minimally invasive to conventional surgical aor-
tic valve replacement, investigators demonstrated that although
RV longitudinal function was reduced with both approaches, it
was more pronounced with conventional surgery.40 Kempny et al
assessed RV function in 101 patients with severe symptomatic
aortic stenosis undergoing transcatheter aortic valve implantation
or conventional surgical aortic valve replacement.41 While RV
function was found to deteriorate significantly with conventional
surgery, patients undergoing transcatheter aortic valve implanta-
tion and, by definition, not exposed to pericardiotomy or CPB,
were shown to be protected from RVI.41 Aortic patient-prosthesis
mismatch (PPM) affecting the coronary reserve can theoretically
result in postoperative pulmonary arterial hypertension (PAH).42
In mitral valve surgery, severe PPM (defined as indexed effective
orifice area
0.9 cm2/m2) can lead to residual PAH and RV-PA
uncoupling, and is associated with a 3-fold increase in postopera-
tive mortality.31,32 Raised left atrial filling pressure caused by per-
sistently abnormally high mitral gradients and the resultant
pulmonary venous, capillary, and eventually arterial hypertension
are the postulated mechanisms of RVI in the context of mitral
PPM.43 Progression of mitral regurgitation in patients with preex-
isting mitral regurgitation undergoing CABG with CPB may also
contribute to postoperative pulmonary hypertension through
raised left atrial pressure mechanisms.44
Right Ventricular (RV) Ischemia Due to Coronary Artery
Complications
Perioperative myocardial infarction occurs in 2.8% of iso-
lated CABG procedures, with significantly higher levels of
venous graft failure compared to arterial grafts.26 Preexisting
coronary disease in vessels supplying the RV would compound
this problem depending on the degree of stenosis.45 However,
not all perioperative myocardial infarction is due to graft
occlusion, and some can be secondary to generalized myocar-
dial stunning and injury during CPB.46 Though the thin-walled
RV has reduced myocardial oxygen demand and an ability to
reduce metabolic demand during ischemia, these protective
features can potentially be compromised by excessive pulmo-
nary pressures and, thus, make it vulnerable perioperatively.
Heart and Lung Transplantation
Right Ventricular Injury (RVI) After Heart Transplantation
RVI occurs in 20% to 60% of adult and 17.7% of pediatric
patients undergoing heart transplantation.47-50 It has been his-
torically attributed to the failure of the RV to adapt to a sudden
2077
increase in afterload in the recipient, leading to RV-PA uncou-
pling.47 Other factors contributing to RVI in the absence of
pulmonary hypertension may lie with the donor heart. An
experimental canine model showed that there is 37 § 10%
decrease in RV preload-recruitable stroke work in donors after
neurologic determination of death and prior to organ procure-
ment.51 RVI in this context may be explained by RV myocar-
dial edema and myocardial stunning due to ischemia-
reperfusion injury following surgical anastomosis, and pro-
inflammatory cytokine and catecholamine surges following a
neurologic determination of death.52 The actual molecular
basis and mechanistic link, however, between brain death and
RVI in the absence of elevated afterload remain unclear.
Primary graft dysfunction leading to isolated RVI is associated
with high mortality.50,53 In a large series of heart transplant recipi-
ents (excluding those with pulmonary hypertension), the reported
overall incidence of primary graft dysfunction was 22%, with mor-
tality in those patients exceeding 50%.54 Primary graft dysfunc-
tion-related RVI is determined per the International Society for
Heart and Lung Transplantation consensus hemodynamic crite-
ria—right atrial pressure >15 mmHg, pulmonary capillary wedge
pressure <15 mmHg, cardiac index <2.0 L/min/m2, transpulmo-
nary gradient (defined as the difference between mean PAP and
left atrial pressure, commonly estimated by pulmonary capillary
wedge pressure) <15 mmHg and PASP <50 mmHg, or the need
for an RV assist device (RVAD) at 24 hours posttransplantation.53
Isolated RVI is present in approximately 45% of patients with pri-
mary graft failure.54 In addition to the aforementioned postulated
mechanisms, it has been hypothesized that primary graft dysfunc-
tion-related RVI may be associated with changes in cardiac myo-
cyte metabolism during cardiac preservation in cold storage, and
longer warm ischemic times due to exposure of the thin-walled
RV to high ambient temperatures in the operating room.52,54
Given the high mortality associated with isolated RVI in the
setting of heart transplantation, identifying patients who may be
at risk for perioperative RVI is paramount since RV-protective
strategies (eg, pulmonary vasodilators, RV-protective ventilation
strategies targeting low driving pressure, extracorporeal circula-
tory support) may be applied early to minimize or mitigate RVI.
Elevated preoperative bilirubin and female sex have been identi-
fied as predictors of posttransplantation RVI and a need for
mechanical circulatory support (MCS).52 In the presence of medi-
cally managed pulmonary hypertension, transpulmonary gradient
greater than 15mmHg predicts posttransplantation mortality.55
Right Ventricular Injury (RVI) After Lung Transplantation
Acute rejection of the transplanted lungs leads to rapid
increase in RV afterload, RV-PA uncoupling, and RVI. The
reported incidence of RVI after lung transplantation in patients
without preexisting pulmonary hypertension ranges between
34% and 39%, and is independently associated with
mortality.56,57 It is expected that RV function in patients
undergoing bilateral lung transplantation for pulmonary hyper-
tension recovers well, though the case series for this treatment
is relatively small.58 Postoperative hypoxemia, hypercarbia, or
acidemia, as well as the use of high doses of vasopressors
2078 V. Zochios et al. / Journal of Cardiothoracic and Vascular Anesthesia 37 (2023) 20732086
following transplantation, can reversibly impair RV function
due to acute pulmonary vasoconstriction.25,59 An increase in
RV afterload, RV-PA uncoupling, and increased oxygen
demand may lead to transient RV diastolic dysfunction.59
These intraoperative factors can theoretically be mitigated by
the intraoperative use of MCS.59 Mean PAP and lung alloca-
tion score have been identified as risk factors for unplanned
perioperative use of MCS in lung transplant recipients.60 Reg-
ular assessment of RV geometry and PAP after lung transplan-
tation as signs of reverse remodeling of the distorted RV
should, therefore, be viewed as integral parts of perioperative
monitoring.57
Surgery for Chronic Thromboembolic Pulmonary
Hypertension
Patients with chronic thromboembolic pulmonary hypertension
develop pulmonary vascular dysfunction, which results in ele-
vated RV afterload, RV remodeling, hypertrophy, and RV-PA
uncoupling.61 Curative pulmonary endarterectomy is associated
with reperfusion lung injury and acute on chronic RVI due to ele-
vated extravascular lung water, hypoxemia, hypercarbia, and
residual pulmonary hypertension, occasionally necessitating
extracorporeal cardiorespiratory support.62,63 For the purposes of
pulmonary endarterectomy, systemic cooling is important, and
deep hypothermic circulatory arrest is used in most centers. Pro-
tocols for rewarming are different for different centers, and dur-
ing this process, arrhythmias are not uncommon. In addition, the
procedure often requires long CPB times (hours) and particular
attention to RV protection from direct exposure to heat from the
environment, including operating room lights. All these factors
combined, as well as frequently preexisting pulmonary hyperten-
sion and a degree of chronic RVI, can lead to residual RVI at the
end of CPB.64 Eventually, the elevated PA load usually normal-
izes, and the RV-PA coupling is restored even when markers of
RV function remain impaired in the postoperative period.65
There is currently a lack of data on the best postoperative
RV-protective strategy in patients with chronic thromboembolic
pulmonary hypertension undergoing pulmonary endarterectomy.
Right Ventricular Injury (RVI) After Left Ventricular Assist
Device Implantation
The incidence of RVI following left ventricular assist device
(LVAD) implantation ranges from 3% to 35%, in part due to
the varying definitions, timing, and severity in the patient pop-
ulation studied, and can be attributed to the patient, periopera-
tive care, and/or the device.66 The Interagency Registry for
Mechanically Assisted Circulatory Support database noted
that RVI declines to less than 10% 36 months after implanta-
tion. The stable prevalence of RVI, over time can be attributed
to a combination of de novo, resolved, and persistent RVI.67
The latest definition of RVI post-LVAD implantation comes
from the Mechanical Circulatory Support Academic Research
Consortium. The 2020 Mechanical Circulatory Support Aca-
demic Research Consortium definition of RVI was divided
into the following 3 distinct periods: early acute, early post-
implant, and late RVI (Table 1).66
A vicious cycle in which decreased myocardial perfusion
leads to systemic venous congestion may be precipitated in
early postoperative RVI.68,69 Acute hypoxemia, hypercarbia,
acidemia, and the systemic inflammatory response from surgery
can cause an increase in PVR and total RV afterload, resulting
in RV-PA uncoupling.69 The loss of pericardial constraint and
anchoring of the LVAD to the LV apex may alter the ability of
the heart to complete its normal twisting motion or wringing
effect.69,70 This change in mechanics could affect the septal
function during and after implantation, thereby reducing the
overall RV function. With the subsequent initiation of LVAD
flow, there is increased blood return to the RA, potentially lead-
ing to systemic venous congestion. The unloading of the LV
and increase in LV output result in elevated RV preload and RV
distention, especially when preimplantation RV function is not
normal, rendering the RV more afterload-sensitive.71 This may
cause increased RV wall stress and myocardial oxygen con-
sumption, decreased RV oxygen supply during systole, and fur-
ther potentiate ischemia.71 Additionally, LV-RV uncoupling
can impair the septal contribution to RV ejection and change
the geometric shape of the RV. Annular dilatation and worsen-
ing tricuspid regurgitation ensue, creating an inability of the RV
to meet the required physiologic demand.69,72
A minimally invasive approach through lateral thoracotomy or
ministernotomy, avoiding the pericardial opening, theoretically
preserves RV geometry and reduces perioperative RVI.73-75 Lat-
eral thoracotomy, in particular, has been associated with a reduced
incidence of RVI, the need for RVAD, and blood product
transfusion.74,75 In left coronary-dependent RV circulation, such
as when there is an anatomic left dominance or physiologic domi-
nance from coronary artery disease with left-to-right collateraliza-
tion, occlusion of the distal anterior descending artery due to its
incorporation into the apical sewing ring can precipitate an ische-
mic injury of the RV.76 Malalignment of the inflow cannula sec-
ondary to suboptimal positioning can cause septal shift, leading to
tricuspid incompetence, precipitating ventricular arrhythmias, and
inadequate LV decompression, leading to left atrial hyperten-
sion.77 Improper deairing techniques may lead to right coronary
artery embolization.78 LVAD outflow graft obstruction from vary-
ing etiologies may result in a low flow state and RV hypoperfu-
sion.79 Delayed sternal closure by preventing compression of the
anteriorly positioned RV outflow tract can help improve
hemodynamics.80,81 It has been postulated that early postimplant
severe RVI may theoretically be prevented by delayed sternal clo-
sure, but data are lacking to support this practice.80,81
Is It Possible to Predict Right Ventricular Injury (RVI) and
Protect the RV in Cardiac Surgery?
Despite the negative association between preoperative RVI and
long-term outcomes following cardiac surgery,82,83 RV metrics of
performance are not incorporated in major risk stratification mod-
els, including the Society of Thoracic Surgeons risk model and
the European System for Cardiac Operative Risk Evaluation
II.84,85 The main factors for this paradox are the lack of a
 V. Zochios et al. / Journal of Cardiothoracic and Vascular Anesthesia 37 (2023) 20732086 2079

Table 1
Mechanical Circulatory Support Academic Research Consortium (MCS-ARC) Definition for Right Ventricular Failure after Left Ventricular Assist Device
Implantation.66

Early Acute RVF Early Post-implant RVF Late RVF

(<30 Days Post-LVAD Implantation)* (>30 Days Post-LVAD Implantation)*

Need for a RVAD at the time of LVAD 1. Need for RVAD <30 days of LVAD implantation 1. Need for RVAD >30 days of LVAD implantation
implantation or
or 2. Need for hospitalization >30 days of LVAD
2. Failure to liberate from positive inotropic support implantation requiring intravenous diuretics or
or iNO < 14 days of LVAD implantation or need positive inotropy for at least 72 hours
to commence this support <30 days of LVAD
implantation for at least 14 days
or
3. Death occurring <14 days of LVAD implanta-
tion, in patients who did not receive RVAD but
remain on vasoactive drug support (positive ino-
tropes, vasopressors) at the time of death and
meet RVF clinical criteria

* Clinical criteria:Presence 2 of the following:

 Ascites
 Peripheral edema (>2+)
 Elevated JVP, at least halfway up the neck in an upright patient
 Elevated CVP or RAP (>16 mmHg)
or
at least 1 of the following:
 Renal failure, serum creatinine x 2 baseline value
 Liver injury, x 2 upper limit normal in ALT and/or AST or total bilirubin >2.0
 Lactatemia (lactate >3 mmol/L)
 ScvO2 <50%
 Cardiac index <2.2 L/min/m2
 Reduction of pump flow of >30% from baseline in the absence of mechanical causes (eg, cardiac tamponade, tension pneumothorax)
ALT, alanine transaminase; AST, aspartate transaminase; CVP, central venous pressure; iNO, inhaled nitric oxide; JVP, jugular venous pressure; LVAD, left
ventricular assist device; RAP, right atrial pressure; RVAD, right ventricular assist device; ScvO2, central venous oxygen saturation.

standardized, validated RVI definition, and the fact that quantifica-
tion of RV function remains exigent and modality-dependent.
It is evident that clinicians are witnessing a clinical research
shift toward the development of risk- stratification algorithms
predicting RVI based not only on preoperative parameters, but
also immediate postoperative clinical measurements. More
accurate prediction models, in conjunction with algorithms
directing patients to treatments based on individual RV met-
rics, should be the common trajectory.
The key to mitigating perioperative RVI is anticipating it and
recognizing factors known to increase RVI risk, eg, prolonged
CPB time, suboptimal myocardial protection, right coronary
artery embolism or graft occlusion, hypoxemia, sepsis, and
donor heart ischemia with or without preexisting PAH (mostly
applicable to heart and lung transplant recipients), as well as
lung injury as a consequence of injurious perioperative mechan-
ical ventilation.86,87 Discussing the aforementioned RV-protec-
tive strategies in detail lies beyond the scope of this review.
Thoracic Surgery
Mechanisms of Right Ventricular Injury (RVI) in One-Lung
Ventilation and Lung Resection Surgery
One-lung ventilation (OLV) and lung resection present a
unique hemodynamic challenge. During OLV, redistribution
of almost the entirety of blood flow to the ventilated, depen-
dent lung results in consistently reported increases in PAP and
PVR.88-90 The maintenance of cardiac output in these condi-
tions depends on both the ability of the pulmonary circulation
to facilitate increased blood flow without excessive increase in
pressure (termed "pulmonary vascular flow reserve"), and the
ability of the RV to increase its contractility in the face of
increased afterload (termed "RV contractile reserve").91 Stud-
ies using pressure-volume loops to assess RV function ele-
gantly demonstrated a reflex-mediated increase in intrinsic RV
contractility in response to increased afterload (known as the
Anrep effect; Fig 2).92 In the majority of patients, OLV is
hemodynamically well-tolerated, though it is likely that in the
minority, pulmonary vascular (such as baseline PAH) or RV
comorbidity results in the inability to adapt.
In the early postoperative period following lung resection,
there is a deterioration in RV function, illustrated by a relative
reduction in RVEF of between 15% and 25%, a finding
recently confirmed using cardiovascular magnetic reso-
nance.93-95 This impairment in RV function has commonly
been observed in the early postoperative period, but was
recently demonstrated to be persistent at 3 months postopera-
tively.95 Importantly, these changes appear consistently in the
majority of patients, and are not associated with any parallel
changes in LV function, suggesting intrinsic RV rather than
global myocardial injury. It has been widely hypothesized that
2080 V. Zochios et al. / Journal of Cardiothoracic and Vascular Anesthesia 37 (2023) 20732086

Fig 2. Annotated pressure-volume loop illustrating RV hemodynamic changes during one-lung ventilation and lobectomy. The same RV PV loop is reproduced in
Figures A-C. Solid line represents preoperative baseline; dashed line represents intraoperative situation during OLV and following lobar PA ligation. (A) During
OLV and following lobar PA ligation, the RVPES is increased while SV remains unchanged. (B) In response to this acutely increased afterload, SV is maintained
by homeometric autoregulation, with a sympathetically mediated increase in RV contractility (the Anrep effect), illustrated by an increase in the gradient of the
RV ESPVR. (C) Maintaining SV in the face of increased afterload results in increased RVSW, illustrated by the changes in the internal area of the PV loop from
baseline (red area only) to OLV and PA ligation (red and pink shaded areas). Novel illustration drawn from data by Wink et al,88 modified and adopted from Shel-
ley B, Glass A, Keast T, et al. Perioperative cardiovascular pathophysiology in patients undergoing lung resection surgery: A narrative review. Br J Anaesth.
2023;130:e66-e79; with permission from Elsevier and Copyright Clearance Center. ESPVR, end-systolic pressure-volume relationship; OLV, one-lung ventilation;
PA, pulmonary artery; PV, pressure-volume; RV, right ventricle; RVPES, right ventricular end-systolic pressure; RVSW, right ventricular stroke work; SV, stroke
volume.

Fig 3. Changes in pulmonary vascular resistance and pulmonary artery pressure occurring during and after lung resection. Novel illustration drawn from data in
Waller et al,89 in which invasive hemodynamic monitoring is performed in patients undergoing pneumonectomy (n = 10) and lobectomy (n = 11). Despite transient
intraoperative increases, PVR and PAP return to baseline within 24 hours postoperatively. Similar findings have been reproduced by several authors.90,93,94 *Indi-
cates p < 0.05 versus baseline value. Insufficient data provided in original publication to allow generation of error bars. Adopted from Shelley B, Glass A, Keast
T, et al. Perioperative cardiovascular pathophysiology in patients undergoing lung resection surgery: A narrative review. Br J Anaesth. 2023;130:e66-e79; with
permission from Elsevier and Copyright Clearance Center. PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance
 V. Zochios et al. / Journal of Cardiothoracic and Vascular Anesthesia 37 (2023) 20732086
such a postoperative decrement in RV function results from
persistently increased afterload reflecting loss of lung paren-
chyma and reduced capacity of the pulmonary vascular
bed.93,96,97 Such a hypothesis has not, however, been easily
proven; though PVR and PAP are increased in the immediate
postoperative period, they return to baseline in the first couple
of postoperative days (Fig 3), failing to explain a persistent
decrement in RVEF.89,90,93,94 Two further potential explana-
tions for reduced RVEF must, therefore, be considered. First,
that reduced RVEF does reflect increased afterload, but a more
holistic approach to afterload assessment is required in order
to demonstrate this association. Though the most commonly
used metric of RV afterload, PVR only reflects static afterload
and, by ignoring pulsatile components of inertia, pulse-wave
reflection, and distensibility, potentially fails to account for up
to half of the true pulmonary-vascular input impedance.98
Using wave-intensity analysis, recent work by Glass et al dem-
onstrated substantially increased pulse-wave reflection within
the lung following lobar resection, changes that were associ-
ated with the postoperative reduction in RVEF.98 Second,
however, it would be plausible that in addition to afterload
changes, RV function may be impaired by an insult to intrinsic
RV contractility. In animal models examining the RV response
to simulated pulmonary thromboembolism, transient clamping
of the PA resulted in persistent RV dysfunction, a phenomenon
not explained by simple mechanical obstruction. Further work,
however, has demonstrated inflammatory gene expression and
neutrophil accumulation in the RV 18 hours following an acute
increase in afterload.99,100 It is plausible, therefore, that the
induction of myocardial inflammation and impairment of RV
function may occur by a similar mechanism following lung
resection, a hypothesis supported by the observation of oxida-
tive and nitrosative stress-associated alterations in myocardial
calcium signaling in a porcine model of thoracotomy and lung
resection.101 Selected studies examining changes in RV func-
tion and afterload following lung resection are summarized in
Table 2.93-95,97,98,102,103,104
Right Ventricular Injury (RVI) After Lung Resection and
Its Effect on Outcomes
The effect of postoperative RVI on clinical outcomes has
not been well-studied. It is likely, however, that RVI affects
both short- and long-term outcomes following lung resection.
Short-term Outcomes
Both atrial fibrillation (AF) and perioperative myocardial
injury (when defined as acute troponin rise in the absence of
overt ischemia) occur commonly after lung resection, and
have significant implications for patient outcomes, and both
have been associated with RVI. Contemporaneous troponin
measurement, alongside cardiovascular magnetic resonance
imaging of RV and LV function, have revealed that elevation
in postoperative troponin levels was associated with decreased
RVEF but not LVEF.95,105 When RV function is observed to
deteriorate on the institution of OLV,96 or when RV systolic
2081
pressure is increased in the postoperative period, postoperative
atrial fibrillation is more common.104 Furthermore, when
patients are admitted unplanned to the intensive care unit post-
operatively, RVI is one of the few independent predictors of
survival.8
Long-term Outcomes
Breathlessness and exercise limitation are common sequelae
of lung resection. Increasingly, however, it is recognized that
changes in lung volumes and function are poorly associated
with functional deficits.106,107 Given that many patients with
chronic obstructive pulmonary disease (a common comorbid-
ity in the thoracic surgical population) are exercise-limited by
cardiac function even without surgery, the potential for RV
function to affect postoperative functional capacity following
lung resection is intuitive.108 Much of the research examining
postoperative RV function in this population has focused on
the measurement of function at rest; research conducted during
exercise, when postoperatively impaired pulmonary vascular
flow or RV contractile reserve might be anticipated to have the
greatest effect, however, is suggestive of a profound effect of
RV function on exercise. Okada et al demonstrated precipitous
increases in PAP during exercise in patients who had under-
gone lung resection, and Nezu et al demonstrated that both
oxygen pulse and maximal heart rate (cardiopulmonary exer-
cise testing indices reflective of cardiac function) were reduced
postoperatively, but breathing reserve was unchanged.93,109
Implications for Practice and Future Directions
RVI is strongly associated with adverse outcomes in the car-
diothoracic surgical setting. There is a spectrum of different
RVI phenotypes that may occur at any stage in the perioperative
period. Any abnormality in RV dimensions and/or function has
been linked to high perioperative morbidity and mortality.4 In
order to characterize abnormal RV biomechanics, clinicians
need to understand the mechanisms of RVI. Postoperative acute
RV dilatation with normal end-organ perfusion, for example, is
a dynamic RVI phenotype that may progress to RV failure and
circulatory shock. The latter would indicate a transition from
adaptive to a maladaptive RV response to loading conditions,
which is difficult to predict unless one understands the underly-
ing pathophysiologic processes discussed.10 Patients at
increased risk of perioperative RVI, such as those with preexist-
ing pulmonary hypertension or abnormal RV dimensions and/or
function, should be monitored closely using echocardiographic
and right heart catheterization-derived hemodynamic measure-
ments.101 This multimodal approach, combined with an under-
standing of RVI mechanisms, theoretically aid in the early
detection of RVI and timely intervention.110 There are, how-
ever, a lack of data relating to preventative, therapeutic, or RVI
syndrome-modifying management, which constitutes an impor-
tant unmet clinical need. These research and knowledge gaps
may have an adverse effect on clinical decision-making and,
eventually, on patient outcomes.110,111 A standardized and vali-
dated perioperative RVI syndrome definition would facilitate
2082 V. Zochios et al. / Journal of Cardiothoracic and Vascular Anesthesia 37 (2023) 20732086

Table 2
Selected Studies Examining Changes in RV Function and Afterload Following Lung Resection*

Author, Year Method of RV RV Function Method of Afterload Afterload Findings Comment and/or
Assessment Findings Assessment Clinical Sequalaey

Lewis et al, 199497 Volumetric PAC  # RVEF postop. PVR $ PVR post op Association between
RVEF PAP $ PAP post op late
cardiorespiratory
symptoms ("
NYHA
classification) and #
RVEF at PA
clamping.
Amar, 1995104 Nil Not reported Echocardiography  $TRJ post op Association between
TRJ velocity " TRJ POD 2-6 in "TRJ (but not
patients with SVT RVSP) on POD 2-6
and development of
SVT.
Okada et al, 199493 Volumetric PAC  # RVEF postop. PVRI $ PVRI postop. Evidence of impaired
and 199694,z RVEF PAP $ PAP postop. PV flow and RV
But "PVRI and PAP contractile reserve
and further #RVEF on exercise postop.
on exercise postop. Association between
# RVEF on exercise
(preop.) and
complications and
prolonged hospital
stay.
Kowalewski et al, Echocardiography  #RVEF after pneumo. Nil Not assessed In pneumo. group,
1999102 RVEF Not lobe patients developing
Echocardiography  " RVEDV and/or SVT found to have
RVEDV and/or RVESV after # postop. RVEF
RVESV pneumo. Not lobe and " postop.
RVEDVI.
Wang et al, 2016103 Echocardiography  "LV and ""RV strain PAP (via TRJ) "PAP after pneumo. No clinical
RV strain (ie, worse) postop. but not lobe assessment made.
> after pneumo.
than lobe
McCall et al, 201995 CMR  RVEF #RVEF postop., PA distensibility # Distensibility on Negative association
persistent at 2 PA acceleration time operative side between RVEF on
months. (PAAT) #PAAT in main PA POD2 and duration
No change in LV of critical care unit
(but not hospital)
stay.
Glass et al, 202398 CMR  RVEF Same cohort as CMR  Wave " wave reflection on Association between
CMR  RV strain McCall et al intensity analysis operative side " wave reflection,
$ strain on POD2 but Distribution of PA Redistribution of redistribution of
"(ie, worse) at 2 flow blood flow to blood flow and
months. nonoperative side #RVEF  first
postop. study to
demonstrate long-
hypothesized
association between
#RV function and "
afterload.

Abbreviations: CMR, cardiovascular magnetic resonance; lobe, lobectomy; NYHA, New York Heart Association; PA, pulmonary artery; PAAT, pulmonary artery
acceleration time; PAC, pulmonary artery catheter; PAP, pulmonary artery pressure; pneumo.; pneumonectomy; POD, postoperative day; postop., postoperatively;
preop., preoperatively; PVR(I); pulmonary vascular resistance (index); RV, right ventricle; RVEDV(I), RV end-diastolic volume (index); RVESV(I), RV end-
systolic volume (index); RVEF, right ventricular ejection fraction; SVT, supraventricular tachyarrhythmia; TRJ, tricuspid regurgitant jet.
* Selected articles intended to reflect the consistency of the observed changes in RV function (regardless of RV assessment technique), absence of increase in
PVR/PAP but increased afterload when assessed by other methods and potential sequalae of postoperative RV dysfunction; not an exhaustive literature review.
y None of these trials were designed and/or powered to examine the clinical sequalae of changes in RV function and/or afterload, but several offer insights sug-
gesting clinical significance of the findings.
z Two manuscripts reporting data from the same cohort of patients.
 V. Zochios et al. / Journal of Cardiothoracic and Vascular Anesthesia 37 (2023) 20732086 2083

Table 3
Main Points, Knowledge Gaps, and Future Directions in Acute RVI in Cardiothoracic Surgical Settings

Main Points

1. The interplay between the RV and pulmonary circulation is crucial in maintaining hemodynamic homeostasis.
2. RV-PA uncoupling is the most common mechanism of RVI in cardiothoracic surgical settings.
3. Perioperative factors affecting RV-PA coupling may be surgical, pharmacologic, or patient-related.
4. RVI is a complex clinical syndrome comprising different phenotypes—from RV diastolic dysfunction to RV failure whereby RV fails to meet flow demand.
5. Altered RV biomechanics in the perioperative period have been linked to perioperative morbidity and mortality.
6. The adaptation of the RV to altered loading conditions in the perioperative period (homeometric and heterometric adaptation) is significantly affected
by concurrent inflammation and systemic hypotension, which commonly occur in cardiothoracic surgical settings.
7. A multimodal approach, including clinical examination, echocardiography, and invasive pulmonary hemodynamics, is usually necessary in order to
characterize, diagnose, and potentially prevent the progression of RVI to circulatory failure.

Key evidence gaps

1. There is currently a lack of a universal RVI definition. What RAP thresholds, echocardiography metrics, and systemic venous congestion measures should be
used to define the syndrome and characterize the different RVI phenotypes?
2. What is the natural history of perioperative RVI in cardiothoracic settings?
3. RV failure is an advanced and/or severe form of RVI that may not be reversible. Which RVI phenotypes require action, and how should clinicians individual-
ize interventions?
4. Are there any biomarkers to aid in early diagnosis of subclinical RVI in cardiac surgery?
5. How can surrogate echocardiography markers of RV-PA coupling be validated?
6. What is the effect of CPB on the pulsatile RV workload?
7. Is there a role for perioperative continuous RV pressure monitoring, and would this approach affect outcomes in cardiac surgery?
8. What is the effect of perioperative pharmacologic and nonpharmacologic interventions (eg, inodilators, inhaled pulmonary vasodilators, lung-protective inva-
sive ventilation, MCS) on RVI mechanisms and mitigation of progression to RV failure?
9. Would systematic protection of the RV in cardiothoracic surgery mitigate RVI and confer outcome benefits?
10. What are the long-term outcomes of cardiac surgical patients with acute perioperative RVI?

Future directions

1. Prospective studies evaluating RV-PA coupling in cardiac surgical patients using invasive and noninvasive diagnostic modalities.
2. In vitro assessment of RV autoregulatory responses to different pulmonary vascular loading conditions using a mock circulation loop and validation against
human data.
3. Identification and validation of biomarkers of RV myocardial injury and remodeling after cardiac and thoracic surgery, and correlation with different RV bio-
mechanics profiles.
4. Investigateing the role of postoperative portal, hepatic, and intrarenal venous flow monitoring in detecting early RVI, and preventing secondary organ injury.
5. Phenotyping of perioperative RVI using multiple diagnostic modalities (eg, clinical examination, echocardiography, right-heart catheterization, venous Dopp-
ler waveforms of the portal, and hepatic and intrarenal veins) and prospective validation of the RVI phenotypes and their time sequence in the perioperative
period.
6. Exploreing the role of artificial intelligence and machine learning in the prediction of postoperative RVI.
Abbreviations: CPB, cardiopulmonary bypass; MCS, mechanical circulatory support; PA, pulmonary artery; RAP, right atrial pressure; RV, right ventricle; RVI,
right ventricular injury.

systematic aggregation of data across clinical trials. Further References

insight into invasive and noninvasive RVI phenotyping is
urgently needed, and characterization of the natural history of
the syndrome, combined with measurement of RV-PA uncou-
pling, should be incorporated into studies testing RV-specific
perioperative therapies, such as pulmonary vasodilators, inodila-
tors, RV-protective invasive ventilation, and MCS. This
approach may enable researchers to ascertain which strategies
protect the RV and mitigate RVI, and whether correcting abnor-
mal RV pathophysiology translates into outcome benefits
(Table 3).10,110,111
Declaration of Competing Interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
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