Curr Cardiovasc Risk Rep (2016) 10: 41
DOI 10.1007/s12170-016-0524-3
SECONDARY PREVENTION AND INTERVENTION (D. STEINBERG, SECTION EDITOR)
Door to Unload: a New Paradigm for the Management
of Cardiogenic Shock
Navin K. Kapur 1 & Michele L. Esposito 1
Published online: 24 October 2016
# Springer Science+Business Media New York 2016
Abstract Cardiogenic shock (CS) remains the most common
cause of in-hospital mortality in the setting of acute myocar-
dial infarction (AMI). Recent data have identified several
concerning trends in the field of AMI-CS that include an over-
all increase in mortality, an increase in patient complexity,
minimal use of acute mechanical circulatory support
(AMCS) devices with the majority being implanted as a bail-
out option. In this review, we will discuss recent trends in CS
and the rationale for the use of acute mechanical circulatory
support pumps early in the clinical treatment of CS.
Keywords Ventricular unloading . Acute mechanical
circulatory support . Cardiogenic shock . Hemodynamics .
Percutaneous ventricular assist device
Introduction
Cardiogenic shock (CS) remains the most common cause of
in-hospital mortality in the setting of acute myocardial infarc-
tion (AMI) [1]. An analysis of the Nationwide Inpatient
Sample Database between 2003 and 2010 reported an increase
in the prevalence of CS among patients presenting with
STEMI (CS-STEMI) from 6 to 10 %. Among patients over
the age of 75, CS-STEMI increased from 7 to 12 %. The
authors report an increasingly complex profile of CS-STEMI
This article is part of the Topical Collection on Secondary Prevention and
Intervention
* Navin K. Kapur
Nkapur@tuftsmedicalcenter.org
1
The Cardiovascular Center, Tufts Medical Center, 800 Washington
Street, Box # 80, Boston, MA 02111, USA
patients with higher rates of concomitant diabetes mellitus,
hypertension, prior coronary disease, obesity, peripheral vas-
cular disease, and chronic renal failure. Despite increasing
prevalence, in-hospital mortality for CS-STEMI decreased
from 45 to 34 % in 2010 with the highest prevalence observed
in patients over 75 years of age (55 %). In this analysis, early
revascularization was performed in only 43 % of patients with
an increase from 26 to 54 % between 2003 and 2010.
Furthermore, left heart catheterization rates increased from
64 to 74 %, but right heart catheterization rates decreased from
10 to 6 % [2]. These data suggest that CS-STEMI is increasing
in prevalence and is persistently associated with excessively
high in-hospital mortality rates, especially among the elderly.
The lower in-hospital mortality rate in 2010 may be partly due
to more aggressive early revascularization, but indicates that
new approaches are needed for patients with STEMI-CS.
Cardiogenic Shock: a Persistent Problem in Need
of New Approaches
A more contemporary and consistently sobering analysis of
patients with AMI-CS undergoing PCI reported that despite
an overall increase in the use of percutaneous coronary inter-
vention (PCI) for AMI-CS, in-hospital mortality increased
from 27 to 30 % and deaths occurring in the catheterization
laboratory increased from 15 to 20 % between 2005 and 2013
[3]. This analysis also confirmed the increasingly complex
profile of patients with AMI-CS who are now more likely to
present greater than 6 h after symptom onset with multi-vessel
coronary disease and high complex (type C) coronary lesions.
Furthermore, the percentage of patients with AMI-CS under-
going PCI at low volume (<500 PCIs/year) centers has in-
creased from 30 to 48 %. Finally, the authors report that
IABP use decreased over this time period with more IABPs
41 Page 2 of 8
being deployed after, not before, PCI. Collectively, these data
identify several concerning trends in the field of AMI-CS that
include an overall increase in mortality, an increase in patient
complexity, minimal use of AMCS, declining use of IABPs
with the majority being implanted as a post-PCI bailout op-
tion, and a geographic shift towards lower volume centers
who may have less experience dealing with complex hemo-
dynamic and coronary patient subsets.
Despite increasing rates of early revascularization, the
prognosis for AMI-CS patients who survive to hospital dis-
charge is poor. Several recent analyses confirm increase rates
of mortality and heart failure within the first 1 year after dis-
charge. One analysis of nearly 8000 patients older than
65 years presenting with an AMI undergoing early revascu-
larization identified that nearly 76 % of survivors go on to
develop heart failure within the next 5 years. Of the survivors
who developed heart failure, 39 % died within 5 years [4]. A
more recent analysis identified a 22 % 1-year mortality rate
and 59 % re-hospitalization rate for patients with AMI-CS
compared to 16 and 52 % respectively for AMI without CS
[5•]. Heart failure-specific readmission rates were 24 % for all
AMI patients and 32 % for patients with AMI-CS. Advanced
age, prior heart failure, and a discharge left ventricular (LV)
ejection fraction of 40 % were predictors of recurrent hospi-
talization or death within 1 year after discharge for AMI-CS.
These data further support the need for new approaches to
improve outcomes for AMI-CS patients.
Solving the Hemodynamic Support Equation
with Acute Mechanical Circulatory Support Devices
One explanation for these persistently poor short- and long-
term outcomes is a focus on the door-to-balloon (DTB) time
as the only approach to improve outcomes in AMI-CS. The
Fig. 1 Solving the hemodynamic support equation in cardiogenic shock.
[Illustration of the three primary clinical objectives in the setting of acute
myocardial infarction complicated by cardiogenic shock. Circulatory
support is defined by an increase in mean arterial pressure. Ventricular
support is defined by a reduction in left ventricular (LV) pressure and
volume, thereby reducing myocardial wall stress and oxygen demand.
Coronary perfusion is defined by an increase in the trans-myocardial
Curr Cardiovasc Risk Rep (2016) 10: 41
DTB time is defined as the interval from the first electrocar-
diogram showing STEMI in the emergency department to
mechanical reperfusion of the occluded culprit coronary ar-
tery. The DTB time is a standard component of the American
College of Cardiology/American Heart Association guide-
lines and a core quality measure of hospital and operator per-
formance [6]. However, recent data suggests that there may
not be any incremental benefit to a DTB time significantly
lower than 90 min in the setting of an anterior STEMI or
CS-STEMI [1]. Since CS is a syndrome driven by impaired
ventricular function leading to systemic hypo-perfusion and
multi-organ failure, new approaches to AMI-CS must focus
equally on stabilizing a patient’s hemodynamic status and re-
establishing coronary flow as quickly as possible.
To solve the problem of hemodynamic instability in AMI-
CS, three primary objectives must be achieved. First, circula-
tory support to maintain an adequate mean arterial pressure
and vital organ perfusion must be provided. Second, ventric-
ular unloading—defined as a reduction in both LV and vol-
ume—to reduce myocardial work and oxygen demand in the
setting of limited myocardial oxygen supply is required.
Third, myocardial perfusion must be increased by sustaining
coronary arterial pressure and reducing left ventricular diastol-
ic pressure, thereby favorably altering the trans-myocardial
perfusion gradient. In the contemporary era, these three com-
ponent of the hemodynamic support equation (Fig. 1) can be
readily achieved with appropriate use of acute mechanical
circulatory support (AMCS) pumps.
Four primary AMCS device platforms are currently used in
clinical practice for hemodynamic support (Fig. 2) and include
(1) the intra-aortic balloon pump (IABP), (2) centrifugally
driven left atrial-to-femoral artery bypass (TandemHeart;
TandemLife Inc), (3) centrifugally driven veno-arterial extra-
corporeal membrane oxygenation (VA-ECMO), and (4)
micro-axial flow catheters (Impella; Abiomed Inc and
gradient, which is determined by the difference between coronary arterial
and LV end-diastolic pressure. The net effect of optimal hemodynamic
support is increased urine output, reduced serum lactate, reduced pulmo-
nary capillary wedge pressure, resolution of ischemic electrocardiograph-
ic changes, and reduced levels of myocardial injury biomarkers such as
CK-MB]
Curr Cardiovasc Risk Rep (2016) 10: 41
Fig. 2 Acute mechanical circulatory support devices for left ventricular support
Percutaneous Heart Pump (PHP); St. Jude Inc) [7, 8]. At pres-
ent, the PHP device is approved for clinical use in Europe, but
is under active investigation in the USA.
The IABP is a catheter-mounted balloon that augments
pulsatile blood flow by inflating during diastole, which dis-
places blood volume in the descending aorta and increases
mean aortic pressure, thereby potentially augmenting coro-
nary perfusion. Da Silva and colleagues demonstrated that
IABP therapy increases coronary blood flow during periods
of active ischemia when microvascular autoregulation is
uncoupled [9]. Upon deflation, during systole, the IABP gen-
erates a pressure sink, which is filled by ejecting blood from
the heart and augments native stroke volume. However, he-
modynamic efficacy of balloon counterpulsation is dependent
on native contractile function (i.e., counterpulsation requires
native pulsation) [10–12]. For this reason, IABP
counterpulsation provides partial circulatory support and LV
unloading, but may improve coronary blood flow. Several
observation and randomized controlled trials have failed to
support routine IABP use in the setting of AMI-CS.
The TandemHeart device is an extra-corporeal centrifugal
flow pump that reduces LV preload by transferring oxygenat-
ed blood from the left atrium (LA) to the descending aorta via
two cannulas: a 21Fr trans-septal inflow cannula in the LA
and an arterial outflow cannula in the femoral artery (FA). The
TandemHeart rapidly increases mean arterial pressure thereby
increasing coronary perfusion pressure. The device unloads
the LV primarily by decreasing LV volume [13, 14].
However, by pressuring the arterial circulation, the
TandemHeart may increase LV pressure, which offsets the
ability of the device to completely unload the LV.
Page 3 of 8 41
Furthermore, flow through the TandemHeart pump is deter-
mined by left atrial volume, which may limit the magnitude of
hemodynamic support provided by the device. The
TandemHeart can also be used to support the failing right
ventricle (RV) by placing the inflow and outflow cannulas in
the right atrium and pulmonary artery respectively [15].
VA-ECMO withdraws deoxygenated venous blood and
returns oxygenated blood to the arterial circulation. Inflow
cannulas are often positioned in the right atrium or across
the superior and inferior vena cava. Outflow cannulas can be
positioned in the femoral or subclavian arteries. By displacing
blood volume from the venous to the arterial circulation, VA-
ECMO reduces right and left ventricular volumes with a con-
comitant increase in mean arterial pressure [13, 14].
Depending on native left ventricular function and the presence
or absence of aortic valve disease, VA-ECMO can be associ-
ated with increased LV systolic and diastolic pressures. For
this reason, VA-ECMO often requires a concomitant system to
reduce LV pressure, known as an LV vent, which can include
an IABP, Impella, or a left atrial drainage cannula [16]. The
net effect of VA-ECMO is to increase mean arterial pressure,
load (not unload) the LV, and potentially increase coronary
blood flow. By draining from the right atrium, VA-ECMO
can also be used to provide RV support.
The Impella is a micro-axial flow catheter placed into the
LV in retrograde fashion across the aortic valve. The pump
transfers kinetic energy from a circulating impeller to the
blood stream, which results in continuous blood flow from
the left ventricle to ascending aorta. The Impella 2.5 LP and
CP devices can be deployed without the need for surgery,
while the Impella 5.0 device requires surgical vascular access.
41 Page 4 of 8
Impella activation rapidly increases mean arterial pressure,
reduces LV diastolic pressure, and increases trans-
myocardial coronary perfusion [1718••]. The Impella RP is
specifically designed to provide RV support by displacing
blood from the right atrium to the pulmonary artery [19]. Of
these four device options, only the Impella and the
TandemHeart device can achieve all three objectives of the
hemodynamic support equation.
The Rationale for a Door to Unload Strategy
in AMI-CS
In the setting of AMI-CS, two major therapeutic priorities
exist, namely, hemodynamic stabilization and rapid coronary
reperfusion. The sequence of which therapy is applied first
remains poorly understood and most contemporary operators
focus on primary coronary reperfusion, not hemodynamic sta-
bilization. However, as described above, new approaches to
the management of AMI-CS are required.
Described best by Braunwald and Kloner in 1985, myocar-
dial reperfusion is a Bdouble-edged sword^ due to the fact that
reperfusion of ischemic myocardium promotes cardiomyocyte
death and microvascular damage through a process referred to
as Bmyocardial ischemia reperfusion injury^ [20]. Once a cor-
onary artery is occluded, the myocardial injury clock begins
immediately ticking. With every passing minute, oxidative
phosphorylation becomes uncoupled, and mitochondrial
adenosine triphosphate (ATP) synthesis is reduced and cardio-
myocyte function becomes impaired.
Fig. 3 The rationale for primary reperfusion versus primary unloading in
acute myocardial infarction and cardiogenic shock. [The fundamental
principle governing contemporary clinical treatment of an acute
myocardial infarction is that Btime is muscle.^ Immediately after
coronary occlusion, myocardial injury progresses from a Bstunned,
reversible condition^ to irreversible damage. Rapid coronary
reperfusion effectively restores oxygen supply, however activates a
Curr Cardiovasc Risk Rep (2016) 10: 41
This loss of ATP generation has two effects. First, intracel-
lular calcium and lactate levels increase while intracellular pH
decreases. Second, reduced ATP synthesis provides the sub-
strate for generation of reactive oxygen species (ROS) that
activate a feed-forward process known as ROS-induced
ROS-release. The net effect of increased ROS levels is the
opening of a mitochondrial permeability transition pore
(mPTP) [21]. Further loss of protective signaling through the
reperfusion injury salvage kinase pathway compounds injury
by enhancing the mPTP opening. Depending on the length of
time spent in this ischemic stage (artery occluded), the myo-
cardium may be simply stunned or may transition to irrevers-
ible damage. Reperfusion will effectively restore blood flow
to the myocardium; however, reperfusion also promotes open-
ing of the mPTP pore and drives further cellular necrosis and
infarct size (Fig. 3). This injury exacerbates AMI-CS by fur-
ther reducing systemic multi-organ perfusion, increasing LV
wall stress, and impairing global myocardial perfusion [22].
For an estimate of the extent of residual damage after success-
ful, timely reperfusion therapy in an anterior STEMI, the re-
sults of the CRISP-AMI trial showed that nearly 40 % of the
myocardium was infarcted as measured by magnetic reso-
nance imaging within 1 week of successful reperfusion thera-
py [23].
Contemporary approaches to stop the myocardial injury
clock without sacrificing the absolute benefit of reperfusion
therapy in STEMI are limited [22]. One of the best-studied
approaches to cardioprotection in acute MI is ischemic condi-
tioning whereby brief, intermittent periods of intentional cor-
onary occlusion are created either before (preconditioning) or
after (postconditioning) the onset of total coronary occlusion.
series of injurious pathways that accelerate myocardial damage and
increase myocardial oxygen demand. In the setting of AMI-CS, rapid
mechanical unloading first stabilizes systemic hemodynamics, reduces
myocardial oxygen demand, and may reduce the propensity for
reperfusion injury. Subsequent coronary revascularization restores
myocardial oxygen supply and allows for myocardial recovery]
Curr Cardiovasc Risk Rep (2016) 10: 41
Other approaches include pharmacologic therapies that target
specific proteins involved in myocardial ischemia-reperfusion
injury, such as cyclosporine. Finally, global approaches, such
as systemic hypothermia, have also been tested without clear
evidence of benefit.
Although promising, critical barriers to current
cardioprotective strategies are (1) the multifactorial nature of
reperfusion injury, thereby limiting the impact of a single-
target pharmacologic strategy; (2) the potential for coronary
vascular injury (dissection or perforation) with ischemic con-
ditioning; and (3) the mandate for rapid coronary reperfusion
and therefore insufficient time for any cardioprotective thera-
py to affect myocardial injury zones. There exists a need for
improved strategies to limit reperfusion injury that broadly
affect the multiple levels of reperfusion injury without causing
further myocardial damage while also providing time for drug
penetration and efficacy.
The rationale for first unloading the heart with an AMCS
device and then focusing on coronary reperfusion is supported
by several observations. First, myocardial perfusion is driven
by a balance of several factors, including coronary perfusion
pressure versus ventricular filling pressure and myocardial
oxygen supply versus demand. Furthermore, increasing sys-
temic perfusion early in the development of AMI-CS should
limit and potentially reverse multi-organ dysfunction in AMI-
CS. As described above, AMCS devices that solve the hemo-
dynamic support equation positively modulate these factors in
favor of optimal myocardial and systemic perfusion.
Second, surgeons often approach AMI-CS by first initiat-
ing cardiopulmonary bypass to unload both the right and left
ventricles, followed by a period of time to harvest bypass
conduits (during which time the culprit artery remains occlud-
ed), and ultimately reperfusion. This surgical mentality of ini-
tiating cardio-pulmonary bypass effectively reduces myocar-
dial oxygen demand before reperfusion and has been associ-
ated with improved clinical outcomes and reduced infarct size
in AMI-CS [24].
Third, multiple preclinical studies have shown that activa-
tion of an AMCS pump prior to coronary reperfusion reduces
infarct size in models of AMI-CS [25–2829•]. Collectively,
these data support that first targeting myocardial oxygen de-
mand by reducing LV pressure and volume attenuates the
wavefront of myocardial ischemia while increasing systemic
and coronary perfusion. Recently, we identified that first re-
ducing myocardial oxygen demand by reducing left ventricu-
lar wall stress, then delaying coronary reperfusion reduces
infarct size. We first tested this hypothesis using the
TandemHeart left atrial to femoral artery bypass pump. In
the control group, 120 min of left anterior descending artery
(LAD) occlusion was followed by 120 min of reperfusion. In
the treatment group, 120 min of LAD occlusion was followed
by activation of the pump and an additional 30 min of LAD
occlusion (total 150 min of ischemic time) and finally by
Page 5 of 8 41
120 min of reperfusion [28]. In this study, we observed a
43 % reduction in infarct size, which correlated with a reduc-
tion in left ventricular stroke work. In a follow-up study, we
employed the Impella CP catheter and observed that first
unloading the LV and delaying reperfusion by 60 min reduced
infarct size and identified a previously unrecognized link be-
tween mechanical unloading and a myocardial protection pro-
gram involving a cardioprotective chemokine known as stro-
mal derived factor 1-alpha [29•].
Finally, several observational clinical studies have identi-
fied the potential benefit of first unloading the LV in the setting
of AMI-CS. O’Neill and colleagues reported that AMI-CS
patients who received an Impella pump prior to coronary re-
perfusion in AMI-CS demonstrated improved 30-day survival
compared to patients who received the pump after reperfusion
[30]. More recently, Shroeter and colleauges identified that
delayed initiation of LV support with an Impella device was
an independent predictor of higher long-term mortality in pa-
tients with AMI-CS [31]. These early datasets further support
the early use of AMCS devices to provide hemodynamic sup-
port in AMI-CS.
Integrating AMCS devices into a Cardiogenic Shock
Program
One of the major challenges to optimizing care for AMI-CS is
the lack of algorithms that can be uniformly applied to pa-
tients. We now propose to conceptual algorithms for consid-
eration. First, in the setting of STEMI, we propose that pa-
tients without clinical evidence of AMI-CS should all receive
urgent primary reperfusion therapy without delay (Fig. 4). In
patients with hypotension, signs and symptoms of AMI-CS,
or a documented cardiac index <2.2 L/min/m2, we recom-
mend first unloading the LV with an AMCS device, followed
by urgent primary reperfusion. For patients in the gray zone of
Bimpending AMI-CS^ who do not have hypotension, but do
Fig. 4 A proposed algorithm for AMCS device use in STEMI and
cardiogenic shock
41 Page 6 of 8
have signs or symptoms suggestive of AMI-CS, we recom-
mend rapid placement of a pulmonary artery (PA) catheter to
measure cardiac index using the Fick method. If the cardiac
index is <2.2, we recommend initiating LV support, followed
by reperfusion. If the CI is >2.2, we recommend primary re-
perfusion followed by monitoring of the PA catheter indices
for 6 h to ensure hemodynamic stability.
For patients presenting without STEMI, but who have
signs and symptoms suggestive of AMI-CS, we recommend
initial evaluation with an echocardiogram and a PA catheter
(Fig. 5). The echocardiogram can effectively diagnose con-
comitant valvular or pericardial disease that may confound
the management of AMI-CS. For patients with systemic hyp-
oxemia or refractory ventricular tachycardia, VA-ECMO is
the optimal AMCS device option. For patients with severe
aortic regurgitation, the TandemHeart pump is the optimal
AMCS device [32]. The PA catheter can be used to stratify
any remaining AMI-CS patient into one of four hemodynamic
profiles based on cardiac filling pressures: LV-dominant, RV-
dominant, BiV-dominant, or Hypovolemic shock. LV-
dominant CS is defined a right atrial (RA) pressure
<14 mmHg and pulmonary capillary wedge pressure
(PCWP) >18 mmHg, which yields an RA:PCWP ratio <0.8
[33]. We recommend either an Impella or a TandemHeart
device for these patients. RV-dominant CS is defined first by
elevated RA pressure, which yield an RA:PCWP ratio >0.8.
Fig. 5 A proposed algorithm for AMCS device use in acute myocardial infarction and cardiogenic shock
Curr Cardiovasc Risk Rep (2016) 10: 41
Next, we apply the pulmonary artery pulsatility index (PAPi),
which is defined as pulmonary artery pulse pressure (PA sys-
tolic–PA diastolic pressure) divided by RA pressure. The PAPi
ratio has strong predictive value for identifying RV failure in
both RV myocardial infarction and in the setting of advanced
heart failure [34–36]. A PAPi ≤1.0 in AMI-CS indicates se-
vere RV failure requiring initiation of a RV AMCS device
including either an Impella RP or TandemHeart RVAD. BiV-
dominant CS is defined first by elevated biventricular filling
pressures. Next, the PAPi formula is applied. For a PAPi >1.0,
an LV AMCS device is applied first and hemodynamics mon-
itored. If the cardiac index and mean arterial pressure do not
improve within 30 min, a concomitant RV AMCS is consid-
ered. For a PAPi <1.0, patients are initiated on immediate
biventricular AMCS using an Impella 5.0 or CP plus an
Impella RP, VA-ECMO with an LV venting pump, or
TandemHeart BiVAD. At our institution, the availability of
the Impella series of pumps and VA-ECMO allows us to man-
age the vast majority of AMI-CS.
Conclusions
These proposed algorithms must be modified according to
each institutions patient profiles, critical care capacity, and
AMCS device preference. However, fundamental principles
Curr Cardiovasc Risk Rep (2016) 10: 41
underlying AMI-CS management are the early use of hemo-
dynamic monitoring with a PA catheter to stratify the type and
severity of AMI-CS and the judicious use of AMCS device
early in the spectrum of AMI-CS. Over the next few years,
increasing use of AMCS devices will translate into a rapid
growth in our understanding of ventricular hemodynamics,
coronary physiology, and optimal management of AMI-CS.
Whether we will ultimately treat patients with a door-to-
unload strategy instead of a DTB strategy remains to be de-
termined by randomized controlled trials and much work
needs to be done to answer several questions before this con-
cept becomes a clinical reality.
Compliance with Ethical Standards
Conflict of Interest Dr. Kapur receives research support from
Abiomed, CardiacAssist, and Maquet as well as speaker honoraria/
consulting fees from Abiomed, Maquet, and St. Jude. Dr. Esposito has
no relevant conflicts of interest.
Human and Animal Rights and Informed Consent This article does
not contain studies with human or animal subjects performed by the
author.
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