U.S. patent application number 16/244998 was filed with the patent office on 2019-07-18 for systems and methods for left ventricular unloading in treating myocardial infarction.
The applicant listed for this patent is Abiomed, Inc., Tufts Medical Center, Inc.. Invention is credited to Noam Josephy, Navin K. Kapur, Richard H. Karas.
Application Number | 20190216995 16/244998 |
Document ID | / |
Family ID | 67213471 |
Filed Date | 2019-07-18 |
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United States Patent
Application |
20190216995 |
Kind Code |
A1 |
Kapur; Navin K. ; et
al. |
July 18, 2019 |
SYSTEMS AND METHODS FOR LEFT VENTRICULAR UNLOADING IN TREATING
MYOCARDIAL INFARCTION
Abstract
We provide herein a method of preventing or limiting the effects
of heart failure in a human patient that has sustained myocardial
infarction by reducing maladaptive cardiac remodeling in the
patient. The method comprises percutaneously inserting a
transvalvular blood pump, comprising a rotor and a cannula, into
the patient's vasculature and positioning the cannula across the
aortic valve of the patient's heart, with a distal end of the
cannula located in the left ventricle of the heart and a proximal
end of the pump located in the aorta. The method then comprises,
prior to reperfusing the heart, operating the positioned pump to
unload the left ventricle at a pumping rate of at least 2.5 L/min
of blood flow for a support period between at least 30 minutes and
less than 60 minutes. Then, after the support period, the method
comprises applying coronary reperfusion therapy to the heart.
Inventors: |
Kapur; Navin K.; (Boston,
MA) ; Karas; Richard H.; (Franklin, MA) ;
Josephy; Noam; (Danvers, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Tufts Medical Center, Inc.
Abiomed, Inc. |
Boston
Danvers |
MA
MA |
US
US |
|
|
Family ID: |
67213471 |
Appl. No.: |
16/244998 |
Filed: |
January 10, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62615462 |
Jan 10, 2018 |
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62732936 |
Sep 18, 2018 |
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62758164 |
Nov 9, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 1/1074 20140204;
A61M 1/125 20140204; A61M 1/1086 20130101; A61M 1/1072 20130101;
A61M 1/122 20140204; A61M 1/1031 20140204 |
International
Class: |
A61M 1/12 20060101
A61M001/12; A61M 1/10 20060101 A61M001/10 |
Claims
1-131. (canceled)
132. A method of supporting a human patient's heart that has
sustained myocardial infarction, comprising the steps of: inserting
a mechanical circulatory support device into the patient after the
myocardial infarction, the mechanical circulatory support device
comprising a cannula inserted into the heart across a valve; prior
to re-perfusing the heart, operating the mechanical circulatory
support device for a support period between at least 30 minutes and
less than 60 minutes, at a rate of at least 2.5 L/min of blood
flow; and after the support period, applying reperfusion therapy to
the heart.
133. The method of claim 132, wherein the mechanical circulatory
support device is operated at a rate that provides a cardiac output
of at least 3.5 L/min of blood flow.
134. The method of claim 132, wherein the heart is unloaded by the
mechanical circulatory support device concurrently with
reperfusion.
135. The method of claim 132, comprising the step of supporting the
heart by an intra-aortic balloon pump or an extracorporeal membrane
oxygenation (ECMO) pump, in combination with the mechanical
circulatory support device.
136. The method of claim 132, wherein reperfusion therapy comprises
at least one of primary percutaneous coronary intervention (PCI)
and fibrinolysis.
137. The method of claim 132, wherein the mechanical circulatory
support device comprises a transvalvular blood pump, the blood pump
percutaneously inserted into the patient and positioned across the
aortic valve of the patient's heart, with a distal end of the pump
located in the left ventricle of the heart, and wherein prior to
re-perfusing the heart, the positioned pump is operated to unload
the left ventricle at a pumping rate of at least 2.5 L/min of blood
flow for the support period of between at least 30 minutes and less
than 60 minutes.
138. The method of claim 137, comprising the step of: removing the
blood pump from the patient's heart after applying the reperfusion
therapy.
139. The method of claim 132, wherein the mechanical circulatory
support device is inserted percutaneously into the patient.
140. The method of claim 132, comprising the steps of: reducing
levels of BAX protein and active Caspase-3 antibody in patient
cardiac tissue near the myocardial infarction; and increasing
levels of BCL-2 and BCL-XL proteins in patient cardiac tissue near
the myocardial infarction.
141. The method of claim 132, comprising the steps of: increasing
stromal derived factor 1.alpha. (SDF-1.alpha.) protein levels in
patient cardiac tissue near the myocardial infarction; maintaining
activity levels of MMP-2 and MMP-9 enzymes in patient cardiac
tissue near the myocardial infarction; and limiting upregulation of
DPP-4 protein expression and activity in patient cardiac tissue
near the myocardial infarction.
142. The method of claim 132, comprising the steps of: reducing
circulating levels of brain natriuretic peptide (BNP) in the
patient's blood; increasing mRNA levels of SERCA expression in
patient cardiac cells near the myocardial infarction; and reducing
levels of calcineurin activity and Type I collagen in patient
cardiac tissue near the myocardial infarction while maintaining
levels of b-MHC in the non-infarct region of the patient's
heart.
143. The method of claim 132, wherein the heart has an ST Segment
Elevation Sum (.SIGMA.STE) of greater than 4, or greater than 5, or
greater than 6.
144. A method of preventing or limiting the effects of heart
failure in a human patient that has sustained myocardial infarction
by reducing maladaptive cardiac remodeling in the patient, the
method comprising the steps of: percutaneously inserting a
transvalvular blood pump, comprising a rotor and a cannula, into
the patient's vasculature and positioning the cannula across the
aortic valve of the patient's heart, with a distal end of the
cannula located in the left ventricle of the heart and a proximal
end of the pump located in the aorta; prior to reperfusing the
heart, operating the positioned pump to unload the left ventricle
at a pumping rate of at least 2.5 L/min of blood flow for a support
period between at least 30 minutes and less than 60 minutes; and
after the support period, applying coronary reperfusion therapy to
the heart.
145. The method of claim 144, wherein the pump is operated at a
pumping rate of at least 3.5 L/min of blood flow.
146. The method of claim 144, comprising the step of: continuing
the operation of the pump in parallel with the application of
coronary reperfusion.
147. The method of claim 144, comprising the step of: continuing
the operation of the pump in parallel with the application of
coronary reperfusion for a total support period of at least 3
hours.
148. The method of claim 144, comprising the step of: reducing at
least one of: the infarct size and left ventricle scar size.
149. The method of claim 144, comprising at least one of the steps
of: reducing levels of BAX protein and active Caspase-3 antibody in
patient cardiac tissue near the myocardial infarction; increasing
levels of BCL-2 and BCL-XL proteins in patient cardiac tissue near
the myocardial infarction; increasing stromal derived factor
1.alpha. (SDF-1.alpha.) protein levels in patient cardiac tissue
near the myocardial infarction; maintaining activity levels of
MMP-2 and MMP-9 enzymes in patient cardiac tissue near the
myocardial infarction; limiting upregulation of DPP-4 protein
expression and activity in patient cardiac tissue near the
myocardial infarction; reducing circulating levels of brain
natriuretic peptide (BNP) in the patient's blood; increasing mRNA
levels of SERCA expression in patient cardiac cells near the
myocardial infarction; and reducing levels of calcineurin activity
and Type I collagen in patient cardiac tissue near the myocardial
infarction while maintaining levels of b-MHC in the non-infarct
region of the patient's heart.
150. The method of claim 144, wherein the heart has an ST Segment
Elevation Sum (.SIGMA.STE) of greater than 4.
151. The method of claim 144, wherein reperfusion therapy comprises
at least one of: primary percutaneous coronary intervention (PCI)
and fibrinolysis.
152. The method of claim 151, wherein PCI comprises implanting a
stent in the patient.
153. A method of preventing or limiting the effects of heart
failure in a human patient that has sustained myocardial infarction
by reducing maladaptive cardiac remodeling in the patient, the
method comprising the steps of: increasing stromal derived factor
1.alpha. (SDF-1.alpha.) protein levels in patient cardiac tissue
near the myocardial infarction; maintaining activity levels of
MMP-2 and MMP-9 enzymes in patient cardiac tissue near the
myocardial infarction; and limiting upregulation of DPP-4 protein
expression and activity in patient cardiac tissue near the
myocardial infarction.
154. The method of claim 153, comprising the steps of: reducing
levels of BAX protein and active Caspase-3 antibody in patient
cardiac tissue near the myocardial infarction; and increasing
levels of BCL-2 and BCL-XL proteins in patient cardiac tissue near
the myocardial infarction.
155. The method of claim 153, comprising the steps of: reducing
circulating levels of brain natriuretic peptide (BNP) in the
patient's blood; increasing mRNA levels of SERCA expression in
patient cardiac cells near the myocardial infarction; and reducing
levels of calcineurin activity and Type I collagen in patient
cardiac tissue near the myocardial infarction while maintaining
levels of b-MHC in the non-infarct region of the patient's
heart.
156. The method of claim 153, wherein the heart has an ST Segment
Elevation Sum (.SIGMA.STE) of greater than 4, or greater than 5, or
greater than 6.
157. The method of claim 153, comprising the steps of:
percutaneously inserting a transvalvular blood pump, comprising a
rotor and a cannula, into the patient's vasculature and positioning
the cannula across the aortic valve of the patient's heart, with a
distal end of the cannula located in the left ventricle of the
heart and a proximal end of the pump located in the aorta; prior to
reperfusing the heart, operating the positioned pump to unload the
left ventricle at a pumping rate of at least 2.5 L/min of blood
flow for a support period between at least 30 minutes and less than
60 minutes; and after the support period, applying coronary
reperfusion therapy to the heart.
158. The method of claim 157, wherein the pump is operated at a
pumping rate of at least 3.5 L/min of blood flow.
159. The method of claim 157, wherein the heart is unloaded by the
blood pump concurrently with reperfusion.
160. The method of claim 157, comprising the step of supporting the
heart by an intra-aortic balloon pump or an extracorporeal membrane
oxygenation (ECMO) pump, in combination with the blood pump.
161. The method of claim 157, wherein reperfusion therapy comprises
at least one of primary percutaneous coronary intervention (PCI)
and fibrinolysis.
162. The method of claim 157, comprising the step of: removing the
blood pump from the patient's heart after applying the reperfusion
therapy.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35
U.S.C. .sctn. 119(e) from U.S. Provisional Application Ser. No.
62/615,462 filed Jan. 10, 2018, U.S. Provisional Application Ser.
No. 62/732,936 filed Sep. 18, 2018, and U.S. Provisional
Application Ser. No. 62/758,164 filed Nov. 9, 2018, the contents of
which are hereby incorporated by reference in their entirety.
BACKGROUND
[0002] Acute myocardial infarction (AMI) due to occlusion of a
coronary artery is a major cause of global morbidity and mortality
in humans. The current paradigm for AMI therapy focuses on primary
reperfusion, which rapidly restores coronary artery blood flow as
soon as possible after AMI, to re-establish myocardial oxygen
supply. However, despite timely reperfusion, up to 25% of patients
experiencing their first AMI will develop heart failure (HF) within
a year. Contemporary ST-segment elevation AMI (STEMI) in-hospital
management focuses on reducing door to balloon (DTB) time to reduce
infarct size. However, despite intense resource allocation to
achieve DTB times under 90 minutes, the incidence of post-AMI heart
failure remains high. For every 5% increase in myocardial infarct
size, 1-year all-cause mortality and HF hospitalizations increase
by 20%, which imposes a significant burden on healthcare resources.
For these reasons, new approaches to limit myocardial damage and
subsequent ischemic HF remain a significant unmet need for AMI
patients.
[0003] One explanation for these poor outcomes is that primary
reperfusion paradoxically may worsen myocardial damage, known as
ischemia-reperfusion injury (IRI). Prior attempts to limit IRI
include vascular conditioning approaches to activate reperfusion
injury salvage kinase (RISK) pathway activity and pharmacologic
approaches, but the clinical benefit of those approaches has not
necessarily been optimal. A critical barrier to these
cardioprotective strategies is the requirement for rapid coronary
reperfusion--they potentially leave insufficient time for any
therapeutic impact on myocardial injury. Thus there exists a need
for improved strategies to limit myocardial damage by promoting
cardioprotective mechanisms that reduce or eliminate IRI.
[0004] Over the past decade, there has been an increasing reliance
on mechanical support devices in routine clinical practice. Support
devices include percutaneously delivered transvalvular axial-flow
pumps (TV-Pumps), intra-aortic balloon pumps, intra-corporeal axial
flow catheters and extracorporeal membrane oxygenation (ECMO)
pumps, and have become popular in the treatment of myocardial
injury. In the case of TV-pumps, such devices assist with the
mechanical pumping of blood out of the left ventricle of the heart
and thereby unload the heart, rapidly reducing left ventricular
(LV) wall stress, stroke work, and myocardial oxygen demand, while
augmenting systemic mean arterial pressure without the need for
surgery. However, it has been reported that the use of TV-pumps
alone did not significantly reduce 30-day mortality in patients
with cardiogenic shock, and, instead, complicated acute myocardial
infarction in certain patients (H. Thiele, "Intraaortic Balloon
Support for Myocardial Infarction with Cardiogenic Shock", New
England Journal of Medicine, Oct. 4, 2012, vol. 367, No. 14, pp.
1287-1296).
[0005] It has been proposed that a combination of mechanical
support and Primary Reperfusion may limit myocardial damage in AMI
patients. It has been reported that by first unloading the LV using
a TV-Pump while delaying coronary reperfusion (Primary Unloading)
reduces myocardial infarct size by 40-50% and increases myocardial
levels of the cardioprotective chemokine stromal derived factor
1.alpha. (SDF-1.alpha.) (N. Kapur, "Mechanical Pre-Conditioning
with Acute Circulatory Support Before Reperfusion Limits Infarct
Size in Acute Myocardial Infarction," JACC: Heart Failure, vol. 3
no. 11, November 2015).
[0006] A preliminary swine model of AMI model has been studied to
compare primary reperfusion therapy with therapy that delays
reperfusion therapy until after unloading the left atrium using a
percutaneously delivered extracorporeal, centrifugal pump, with
initial indications that delaying coronary reperfusion
(P-unloading) may reduce myocardial injury. Another study has
applied a percutaneously delivered transvalvular pump directly into
the left ventricle of an animal and observed unloading implications
when delaying coronary reperfusion for 60 min. The implications for
treating MI in humans has not been well understood.
SUMMARY
[0007] The present disclosure relates to an improved method of
supporting a human patient's heart that has sustained myocardial
infarction, with the surprising result that the sequence and timing
of applying support to the heart prior to reperfusion can improve
the heart and reduce the impact of an infarction. The technology
can be further applied to prevent or limit the effects of heart
failure in a human patient. This can be done by, for example,
reducing maladaptive cardiac remodeling in the patient. The method
(and systems configured for application) stabilizes or reduces the
size of the infarct, which is beneficial to the patient's heart.
Certain applications include applying a mechanical circulatory
support device to reduce the size of an infarct; some application
include applying reperfusion therapy after a period of delay
wherein the heart is supported with a mechanical circulatory
device. In general, the method is applied by taking a counter
approach to conventional modes and theories in the field--rather
than immediately applying reperfusion therapy to a patient that has
suffered a heart attack, the method (and systems) first supports
the heart by reducing myocardial oxygen demand (e.g., by unloading
the heart) for a period of time and then, after that support
period, restores the oxygen supply to the affected area of the
heart (e.g., by reperfusion). The methods thus seek to reduce the
time between an AMI and the initiation of mechanical circulatory
support, such period referred to conveniently, as the "door to
unload." It has been found that taking such an approach can
increase the myocardial salvage of the human heart and reduce the
size of the infarct in the human heart. Additionally, such an
approach has the surprising effect of preventing or limiting the
effects of heart failure in a human patient by, for example,
reducing maladaptive cardiac remodeling in the patient.
[0008] According to an embodiment of the present disclosure, there
is provided a method of supporting a human patient's heart. The
method comprises the steps of (i) inserting a mechanical
circulatory support device into the human patient after the
myocardial infarction, (ii) prior to re-perfusing the heart,
operating the mechanical circulatory support device for a defined
support time (the support period), and (iii) after the support
period, applying reperfusion therapy to the heart (e.g., inserting
a stent, or applying drug therapy to free a narrowed or occluded
area in the coronary vasculature). The support period is preferably
longer than 15 minutes. For example, the support period may be
least 30 minutes and less than 60 minutes. The mechanical
circulatory support device is a cardiac assist device that operates
to pump at a rate of at least 2.5 L/min of blood flow.
[0009] According to another embodiment of the present disclosure,
there is provided a method of supporting a patient's heart that has
sustained myocardial infarction. The method comprises the step of
percutaneously inserting a transvalvular blood pump into the
patient and positioning the pump across the aortic valve of the
patient's heart, with a distal end of the pump located in the left
ventricle of the heart. Then, prior to re-perfusing the heart, the
method proceeds with the step of operating the positioned pump to
unload the left ventricle at a pumping rate of at least 2.5 L/min
of blood flow for a pumping period of greater than 15 minutes.
After the pumping period, the method then comprises the step of
treating the heart with re-perfusion therapy.
[0010] According to a further embodiment of the present disclosure,
there is provided a method of reducing the size of a myocardial
infarction scar in a patient's heart. The method comprises the step
of percutaneously inserting a transvalvular microaxial blood pump
into the patient, and positioning the pump across the aortic valve
of the patient's heart with a distal end of the pump located in the
left ventricle of the heart. The method then comprises, prior to
re-perfusing the heart, operating the positioned pump to unload the
left ventricle for a pumping period of longer than 15 minutes at a
pumping rate of at least 2.5 L/min of blood flow. After the pumping
period, the method comprises applying reperfusion therapy to the
heart.
[0011] According to another embodiment of the present disclosure,
there is provided a method of supporting a myocardial infarcted
heart. The method comprises percutaneously inserting a mechanical
circulatory support device into the patient after myocardial
infarction of the patient's heart, prior to re-perfusing the heart,
operating the device to unload the left ventricle at a rate of at
least 2.5 L/min of blood flow (e.g., 3.5 L/min) for an unloading
period of longer than 15 minutes, and after the unloading period,
applying reperfusion therapy to the heart.
[0012] According to another embodiment of the present disclosure,
there is provided a method of supporting a patient's heart with a
myocardial infarction. The method comprises the steps of (i)
reducing levels of BAX protein and active Caspase-3 antibody in
patient cardiac tissue in the myocardial infarction area (the area
at risk), and (ii) increasing levels of BCL-2 and BCL-XL proteins
in patient cardiac tissue in the myocardial infarction area.
[0013] According to another embodiment of the present disclosure,
there is provided a method of supporting a patient's heart with a
myocardial infarction comprising at least one of (i) reducing
levels of BAX protein and active Caspase-3 antibody in patient
cardiac tissue near the myocardial infarction, (ii) increasing
levels of BCL-2 and BCL-XL proteins in patient cardiac tissue in
the myocardial infarction area, (iii) increasing stromal derived
factor 1.alpha. (SDF-1.alpha.) protein levels in patient cardiac
tissue in the myocardial infarction area, (iv) maintaining activity
levels of MMP-2 and MMP-9 enzymes in patient cardiac tissue in the
myocardial infarction area, (v) limiting upregulation of DPP-4
protein expression and activity in patient cardiac tissue near the
myocardial infarction, (vi) reducing circulating levels of brain
natriuretic peptide (BNP) in the patient's blood, (vii) increasing
mRNA levels of SERCA expression in patient cardiac cells near the
myocardial infarction, and (viii) reducing levels of calcineurin
activity and Type I collagen in the myocardial infarction area
while maintaining levels of b-MHC in the non-infarct region of the
patient's heart.
[0014] According to another embodiment of the present disclosure,
there is provided a method of supporting a patient's heart with a
myocardial infarction comprising increasing stromal derived factor
1.alpha. (SDF-1.alpha.) protein levels in patient cardiac tissue
near the myocardial infarction. The method may comprise maintaining
activity levels of MMP-2 and MMP-9 enzymes in patient cardiac
tissue in the myocardial infarction area. The method may also
comprise limiting upregulation of DPP-4 protein expression and
activity in patient cardiac tissue in the myocardial infarction
area. Such methods may be performed with a mechanical circulatory
support device, such as a transvalvular or extracorporeal pump.
[0015] According to further embodiment of the present disclosure,
there is provided a method of supporting a patient's heart with a
myocardial infarction comprising reducing circulating levels of
brain natriuretic peptide (BNP) in the patient's blood. The method
also comprises increasing mRNA levels of SERCA expression in
patient cardiac tissue in the myocardial infarction area. The
method further comprises reducing levels of calcineurin activity
and Type I collagen in patient cardiac tissue near the myocardial
infarction while maintaining levels of b-MHC in the non-infarct
region of the patient's heart.
[0016] According to another embodiment of the present disclosure,
there is provided a method of supporting a patient's heart with a
myocardial infarction comprising (i) reducing levels of BAX protein
and active Caspase-3 antibody in patient cardiac tissue in the
myocardial infarction area, (ii) increasing levels of BCL-2 and
BCL-XL proteins in patient cardiac tissue in the myocardial
infarction area, (iii) increasing stromal derived factor 1.alpha.
(SDF-1.alpha.) protein levels in patient cardiac tissue in the
myocardial infarction area, (iv) maintaining activity levels of
MMP-2 and MMP-9 enzymes in patient cardiac tissue in the myocardial
infarction area, (v) limiting upregulation of DPP-4 protein
expression and activity in patient cardiac tissue in the myocardial
infarction area, (vi) reducing circulating levels of brain
natriuretic peptide (BNP) in the patient's blood, (vii) increasing
mRNA levels of SERCA expression in patient cardiac cells in the
myocardial infarction area, and (viii) reducing levels of
calcineurin activity and Type I collagen in patient cardiac tissue
in the myocardial infarction area while maintaining levels of b-MHC
in the non-infarct region of the patient's heart.
[0017] According to an embodiment of the present disclosure, there
is provided a cardioprotective system for supporting a patient's
heart that has sustained myocardial infarction. The system
comprises a mechanical circulatory support device configured to be
inserted into the patient, and a reperfusion therapy device. The
system is configured such that prior to operating the reperfusion
therapy device, the mechanical circulatory support device is
configured to operate for a support period of greater than 15
minutes at a rate of at least 2.5 L/min of blood flow.
[0018] According to another embodiment of the present disclosure,
there is provided a cardioprotective system for supporting a
patient's heart that has sustained myocardial infarction. The
system comprises a blood pump configured to be percutaneously
inserted into the patient after the myocardial infarction, the pump
sized and shaped to be positioned across the aortic valve of the
patient's heart, with a distal end of the pump configured to be
located in the left ventricle of the heart. The system also
comprise a reperfusion therapy device. The system is configured
such that the blood pump is programmed to be operated prior to
operating the reperfusion therapy device and thereafter pump blood
at a rate of at least 2.5 L/min of blood flow for a pumping period
of longer than 15 minutes.
[0019] According to a further embodiment of the present disclosure,
there is provided a method of treating a human heart that has
sustained myocardial infarction, the myocardial infarction having
an infarct size and positioned within a portion of the heart, the
method comprising reducing the infarct size.
[0020] According to another embodiment of the present disclosure,
there is provided a method of preventing or limiting the effects of
heart failure in a human patient that has sustained myocardial
infarction by reducing maladaptive cardiac remodeling in the
patient. Adaptations of the method comprise percutaneously
inserting a transvalvular blood pump, comprising a rotor and a
cannula, into the patient's vasculature and positioning the cannula
across the aortic valve of the patient's heart, with a distal end
of the cannula located in the left ventricle of the heart and a
proximal end of the pump located in the aorta. Prior to reperfusing
the heart, the method then comprises the step of operating the
positioned pump to unload the left ventricle at a pumping rate of
at least 2.5 L/min of blood flow for a support period between at
least 30 minutes and less than 60 minutes. After the support
period, the method then comprise the step of applying coronary
reperfusion therapy to the heart. Maladaptive cardiac remodeling
includes, but is not limited to, one or more of: changes in the
size, shape, structure, and function of the heart.
[0021] According to a further embodiment of the present disclosure,
there is provided a system for preventing or limiting the effects
of heart failure in a human patient that has sustained myocardial
infarction by reducing maladaptive cardiac remodeling in the
patient. The system comprises a blood pump, comprising a rotor and
a cannula, the blood pump configured to be percutaneously inserted
into the patient's vasculature such that the cannula is positioned
across the aortic valve of the patient's heart, with a distal end
of the cannula located in the left ventricle of the heart and a
proximal end of the pump located in the aorta. The system may
additionally comprise a controller coupled to the pump so as to
control the operation of the pump. The system also comprises a
coronary reperfusion therapy device. In this embodiment, the
controller programs the blood pump to unload the left ventricle at
a pumping rate of at least 2.5 L/min of blood flow for a support
period between at least 30 minutes and less than 60 minutes prior
to operating the coronary reperfusion therapy device.
[0022] In certain implementations, the support period is about 30
minutes, or may be between 15 and 30 minutes. In some
implementations, the support period is longer than 30 minutes or
longer than 45 minutes. In some implementations, the mechanical
circulatory support device pumps at a rate of at least 3.5 L/min of
blood flow. In certain implementations the device provides a
cannula placed into the patient's heart and pumps blood through the
cannula. In some implementations the device is a microaxial blood
pump with a motor and an onboard rotor and stator that mechanically
operates to pump blood from the heart; in some implementations the
device operates by an external motor and may deploy the pump motor
external to the patient and rely on a long cannula extending
through the patient's vasculature to the heart. An example of a
suitable mechanical circulatory support device is a transvalvular
microaxial pump (e.g., an Impella.RTM. blood pump, such as the
Impella CP, or a similar device), where the pump is inserted
percutaneously or surgically into the aorta and across the aortic
valve, allowing the pump to pump blood out of the left ventricle
and thereby "unload" the left ventricle. In some adaptations, the
method includes percutaneously inserting a transvalvular micro
axial pump blood pump (TV pump), comprising a rotor and a cannula,
into the patient's vasculature and positioning the cannula across
the aortic valve of the patient's heart, with a distal end of the
cannula located in the left ventricle of the heart and a proximal
end of the pump located in the aorta. An extracorporeal pump may
also be used (e.g., Tandem Heart) to unload a heart chamber (such
as an atria or ventricle) according to methods disclosed herein.
According to some adaptations, the left or right atria may be
unloaded, as may the right ventricle.
[0023] In certain implementations, the heart is unloaded by the
mechanical circulatory support device concurrently with reperfusion
(for example, after unloading the heart). The period of unloading
can be at least 30 minutes, 3 hours, or longer. Various mechanical
circulatory support devices may be used in the method of the
present disclosure, either alone or in combination. For example an
intra-aortic balloon pump may be used to provide support to the
heart after a period of delay. In some implementations, a
combination of devices is used. For example, a TV-pump may be used
to unload the left ventricle while also using an extracorporeal
membrane oxygenation (ECMO) pump, or intra-aortic balloon pump, or
other mechanical circulatory support system in combination. In some
implementations, the reperfusion therapy in the method of the
present disclosure comprises at least one of primary percutaneous
coronary intervention (PCI) and fibrinolysis.
[0024] In some implementations, methods comprise one or more of the
following steps: (i) reducing levels of BAX protein and active
Caspase-3 antibody in patient cardiac tissue near a myocardial
infarction; (ii) increasing levels of BCL-2 and BCL-XL proteins in
patient cardiac tissue near a myocardial infarction; (iii)
increasing stromal derived factor 1.alpha. (SDF-1.alpha.) protein
levels in patient cardiac tissue near a myocardial infarction; (iv)
maintaining activity levels of MMP-2 and MMP-9 enzymes in patient
cardiac tissue near a myocardial infarction; (v) limiting
upregulation of DPP-4 protein expression and activity in patient
cardiac tissue near a myocardial infarction; (vi) reducing
circulating levels of brain natriuretic peptide (BNP) in the
patient's blood; (vii) increasing mRNA levels of SERCA expression
in patient cardiac cells near a myocardial infarction; and (viii)
reducing levels of calcineurin activity and Type I collagen in
patient cardiac tissue near a myocardial infarction while
maintaining levels of b-MHC in the non-infarct region of the
patient's heart. The methods may be applied so that any combination
(or all) of the foregoing steps are performed. Implementation of
one or more of steps (i)-(viii) in any of the methods of the
aforementioned embodiments has the surprising result of preventing
or limiting the effects of heart failure in a human patient. This
can be done by, for example, reducing maladaptive cardiac
remodeling in the patient.
[0025] In some implementations, the methods may be applied to
reduce infarct size in patients having elevated .SIGMA.STE levels.
For example, the method may be applied by unloading the left
ventricle of a patient having an MI and an .SIGMA.STE level of at
least 4 (e.g., 5 or 6 or greater than 6), and reducing the infarct
size in that patient. In certain implementations, the methods may
be applied to reduce the infarct size and the left ventricle scar
size. In some implementations, the method also comprises increasing
blood flow from the left ventricle of the patient's heart by
applying mechanical circulatory support to the patient. In certain
implementations, the increased blood flow is provided at a rate of
at least 2.5 L/min of blood flow for an unloading period of longer
than 15 minutes. In certain implementations, the method also
comprises the step of applying reperfusion therapy to the patient
cardiac tissue near the myocardial infarction after applying
mechanical circulatory support. In further implementations, the
system comprises one or more of the following devices that are
operated after or during operation of the mechanical circulatory
support device: an intra-aortic balloon pump, and an extracorporeal
membrane oxygenation (ECMO) pump.
[0026] In some implementations, reducing the infarct size is done
by reducing myocardial oxygen demand of the heart in the portion of
the heart containing the infarction, followed by restoring oxygen
supply to the portion of the heart containing the infarction. In
certain implementations, the method comprises reducing levels of at
least one of BAX protein and active Caspase-3 in cardiac tissue. In
other implementations, the method comprises increasing levels of at
least one of BCL-2 and BCL-XL. In further implementations, the
method comprises increasing a myocardial salvage index (MSI) of the
heart.
[0027] In certain implementations, the method also comprises the
steps of (i) inserting a blood pump into the patient's vasculature,
(ii) prior to applying reperfusion therapy to the heart, actuating
the pump during a support period to adjust blood flow within the
vasculature, and (iii) after the support period, applying
reperfusion therapy to the heart. In some implementations, the
support period is at least 15 minutes. In other implementations,
the support period is at least 30 minutes, between about 20 minutes
and about 40 minutes, or at least 45 minutes.
[0028] In further implementations, the method also comprises the
step of unloading the heart's left ventricle at a pumping rate of
at least 2.5 L/minute during the support period. In some
implementations, the blood pump is a micro axial blood pump, and
unloading the left ventricle of the heart comprises inserting a
distal end of the pump into the left ventricle and a proximal end
of the pump in the aorta, and actuating the pump to pump blood from
the left ventricle into the aorta. In certain implementations, the
method comprises the steps of (i) inserting a balloon pump into the
aorta of the heart, and (ii) inflating and deflating the balloon to
adjust blood flow within the aorta. In other implementations, the
pump is a catheter-based intravascular blood pump.
[0029] In some implementations, the method comprises at least one
of (i) increasing the left ventricular ejection fraction of the
heart, (ii) decreasing microvascular obstruction in the heart,
(iii) reducing the left ventricular end systolic volume of the
heart, and (iv) reducing the left ventricular end diastolic volume
of the heart. In other implementations, the method comprises
reducing myocardial oxygen demand of the heart in the portion of
the heart containing the infarction for a period of at least 15
minutes, followed by restoring oxygen supply to the portion of the
heart containing the infarction. In certain implementations, the
heart is unloaded by the mechanical circulatory support device
concurrently with performing reperfusion therapy on the heart. In
some implementations, reperfusion therapy comprises at least one of
primary percutaneous coronary intervention (PCI) and
fibrinolysis.
[0030] In further implementations, the method also comprises the
steps of (i) reducing circulating levels of brain natriuretic
peptide (BNP) in the patient's blood, (ii) increasing mRNA levels
of SERCA expression in patient cardiac cells near the myocardial
infarction, and (iii) reducing levels of calcineurin activity and
Type I collagen in patient cardiac tissue near the myocardial
infarction while maintaining levels of b-MHC in the non-infarct
region of the patient's heart. In some implementations, the method
also comprises removing the blood pump from the patient's heart
after applying the reperfusion therapy. In other implementations,
the method also comprises increasing blood flow to patient cardiac
tissue near the myocardial infarction.
[0031] In some implementations, the methods according to any of the
foregoing embodiments may comprise continuing the operation of the
pump in parallel with the application of coronary reperfusion. In
certain implementations, the pump is operated in parallel with the
application of coronary reperfusion for a total support period of
at least 3 hours. In other implementations, the methods may
comprise operating the pump so as to sufficiently unload the heart
to change genetic expression in cells within the myocardial infarct
zone. Unloading the heart is such a manner has the advantage of
preventing or limiting the effects of heart failure in a human
patient. This can be done by, for example, reducing maladaptive
cardiac remodeling in the patient. In further implementations, the
methods may comprise providing the patient with drug therapy in
combination with operating the pump. In certain implementations,
the drug therapy may comprise providing the patient with medicament
comprising at least one of: beta blockers, afterload reduction
agents, neurohormonal agents, and ace inhibitors.
[0032] Further advantageous implementations of the present
disclosure are provided in the examples and claim embodiments
listed below.
[0033] Variations and modifications will occur to those of skill in
the art after reviewing this disclosure. The disclosed features may
be implemented, in any combination and subcombination (including
multiple dependent combinations and subcombinations), with one or
more other features described herein. The various features
described or illustrated, including any components thereof, may be
combined or integrated in other systems. Moreover, certain features
may be omitted or not implemented.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] This patent or patent application filed contains at least
one drawing executed in color. Copies of this patent or patent
application publication with color drawing(s) will be provided by
the Office upon request and payment of the necessary fee.
[0035] The foregoing and other objects and advantages will be
apparent upon consideration of the following detailed description,
taken in conjunction with the accompanying drawings, in which like
reference characters refer to like parts throughout, and in
which:
[0036] FIG. 1 shows an illustrative cardioprotective system
according to an implementation of the present disclosure;
[0037] FIG. 2 shows an illustrative method of supporting a
patient's heart that has sustained myocardial infarction;
[0038] FIG. 3 shows a flow chart outlining the methodology of the
study in Example 1 using the method of FIG. 2;
[0039] FIG. 4 shows an unload to balloon time scatter plot for the
study in Example 1 using the method of FIG. 2;
[0040] FIGS. 5A-5C show CMR box-whisker plots stratified by
ST-elevation sum for the results of the study in Example 1 using
the method of FIG. 2;
[0041] FIG. 6A shows a flowchart illustrating the effect of
reperfusion alone (group 1), left ventricular unloading for 15 min
(group 2) or 30 min (group 3) before reperfusion, or left
ventricular unloading after reperfusion (group 4) in the study of
Example 2 using the method of FIG. 2;
[0042] FIG. 6B shows infarct area as a percentage of the area at
risk for each group (1-way analysis of variance=0.017 across all 4
groups) according to the study of Example 2;
[0043] FIG. 7A shows a genomic heat map illustrating the shift in
gene expression among sham-operated controls, using reperfusion
alone (group 1), and using left ventricular (LV) unloading for 30
min before reperfusion (group 3) (n=3 per group);
[0044] FIG. 7B shows a graph illustrating further results of the
study referenced in FIG. 3, showing relative messenger ribonucleic
acid levels of representative genes from key components of the
electron transport chain from within the infarct zone of group 1
(blue) or group 3 (orange) of FIG. 7A, *p<0.05 versus sham
control; #p<0.05 versus primary reperfusion;
[0045] FIG. 7C shows representative transmission electron
micrographs of cardiomyocyte mitochondria from sham controls and
from within the infarct zone of group 1 and group 3 of FIG. 7A;
[0046] FIGS. 8A and 8B show results of a second study conducted
according to the method of FIG. 2, showing Western blots and
quantification graphs for left ventricular (LV) protein levels of
stromal-derived factor-1.alpha. (SDF1.alpha.) and CXCR4 normalized
to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for sham
controls and each of the groups having acute myocardial infarction
with quantification (group 1: reperfusion alone; group 2: LV
unloading for 15 min before reperfusion; group 3: LV unloading for
30 min before reperfusion; and group 4: LV unloading 30 min after
reperfusion; n=4 per group);
[0047] FIGS. 8C and 8D show quantification of mRNA levels of SDF1
and CXCR4 taken from sham controls and from tissue within the
infarct zones of Group 1 and Group 3 (n=4 per group) of FIG.
8A;
[0048] FIGS. 8E and 8F show quantification of mRNA levels of SDF1
and CXCR4 taken from sham controls and from tissue within the
infarct zones of Group 1 and Group 3 (n=4 per group) of FIG.
8A;
[0049] FIGS. 8G and 8H show quantification of dipeptidyl
peptidase-4 (DPP4) protein levels and activity from samples taken
from sham controls and the infarct zones of groups 1 and 3 (n=4 per
group) of FIG. 8A, *p<0.05 versus sham, #p<0.05 versus group
1;
[0050] FIG. 8I shows quantification of infarct size as a percentage
of the area at risk among groups subjected to LV unloading for 30
min with intracoronary delivery of either vehicle or the CXCR4
inhibitor AMD3100 followed by reperfusion (n=4 per group) using the
method of FIG. 2;
[0051] FIG. 8J shows quantification of phosphorylated and total
Akt, phosphorylated and total extracellular-regulated kinase (ERK),
and phosphorylated and total glycogen synthase kinase 3.beta.
(GSK3b) (n=4 per group) in the infarct zone after using the method
of FIG. 2, *p<0.05 versus LV unloading+vehicle;
[0052] FIGS. 9A-9C show Western blots and corresponding
quantification of left ventricular (LV) protein levels of
pro-apoptotic (Bax, Caspase-3) and antiapoptotic (B-cell lymphoma-2
[BCL-2] and B-cell lymphoma-extra-large [BCL-XL]) normalized to
beta-actin levels from sham controls and the infarct zones of
groups 1 and 3 (n=3 per group) as defined in FIG. 8A, *p<0.05
versus sham; #p<0.05 versus group 1;
[0053] FIGS. 9D and 9E show TUNEL-positive staining for
deoxyribonucleic acid fragmentation from LV tissue from sham
controls and from within the infarct zone in group 1 and group 3
(n=3 per group) of FIG. 9A;
[0054] FIG. 10A shows quantification of LV scar size 28 days after
either primary reperfusion or primary unloading using late
gadolinium enhancement (LGE) by cardiac magnetic resonance imaging
(CMR) or according to anatomic pathology (n=6 per group) in the
infarct zone after using the method of FIG. 2;
[0055] FIG. 10B shows regression plot showing correlation between
LGE-CMR and anatomic pathologic quantification of LV scar size;
[0056] FIGS. 10C and 10D show representative CMR images showing LV
scar within the blue or red circles;
[0057] FIG. 10E shows circulating levels of SDF-1.alpha. over 28
days after either P-reperfusion (PR) or P-unloading (PU) (n=4 per
group);
[0058] FIG. 10F shows protein levels of SDF-1.alpha. within the
infarct zone 28 days after sham operation, P-reperfusion, or
P-unloading (n=6 per group);
[0059] FIG. 10G shows regression plot showing the correlation
between LV scar size as a percentage of the total left ventricle
versus plasma SDF-1.alpha. levels 28 days after myocardial
infarction. *p<0.05 versus sham; .dagger.p<0.05 versus
P-reperfusion;
[0060] FIGS. 11A-11C show circulating levels, mRNA levels, and
protein levels of B-type natriuretic peptide (BNP) from LV tissue
(noninfarct zone) 28 days after primary reperfusion or primary
unloading using the method of FIG. 2;
[0061] FIGS. 11D-11G show messenger ribonucleic acid (mRNA) levels
of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA),
calcineurin, type I collagen (COL1), and beta-myosin heavy chain
(b-MHC) from LV tissue (noninfarct zone) 28 days after primary
reperfusion or primary unloading using the method of FIG. 2;
and
[0062] FIG. 12 illustrates schematically the effect of mechanically
unloading the left ventricle for a minimum of 30 min before
reperfusion which limits expression of proteolytic enzymes that
degrades stromal-derived factor-1.alpha. (SDF1.alpha.), thereby
increasing cardioprotective signaling improving cell survival, and
reducing both acute infarct size and subsequent myocardial scar
size 28 days after acute myocardial infarction. DPP-4=dipeptidyl
peptidase-4; LV=left ventricular; MMP=matrix metalloproteinase.
DETAILED DESCRIPTION
[0063] To provide an overall understanding of the systems and
methods, certain illustrative implementations will be described.
Although the implementations and features described herein are
specifically described for use in connection with a circulatory and
reperfusion therapy system, it will be understood that the
components and other features outlined below may be combined with
one another in any suitable manner and may be adapted and applied
to other types of circulatory therapy and reperfusion therapy
devices. Furthermore, it should be noted that while certain
implementations are discussed herein with regards to specific
devices for circulatory and reperfusion therapy, these various
implementations may be used in various combinations to increase
both the efficacy of treatment and sustain patient life after
AMI.
[0064] FIG. 1 illustrates a system 100 for providing a combination
of mechanical support and Primary Reperfusion according to an
implementation of the present disclosure. System 100 aims to limit
myocardial damage in a human patient 110 who has experienced AMI in
the heart 120. The system 100 comprises a circulatory unit 130 and
a device (or other source) for providing reperfusion therapy 140.
The circulatory unit 130 is in communication with a control unit
150. Control unit 150 may monitor signals issued by the circulatory
unit 130 and, accordingly, control the operation of the devices (or
other source) comprising the circulatory unit 130. These signals
may be indicative of any one of the following: the operational
state of the circulatory unit 130, the position and state of the
device for reperfusion therapy 140, and the state of the patient's
heart. Samples from the AMI patient, e.g. blood or cardiac tissue,
may be obtained from either the circulatory unit 130 or the device
for reperfusion therapy 140, or from a biopsy or other source, for
characterization and further testing. This may be done via a
testing kit or a laboratory to extract various indicia from these
samples so that they can be monitored by a clinician. Such indicia
may include, for example, the myocardial infarction scar size, and
associated parameters that will be detailed in the following
sections.
[0065] The circulatory unit 130 comprises a mechanical circulatory
support device that can be inserted, for example, in the left
ventricle of the patient's heart. Such a mechanical circulatory
support device is capable of changing the blood flow above and
beyond the actual cardiac output of the heart. For example, the
mechanical circulatory support device may be inserted into the left
ventricle of the heart of a patient with AMI and actuated to unload
the heart by pumping blood out of the ventricle. This can assist
the heart in several possible ways. For example, the myocardium
wall stress is reduced. This is beneficial as the mechanism of
unloading may assist in myocardial salvage and repair. According to
an implementation of the present disclosure, the mechanical
circulatory support device may comprise a transvalvular microaxial
blood pump. Examples of such blood pumps include, but are not
limited to, Impella 2.5.TM. and Impella CP.RTM. by Abiomed, Inc.,
Danvers, Mass. Other types of mechanical circulatory support
devices may be used to assist the heart, such as extracorporeal
pumps. For example, extracorporeal membrane oxygenation (ECMO) or
intraaortic balloon pumps may be used. In some adaptations a
transvalvular pump is used in combination with another such
device.
[0066] In addition to the mechanical circulatory support device,
the circulatory unit 130 may also comprise additional pump devices
that assist with the unloading of the heart. Examples of such pump
assist devices include, but are not limited to, any one of the
following: an intra-aortic balloon pump, and an extracorporeal
membrane oxygenation (ECMO) pump. For example, a transvalvular pump
may unload the heart while a balloon pump or ECMO device is applied
to further assist the patient. Additionally, the circulatory device
may comprise a cannula portion in fluid communication with a pump
in which the distal end of the cannula may be positioned within the
heart of the patient, and the pump may be positioned at any one of:
(a) within the heart with the cannula, (b) outside the heart but
within the patient, and (c) outside the patient.
[0067] In an implementation of the present disclosure, the device
140 is used to administer reperfusion therapy to the patient
undergoing AMI. Such reperfusion therapy includes, for example,
primary percutaneous coronary intervention (PCI). These procedures
may involve the use of a coronary stent delivered into the distal
left anterior descending artery (LAD). Examples of such coronary
stents include, but are not limited to, the Promus PREMIER.TM. and
the REBEL.TM. bare-metal Platinum Chromium Coronary Stents, and the
SYNERGY.TM. Bioabsorbable Polymer Stent, all by Boston Scientific,
Marlborough, Mass. In certain embodiments, reperfusion therapy 140
may comprise drug or medicament that is capable of assisting in
fibrinolysis, thereby providing reperfusion therapy either in
combination with or as an alternative to a stent or other
device.
[0068] A kit or laboratory is capable of generating the following
clinical indicia relevant to myocardial infarction : BAX, BCL-2,
BCL-XL, DPP-4 and stromal derived factor 1.alpha. (SDF-1.alpha.)
protein levels, active Caspase-3 antibody levels, MMP-2 and MMP-9
enzyme levels in patient cardiac tissue near or in the zone of the
myocardial infarction site; mRNA levels of SERCA expression in
patient cardiac cells near or in the zone of the myocardial
infarction; calcineurin activity levels and Type I collagen levels
near or in the zone of the myocardial infarction; brain natriuretic
peptide (BNP) levels in blood taken from the left ventricle of the
patient's heart; myocardial salvage index; and ST elevation sum(s)
from an electrocardiographic map.
[0069] FIG. 2 shows a flowchart of an illustrative method 200 for
unloading the left ventricle of the heart in a patient with AMI.
The method starts at step S210 where a circulatory device, such as
the mechanical circulatory device of the circulatory unit 130 in
FIG. 1, is inserted into the patient after myocardial infarction.
Such insertion may be achieved by using a vascular access sheath
deployed into the right internal jugular vein, left carotid artery,
and one or more of femoral arteries and veins of the patient.
Further clinical details of such insertion procedures, and
associated exemplary supportive data for method 200, are detailed
in Examples 1 and 2 in the following sections.
[0070] The method 200 then continues to step S220 where the
circulatory device is operated in step S230 to support the heart,
for example by unloading the patient's heart after myocardial
infarction. Here the circulatory device is operated to achieve a
pumping rate of at least 2.5 L/min of blood flow from the left
ventricle of the heart. In certain implementations, the circulatory
device is operated to achieve a blood flow rate from the left
ventricle of the heart of at least 3.5 L/min of blood flow per
cardiac output. The unloading is performed for a period (the
support period t_sp) that is sufficiently long so as to facilitate
a reduction in infarct size. In some implementations, operation of
the circulatory device is terminated after the support period t_sp
has elapsed. In other implementations, the support period is merely
used as a marker to indicate the elapse of time t_sp since the
circulatory device has commenced operation, and operation of the
circulatory device need not be stopped after t_sp has elapsed.
Example 1, as detailed in the following sections, provides
supportive data for the step of unloading a patient's heart after
myocardial infarction using the method 200 of the present
disclosure. According to some implementations, the support period
t_sp is longer than 15 mins. In other implementations, the support
period t_sp is longer than 30 mins.
[0071] After the heart has been unloaded in step S230 for the
support period, the method progresses to step S240 in which a
reperfusion therapy is applied to the patient's heart. Reperfusion
therapy is administered using a reperfusion device, drug, or other
technique, FIG. 1 applies a reperfusion device 140. Clinical
details of such reperfusion therapy procedures, and associated
exemplary supportive data for method 200, are provided in Examples
1 and 2 below. According to an implementation of the present
disclosure, reperfusion therapy may be applied to the patient's
heart after unloading the left ventricle of the heart. In other
implementations, reperfusion therapy may be applied to a patient's
heart while the left ventricle is still being unloaded by the
circulator unit. In this implementation, the parallel use of the
reperfusion device and the circulatory device is only carried out
after the heart is unloaded with the circulatory device for the
length of the support period t_sp.
[0072] It is presently believed that supporting the heart after MI
with mechanical circulatory support prior to apply reperfusion
therapy will have a beneficial effect on the patient's heart. One
or more benefits may be detected in tissue or blood samples taken
from the patient. Such benefits may include one or more of the
following results: reducing levels of BAX protein and active
Caspase-3 antibody in patient cardiac tissue near the myocardial
infarction; increasing levels of BCL-2 and BCL-XL proteins in
patient cardiac tissue near the myocardial infarction; increasing
stromal derived factor 1.alpha. (SDF-1.alpha.) protein levels in
patient cardiac tissue near the myocardial infarction; maintaining
activity levels of MMP-2 and MMP-9 enzymes in patient cardiac
tissue near the myocardial infarction; limiting upregulation of
DPP-4 protein expression and activity in patient cardiac tissue
near the myocardial infarction; reducing circulating levels of
brain natriuretic peptide (BNP) in blood taken from the left
ventricle of the patient's heart; increasing mRNA levels of SERCA
expression in patient cardiac cells near the myocardial infarction;
reducing levels of calcineurin activity and Type I collagen in
patient cardiac tissue near the myocardial infarction while
maintaining levels of b-MHC in the non-infarct region of the
patient's heart; reducing the size of the infarct; increasing the
myocardial salvage index of the heart; and exhibiting a heart ST
elevation sum in excess of six. These results can be achieved using
the systems and methods identified in the present disclosure.
[0073] Examples 1 and 2 detailed below illustrate the results of
studies performed by applying an inventive method to patients who
had suffered a heart attack. The studies were conducted by
inserting a blood pump into the patient's vasculature after the
patient suffered AMI, but prior to applying reperfusion therapy to
the heart, actuating the pump during a support period to adjust
blood flow within the vasculature, and then after the support
period, applying reperfusion therapy to the heart. The results
indicate that infarct size was reduced and myocardial salvage index
was increased as compared to conventional methods that apply
reperfusion therapy immediately (or as soon as possible) after
infarction. Additional results indicate that the method increases
the left ventricular ejection fraction of the heart, decreases
microvascular obstruction in the heart, reduces the left
ventricular end systolic volume of the heart, and reduces the left
ventricular end diastolic volume of the heart.
EXAMPLE 1
DTU-STEMI Pilot Study
[0074] The safety and feasibility of activating an unloading device
was studied, with or without a delay to coronary reperfusion, to
begin exploring whether in the setting of unloading, delaying
reperfusion improves myocardial salvage in a human patient. The
Door-To-Unload in STEMI Pilot Trial is the first exploratory study
testing the feasibility and safety of left ventricle (LV) unloading
before reperfusion in STEMI without cardiogenic shock.
[0075] A. Method
[0076] The DTU-STEMI study was a prospective, multicenter,
randomized pilot trial involving 14 centers in the United States to
explore the feasibility, safety and potential benefit of mechanical
unloading prior to coronary reperfusion in patients presenting with
anterior STEMI. All patients received acute mechanical unloading
with the Impella CP system (Abiomed Inc., Danvers, Mass.) and were
then randomized to one of two arms: LV unloading followed by
immediate reperfusion (U-IR) or LV unloading with a 30-minute delay
to reperfusion (U-DR). The process flow for U-IR and U-DR
methodologies is shown in FIG. 3. This comparison was specifically
designed to precondition the myocardium for 30 minutes before
reperfusion by comparing infarct sizes in the U-DR versus U-IR
arms. Patients 21-80 years of age presenting between 1 to 6 hours
from chest pain onset and with ST-segment elevation of .gtoreq.2 mm
in two or more contiguous anterior leads or .gtoreq.4 mm total
ST-segment deviation sum in the anterior leads were eligible for
enrollment.
[0077] Patients were randomized to either U-IR or U-DR arms
immediately after femoral vascular access was obtained. The Impella
CP was placed prior to diagnostic coronary angiography and
operators were instructed to perform percutaneous coronary
intervention (PCI) using second-generation drug eluting stents and
to follow guideline-directed post-AMI care. In the U-DR group,
operators were allowed to shorten the time between unloading and
reperfusion if deemed clinically necessary. After PCI, the Impella
CP was explanted after a minimum of 3 hours of LV support.
[0078] The primary safety outcome was a composite of major adverse
cardiovascular and cerebrovascular events (MACCE) including
cardiovascular mortality, reinfarction, stroke, or major vascular
events at 30 days. Table 1 contains definitions used to adjudicate
each component of MACCE. Additional safety parameters included
all-cause mortality, hemolysis, acute renal dysfunction,
hospitalization for heart failure, ventricular arrhythmias, LV
thrombus, bleeding and minor vascular events. The primary efficacy
endpoint was an assessment of infarct size as percent of total LV
mass at 30 days using CMR. Secondary efficacy endpoints included
infarct size by CMR at 3-5 days and 30 days. Exploratory endpoints
included a comparison of infarct size normalized to area at risk at
3-5 days between groups. CMR protocols used in the study have been
previously described. Qualifying 12-lead electrocardiograms were
evaluated to quantify ST Segment Elevation Sum (.SIGMA.STE), a
well-established clinical marker of area at risk in STEMI.
Specifically, .SIGMA.STE was quantified by measuring the magnitude
of ST-segment elevation 0.08 seconds after the J-point across
precordial leads as compared to the isoelectric segment in an
independent core lab, blinded to the study group allocation.
TABLE-US-00001 TABLE 1 Baseline Characteristics U-DR (n = 25) U-IR
(n = 25) Age, mean (stdev), y 60.6 (10.7) 58.8 (11.4) Male sex No.
(%) 21 (84.0) 17 (68.0) Race, No. (%) American Indian/Alaskan
Native 1 (4.0) 0 (0.0) Asian 2 (8.0) 5 (20.0) Black or African
American 4 (16.0) 4 (16.0) White or Caucasian 18 (72.0) 16 (64.0)
Other 0 (0.0) 0 (0.0) BMI, mean (stdev), kg/m.sup.2 30.0 (6.0) 29.6
(9.8) Height, mean (stdev), cm 175.4 (8.5) 169.8 (15.3) Weight,
mean (stdev), kg 92.8 (21.1) 83.7 (19.6) Medical history, No. (%)
Hypertension (receiving drug therapy) 14 (56.0) 12 (48.0) Stroke 0
(0.0) 1 (4.0) Transient ischemic attack 1 (4.0) 1 (4.0) Current
nicotine use 8 (32.0) 5 (20.0) Dyslipidemia (receiving drug
therapy) 9 (36.0) 14 (56.0) Renal insufficiency 0 (0.0) 0 (0.0)
Diabetes mellitus 6 (24.0) 4 (28.6) Prior peripheral arterial
disease 0 (0.0) 0 (0.0) At presentation Blood pressure, mean
(stdev), mmHg mmHg Systolic 149 (34) 157 (26) Diastolic 88 (15) 95
(19) MAP 108 (20) 116 (20) Heart rate, mean (stdev), beats/min 89
(22) 87 (16) Pre-Impella LVEDP n = 22 n = 23 LVEDP, mean (stdev),
mmHg 25.0 (9.6) 24.0 (8.1) Heart rate, mean (stdev), bpm 87.9
(19.6) 76.5 (13.6) Anterior ST Elevation Sum, n (%), mm n = 25 n =
25 0-<2 0 (0.0) 2 (8.0) 2-<4 1 (4.0) 2 (8.0) 4-<6 3 (12.0)
2 (8.00) >6 21 (84.0) 19 (76.0) Baseline LVEF n = 22 n = 23
LVEF, mean (stdev) 32.7 (12.7) 41.9 (12.3)
[0079] Baseline demographic and clinical variables were summarized
for the two treatment groups. The study was powered to detect a
large difference in infarct size assuming a large standard
deviation that may be expected in a small STEMI study.
Specifically, a power of 0.88 and an alpha of 0.05 was used to
detect an absolute difference in infarct size of 10% with an
assumed standard deviation of 10%. All continuous variables were
summarized as means with standard deviations as well as medians and
interquartile ranges and compared between treatment groups using
the appropriate parametric or non-parametric tests. Categorical
variables were summarized as frequencies and percentages and
compared between treatment groups using Pearson's .chi.2 test for
contingency tables or Fisher Exact test, as appropriate. All
statistical tests and/or confidence intervals, as appropriate, were
performed at .alpha.=0.05 (2-sided). All p-values reported larger
than 0.01 are rounded to two decimal places, and those between 0.01
and 0.001 were rounded to three decimal places. The comparability
among treatment groups was evaluated with respect to all clinically
relevant demographic and baseline characteristic variables.
[0080] B. Results
[0081] A total of 50 patients with anterior STEMI were enrolled and
randomized to either the U-IR or U-DR arms (n=25/group) between
April 2017 and May 2018. Baseline characteristics were not
statistically different between the groups, as shown in Table 1.
Mean age of trial participants was 59.7 years and 38 patients (76%)
were male. Patients were hypertensive on presentation with time
from chest pain onset to LV Unloading not statistically different
between the groups (176.2.+-.73.4 minutes vs 200.2.+-.151.8
minutes, U-DR vs U-IR, p=0.48). .SIGMA.STE was >4 in 90%
(n=45/50) of patients. Prior to Impella CP placement, LV
end-diastolic pressure was elevated in both groups (25.0.+-.9.6 and
24.0.+-.8.1mmHg, U-DR vs U-IR, p=0.73). Baseline LVEF was obtained
using left ventriculography prior to randomization in 90% (n=45/50)
patients using the required PCI arterial vascular access (either
femoral or radial per the discretion of the operator). Baseline
LVEF was 37.4% (13.2) in the total population and lower in the U-DR
group (41.9% (12.3) vs 32.7% (12.7), U-IR vs U-DR, p=0.02). The
Impella CP was successfully implanted in all 50 patients with a
mean power (P-level) of 7.6.+-.1.0 and mean device flow of
2.8.+-.0.4 L/min during the 3 hours of support required by the
study protocol, indicating successful unloading of the LV. Mean
time from the start of the procedure to Impella CP implantation and
activation was 15.4 (8.4) minutes for the total population. All
timing elements are shown in Table 2. Radial artery access was used
for PCI in 60% (n=30/50) of patients. The use of a vascular closure
device was at the discretion of the operators. In 29/50 of the
patients a femoral artery closure device was used (14/25, 56% vs
15/25, 60% U-DR vs U-IR, p=0.99). The left anterior descending
artery was identified as the culprit coronary artery and treated
with stenting in 98% (n=49/50) of patients, as shown in Table 2.
One patient randomized to the U-DR arm did not have any coronary
lesions requiring PCI. All patients undergoing PCI received a P2Y12
inhibitor prior to PCI. 8% of patients received bivalirudin and 94%
received unfractionated heparin. Among these, one patient received
both bivalirudin and unfractionated heparin. 8% of patients
received a glycoprotein 2b/3a receptor inhibitor in addition to
dual antiplatelet therapy prior to PCI. Coronary angiography was
performed after LV unloading was initiated.
TABLE-US-00002 TABLE 2 Timing Elements All Patients U-DR U-IR Value
Total Door to Balloon DTB, mean (stdev), minutes 84.4 (27.6) 96.7
(26.1) 72.6 (24.0) 0.002 DTB, median (IQR), minutes 82.0
(62.0-104.0) 98.0 (76.0-112.5) 68.0 (55.0-87.0) Symptom to Unload n
= 50.sup.T n = 25.sup.T n = 25.sup.T Symptom to Unload, mean 188.2
(118.6) 176.2 (73.4) 200.2 (151.8) 0.48 Symptom to Unload, median
169.5 (121.0-222.5) 153.0 (119.0-196.0) 174.0 (124.0-223.0) (IQR),
minutes Arrival to Lab to Impella Insertion n = 50 n = 25 n = 25
Insertion Time, mean (stdev), 15.4 (8.4) 15.1 (7.9) 15.8 (9.0) 0.78
Insertion Time, median (IQR), 15.0 (12.0-20.0) 15.0 (8.0-20.0) 15.0
(12.0-20.0) minutes Unload to Coronary Balloon n = 49.sup.Y n =
24.sup.Y n = 25 Unload to Balloon, mean (stdev), 22.1 (12.9) 34.08
(2.6) 10.5 (6.7) <0.001 Unload to Balloon, median (IQR), 30.0
(10.0-34.0) 34.0 (32.0035.3) 10.0 (5.0-12.0) minutes Duration of
Support n = 50 n = 25 n = 25 Duration of Support, mean 6.7 (6.4)
8.2 (7.9) 5.2 (3.9) 0.10 Duration of Support, median 4.0 (3.4-5.8)
3.9 (3.4-11.9) 4.2 (3.4-4.9) .sup.TBased on source documents;
.sup.YOne patient in the U-DR arm did not have PCI.
[0082] Thrombolysis in Myocardial Infarction (TIMI) 0 to 1 flow was
observed in 52% (n=26/50) of patients before PCI. Post-PCI TIMI 3
flow was observed in 100% (n=49/49) of patients undergoing PCI.
[0083] All patients assigned to the U-DR arm completed 30 minutes
of LV Unloading prior to reperfusion without need for bailout PCI
in any patient, as shown in FIG. 4. Timing elements including
device implantation to balloon reperfusion are shown in Table 2.
Mean DTB time was longer in the U-DR arm (96.7.+-.26 vs 72.6.+-.24
mins, U-DR vs U-IR, p=0.002) driven by a prolonged unload to
balloon time in the U-DR group (34.1.+-.3 vs 10.5.+-.7 mins, U-DR
vs U-IR, p<0.001).
[0084] The composite 30-day MACCE events rate for the combined 50
patient cohort was 10% (n=5/50) is shown in Table 3. Extension of
the DTB time in the U-DR group did not increase 30-day MACCE (12%
[3 events] vs 8% [2 events], U-DR vs U-IR, p=1.00). Overall
cardiovascular mortality was 4% (n=2/50) with 1 death per group. No
non-cardiovascular mortality was observed. One patient had a stroke
one day after enrollment (2%; n=1/50) and two patients had major
vascular events (4%; n=2/50) related to flow limiting dissections
of the femoral artery at device removal.
TABLE-US-00003 TABLE 3 MACCE rate at 30 Days Table 3 MACCE rate at
30 days U-DR U-IR n = 25 95% CI n = 25 95% CI P Value MACCE No. (%)
3 (12%) [2.55%, 31.22%] 2 (8%) [0.98%, 26.03%] 0.99 CV Mortality,
No. (%) 1 (4%) [0.10%, 20.35%] 1 (4%) [0.10%, 20.35%] 0.99
Reinfarction, No. (%) 0 (0%) [0.00%, 13.72%] 0 (0%) [0.00%, 13.72%]
-- Stroke/TIA, No. (%) 0 (%) [0.00%, 13.72%] 1 (4%) [0.10%, 20.35%]
0.99 Major Vascular Events, 2 (8%) [0.98%, 26.03%] 0 (0%) [0.00%,
13.72%] 0.49 No. (%)
[0085] Bleeding in Academic Research Consortium (BARC).epsilon.2
bleeding was observed in 14% (n=7/50) of patients. No BARC 3C
(intracranial), 4 (CABG-related) or 5 (fatal) events were observed.
Blood transfusions were administered to 6% (n=3/50) of patients
with each patient requiring a single unit of packed red blood cells
only. Tables 3 and 4 provide details of all additional clinical
events.
TABLE-US-00004 TABLE 4 Cardiac Magnetic Resonance Studies, all
patients 30 days CMR Table 4A. All Patients U-DR U-IR P value
Infarct Size, No. (%) 40 (80.0) 21 (84.0) 19 (76.0) 0.53 mean
(stdev) % 14.1 (11.3) 13.1 (11.3) 15.3 (11.5) median (IQR) 11.1
(5.0-22.8) 10.4 (5.0-26.1) 13.0 (3.8-22.9) LVEF, No. (%) 40 (80.0)
21 (84.0) 19 (76.0) 0.87 mean (stdev) % 48.9 (13.0) 49.2 (12.9)
48.5 (13.4) median (IQR) 47.3 (38.2-60.9) 47.4 (39.4-61.0) 47.2
(35.9-59.9) LVESV, No. (%) 39 (78.0) 20 (80.0) 19 (76.0) 0.86 mean
(stdev) ml 77.1 (39.1) 76.0 (43.9) 78.3 (34.4) median (IQR) 65.5
(43.7-105.3) 69.0 (38.7-100.6) 65.5 (50.2-106.0) LVEDV, No, (%) 39
(78.0) 20 (80.0) 19 (76.0) 0.63 mean (stdev) ml 144.3 (44.2) 140.9
(50.8) 147.9 (37.1) median (IQR) 149.6 (106.1-171.0) 147.8
(97.8-171.6) 149.6 (119.2-171.0) 3-5 days CMR Table 4B. All
Patients U-DR.sup..DELTA. U-IR P value Infarct Size, No. (%) 40
(80.0) 20 (80.0) 20 (80.0) 0.58 mean (stdev) % 17.9 (13.5) 16.7
(13.3) 19.1 (14.0) median (IQR) 15.3 (6.7-30.1) 15.2 (6.7-23.9)
15.3 (7.4-30.5) Infarct/AAR, No.(%) 40 (80.0) 20 (80.0) 20 (80.0)
0.28 mean (stdev) % 47.9 (21.4) 44.2 (18.9) 51.6 (23.6) median
(IQR) 50.3 (31.3-66.2) 47.3 (28.8-59.5) 57.1 (38.4-71.8) MVO.sup.T,
No. (%) 40 (80.0) 20 (80.0) 20 (80.0) 0.22 mean (stdev) % 2.0 (3.6)
1.3 (2.7) 2.7 (4.4) median (IQR) 0.0 (O.O-2.2) 0.0 (0.0-1.7) 0.7
(0.0-3.0) Salvage Index.sup.Y, No. 40 (80.0) 20 (80.0) 20 (80.0)
0.28 mean (stdev) % 52.1 (21.4) 55.8 (18.9) 48.4 (23.6) median
(IQR) 49.8 (34.0-67.0) 52.7 (41.3-71.0) 43.0 (28.2-59.8) LVEF, No.
(%) 41 (82.0) 21 (84.0) 20 (80.0) 0.69 mean (stdev) % 45.5 (11.8)
44.7 (9.2) 46.2 (14.3) median (IQR) 45.0 (37.2-S3.7) 45.0
(37.9-52.2) 47.3 (32.6-54.9) LVESV, No. (%) 40 (80.0) 20 (80.0) 20
(80.0) 0.69 mean (stdev) ml 80.5 (34.7) 82.7 (39.4) 78.3 (30.1)
median (IQR) 79.6 (58.8-96.8) 79.6 (60.6-93.8) 80.8 (57.8-102.9)
LVEDV, No, (%) 40 (80.0) 20 (80.0) 20 (80.0) .088 mean (stdev) ml
144.1 (40.3) 145.1 (47.8) 143.1 (32.5) median (IQR) 143.6
(123.7-167.4) 143.9 (118.0-167.4) 143.6 (123.7-167.4) .sup..DELTA.A
patient in the U-DR arm had a test without contrast, the core
laboratory could only read the LVEF .sup.TMVO: microvascular
obstruction .sup.YMyocardial Salvage Index (MSI) = 1 - infarct
size/area at risk (AAR)
[0086] CMR was performed in 82% (n=41/50) of patients between days
3 to 5 and in 80% (n=40/50) at 30 days of follow up. The primary
efficacy endpoint of infarct size normalized to total LV mass at 30
days was 14.1% (n=40/50) for the total group. No difference was
observed between groups (13.1.+-.11.3% vs 15.3.+-.11.5%, U-DR vs
U-IR, p=0.53). Among the secondary and exploratory endpoints, at
3-5 days, mean infarct size normalized to total LV mass of
17.9.+-.13.5% and Infarct size normalized to the area at risk of
47.9.+-.21.4% were observed for the total group (n=40; Table 4).
Infarct size normalized to the area at risk was not statistically
different between the groups (44.2.+-.18.9 vs 51.6.+-.23.6, U-DR vs
U-IR, p=0.28). Mean microvascular obstruction was 1.3% versus 2.7%
for the U-DR and U-IR groups respectively (p=0.22). LV ejection
fraction and LV volumes were not statistically different between
the groups at 3-5 days and 30 days. TIMI flow did not correlate
with infarct size in the U-IR and U-DR groups.
[0087] Among patients with CMR data available at 3-5 days, a
.SIGMA.STE>4, .SIGMA.STE>5, and .SIGMA.STE>6 was observed
in 88% (n=35/40), 83% (n=33/40), and 75% (n=30/40) of patients
respectively. Compared to the U-IR group, infarct size normalized
to the area at risk was significantly decreased in the U-DR group
with a .SIGMA.STE>6 (44.1% vs 59.9%, U-DR vs U-IR, p=0.04, as
shown in FIG. 5).
[0088] C. Analysis of Results
[0089] The DTU-STEMI safety and feasibility pilot study represents
the first human experience of mechanically unloading the LV and
intentionally delaying coronary reperfusion (Primary Unloading) in
anterior STEMI using the method 200 of the present disclosure.
These findings suggest for the first time that it is feasible to
alter STEMI therapy by first focusing on reducing myocardial oxygen
consumption (unloading) and then restoring coronary
reperfusion.
[0090] Multiple attempts to limit infarct size have been tested,
however no prior clinical trial has intentionally extended the
delay to reperfusion after initiating a cardioprotective treatment
strategy. Given the disruptive concept of first unloading the LV
and delaying reperfusion, 30-day MACCE was selected as the primary
safety endpoint to provide a rigorous and sensitive analysis of any
potential risk associated with the DTU-STEMI strategy. In both the
U-IR and U-DR arms, overall MACCE rates were relatively low without
any incidence of reinfarction or any prohibitive safety signals.
Among the individual MACCE elements, CV mortality was observed in
one patient for each arm of the study and approaches national
benchmarks for 30-day STEMI mortality rates. One patient was
diagnosed with an acute exacerbation of pulmonary fibrosis on
post-op day 3 and expired 10 days later from respiratory failure,
the second mortality was a patient who presented in cardiogenic
shock which was detected only after enrollment. Major vascular
event rates in the DTU-STEMI study were comparable to the pump arm
of the Intra-aortic Balloon Counterpulsation and Infarct Size in
Patients with Acute Anterior Myocardial Infarction Without Shock
(CRISP-AMI) study. Overall BARC bleeding >2 in the DTU-STEMI was
lower than reported in a recent analysis of bleeding events
involving percutaneous ventricular assist devices, and, as
expected, higher than those reported in other STEMI trials
involving drug therapy or lower French size devices. A key aspect
of testing the concept feasibility was gaining a better
understanding of the time required to establish LV unloading prior
to PCI and its impact on door-to-balloon and overall ischemic time.
From the start of the procedure to insertion and activation of the
Impella CP required 15.4 minutes on average for the total 50
patient study, as shown in Table 2. This time includes prepping,
draping, vascular access, left ventriculography and insertion of
the Impella device. This observation highlights key insights gained
from this pilot study including: 1) it is feasible to implant and
activate this unloading device in a timely manner during an
anterior STEMI, 2) despite this inherent delay, operators were able
to achieve average door to balloon times of 84.4 (27.6) minutes
across all 50 patients, and 3) despite this inherent delay, overall
infarct sizes were low relative to recent reports including
CRISP-AMI and did not correlate with DTB times. These findings
support that the DTU-STEMI strategy may be safely tested in a
larger pivotal trial.
[0091] By providing 30 minutes of LV unloading before reperfusion,
we postulated that a cardioprotective shift in myocardial signaling
and coronary perfusion limits myocardial damage. For this reason,
patients with a larger area of myocardium at risk may achieve more
benefit with a mechanical preconditioning before reperfusion. This
is consistent with the observation that patients with higher
.SIGMA.STE, a well-established marker of myocardium area at risk in
STEMI, demonstrated lower infarct size and a higher index of
myocardial salvage with 30 minutes of unloading before reperfusion
compared to unloading and immediate reperfusion alone. Multiple
studies have confirmed that infarct size and myocardial salvage
quantified by single-photon emission computed tomography (SPECT) or
CMR correlate directly with clinical outcomes including MACE at 6
months after STEMI. Infarct size normalized to the area at risk in
both arms of the DTU-STEMI study is lower than reported values for
recent STEMI studies involving IABPs or beta-blocker therapy. The
patients in the U-DR group presented with a lower EF and a high
rate of ST elevation .gtoreq.6, which despite the randomization of
patient can be seen given the small number of patients, however
this did not translate into did not translate to a larger infarct
or lower EF at 30 days. These findings suggest that the DTU-STEMI
strategy does not increase infarct size and further that among
patients with high ST-elevation, extending the delay to reperfusion
may improve myocardial salvage.
[0092] The DTU-STEMI pilot study overcomes a critical barrier to
progress in the field of cardioprotection and myocardial recovery
by suggesting for the first time that it is possible to delay
coronary reperfusion, thereby allowing enough time for LV unloading
to precondition the myocardium and reduce ischemia-reperfusion
injury and overall myocardial damage in AMI.
EXAMPLE 2
[0093] In the setting of myocardial ischemia-reperfusion injury,
increased expression of proteases, including matrix metalloprotease
(MMP)-2 and MMP-9 and dipeptidyl peptidase-4 (DPP-4), cleave the
N-terminus of stromal-derived factor (SDF)-1.alpha., thereby
rendering the cytokine inactive. Any remaining SDF-1.alpha. can
bind to CXCR4, which promotes phosphorylation of the RISK pathway
including extracellular regulated kinase (Erk), protein kinase b
(Akt), and glycogen synthase kinase 3b (GSK3b). RISK activation
promotes cell survival by limiting cardiomyocyte apoptosis and
maintains mitochondrial integrity by preventing opening of the
mitochondrial trans-permeability pore. The mechanisms underlying
the cardioprotective benefit of P-unloading and whether the acute
decrease in infarct size results in a durable reduction in left
ventricular (LV) scar and improvement in cardiac function are
further explained herein. This study tested the importance of
delayed myocardial reperfusion, explored cardioprotective
mechanisms, and determined the late-term impact on myocardial
function associated with P-unloading.
[0094] A. Methods
[0095] Studies were conducted in adult, male Yorkshire swine. The
Institutional Animal Care and Use Committee at Tufts Medical Center
approved the study protocol. All experiments were performed
according to the committee's guidelines. Animals were premedicated
with Telazol (0.8 ml/kg, intramuscular; Zoetis Services LLC,
Parsippany, N.J.). General anesthesia was induced and maintained
with isoflurane (1% to 2%). All animals were intubated and
mechanically ventilated (Harvard Apparatus, Holliston, Mass.) with
room air and supplemented oxygen to maintain physiological pH and
oxygen saturation. Surface electrocardiography leads, an orogastric
tube, peripheral 18 G venous catheters, and a rectal thermistor
were placed in all animals. Heating pads were used as needed to
maintain a core body temperature >99.degree. F. Vascular access
sheaths were then deployed into the right internal jugular vein
(10-F), left carotid artery (7-F), and both femoral arteries (7-F)
and veins (10-F). Unfractionated heparin boluses with a goal
activated clotting time of 300 to 400 s, continuous lidocaine
infusion (1 mg/kg), and noradrenaline (0.16 mg/min) were initiated
in all animals.
[0096] A 6-F Judkins right coronary catheter (Boston Scientific,
Marlborough, Mass.) engaged the left coronary artery via the right
femoral artery, and baseline angiograms were recorded. A 0.014-inch
guidewire was delivered into the distal left anterior descending
artery (LAD) and a 3.0.times.8 mm bare-metal stent (Boston
Scientific) for acute studies or a 3.0.times.8 mm angioplasty
balloon (Boston Scientific) for chronic studies was deployed in the
mid-LAD after the first diagonal branch with angiographic
confirmation of LAD occlusion. Coronary angiography also performed
immediately after reperfusion and again after the end of the study
protocol confirmed patency of the LAD. LAD stents were used in the
acute animal study to mark the exact location for repeat balloon
occlusion during Evans blue counterstaining. Animals were then
euthanized with pentobarbital and phenytoin after 120 min of
reperfusion.
[0097] The swine were divided into 4 groups (n=4 per group), as
shown in FIG. 6A. All groups underwent 90 min of LAD occlusion. In
group 1, LAD occlusion followed by 120 min of reperfusion served as
the control group. In groups 2 and 3, LAD occlusion was followed by
insertion and activation of a TV-pump (Impella CP, Abiomed,
Danvers, Mass.) via a 14-F sheath in the left femoral artery and
maintained at maximal support (44,000 rotations/min, achieving 3.5
1/min). This action was followed by an additional 15 min (group 2)
or 30 min (group 3) of occlusion, respectively, and then 120 min of
reperfusion with LV unloading. In group 4, LAD occlusion was
followed by reperfusion, and after 30 min of reperfusion, a TV-pump
was inserted and activated for the remaining 90 min of
reperfusion.
[0098] At the end of each study, animals were euthanized for
determination of myocardial infarct size. Three sham-operated
animals were intubated, anesthetized, and mechanically ventilated
without myocardial infarction or mechanical unloading. LV tissue
samples obtained from sham controls were used for tissue
analysis.
[0099] To assess the functional role of SDF-1.alpha./CXCR4
signaling or the cardioprotective effect of LV unloading, an
over-the-wire coronary angioplasty balloon was used to deliver a
pharmacological inhibitor of the SDF-1.alpha. receptor, CXCR4
(known as AMD3100), into the area at risk while maintaining
occlusion of the LAD in a closed-chest animal model of AMI. Adult
male swine were treated with intracoronary injections of either
vehicle or AMD3100 (3 mg/kg/min, intracoronary over 10 min; n=4 per
group) initiated at the onset of LV unloading for 30 min before
reperfusion. The dose of AMD3100 was chosen based on previous
reports (Hu X, Dai S, Wu W J, et al. Stromal cell derived factor-1
alpha confers protection against myocardial ischemia/reperfusion
injury: role of the cardiac stromal cell derived factor-1 alpha
CXCR4 axis. Circ 2007; 116:654-63).
[0100] To study the long-term effects of LV unloading on infarct
size, 19 adult male Yorkshire swine were subjected to either 90 min
of mid-LAD occlusion followed by immediate reperfusion
(P-reperfusion) or 30 min of unloading before reperfusion
(P-unloading). Five animals died of ventricular arrhythmias during
LAD occlusion before randomization or pump implantation. Of the
remaining 14 animals that successfully completed the protocol, 2
animals died in the P-reperfusion group within 6 h after
reperfusion due to refractory ventricular fibrillation. No animals
died in the P-unloading group. In total, 7 (37%) of 19 animals died
during the study protocol. The surviving 12 animals were used for
analysis in the chronic study, in either the P-reperfusion group
(n=6), or the P-unloading group (n=6), as shown in FIG. 6A. Animal
weights were 76.7.+-.6.9 kg in the P-unloading group and
76.2.+-.2.4 kg in the P-reperfusion group (p=0.84). After
reperfusion, all animals were recovered and monitored for 28 days.
After 28 days, animals were re-anesthetized and underwent repeat
catheterization to assess infarct size according to cardiac
magnetic resonance imaging (MRI) and LV hemodynamics.
[0101] Changes in LV pressure and volume were assessed by using a
5-F conductance catheter system (Sigma M, CD Leycom, Hengelo, the
Netherlands) deployed via the left carotid into the left ventricle.
Ventricular pressure and volume were measured at 28 days after the
initial infarct in the chronic-phase study by using a solid-state
pressure transducer and dual-field excitation mode, respectively,
as previously described. Time-varying electrical conductance has
measured across 5 to 7 ventricular blood segments delineated by
selected catheter electrodes. Correct positioning of the
conductance catheter along the long-axis of the left ventricle was
confirmed by fluoroscopy. Parallel conductance was assessed by
injecting 20 ml of hypertonic (6%) saline into the right internal
jugular vein. Absolute LV volumes were measured by subtracting
parallel conductance from total conductance volumes. Stroke volume
is calculated as the difference in conductance volumes at +dP/dtmax
and -P/dtmin. LV stroke work was calculated as the product of peak
LV peak systolic pressure and stroke volume.
[0102] A-1. Determination of Myocardial Infarct Size
[0103] Upon completion of the acute study protocol, balloon
occlusion was performed within the mid-LAD stent and Evans blue
injected into both coronary vessels to delineate the area-at-risk
followed by removal and sectioning of the left ventricle. Biopsy
specimens were obtained from the antero-apical left ventricle
distal to the site of stent deployment (infarct zone) and from the
postero-basal wall (noninfarct zone) for molecular analysis; LV
slices were then incubated in 1% triphenyltetrazolium chloride, as
previously described. To quantify LV scar size 28 days after MI,
the left ventricle was sectioned into five 1-cm slices and then
incubated in triphenyltetrazolium chloride without Evans blue. LV
slices were then photographed, and 3 blinded reviewers used
digitized planimetry to quantify the total myocardial area,
area-at-risk, and infarct zone.
[0104] Animals in the chronic-phase study underwent a cardiac MRI
with late-gadolinium enhancement (LGE) 28 days after the initial
infarct using a Philips Achieva 1.5-T scanner (Philips Healthcare,
Best, the Netherlands). Steady-state free precession breathhold
cine images were obtained in 3 long-axis planes and sequential
short-axis slices from the atrioventricular ring to the apex. LV
and right ventricular volume, mass, and ejection fraction were
measured by using standard volumetric techniques and analyzed with
commercially available software (QMASS version 7.4, Medis Medical
Imaging Systems, Leiden, the Netherlands) by a blinded observer
experienced in cardiac magnetic resonance (CMR) analysis. LGE
images were acquired 10 to 15 min after intravenous administration
of 0.2 mmol/kg gadolinium-diethylenetriamine penta-acetic acid with
breath-hold 2-dimensional, phase-sensitive inversion recovery
sequences in identical places as in cine images. LGE regions were
defined by using full width at one-half maximum (>50% of maximum
myocardial signal intensity) with manual adjustment when needed.
Areas with LGE were summed to generate a total volume of LGE and
are expressed as a proportion of total LV myocardium (% LGE).
[0105] Whole-transcriptome expression analysis was performed on
ribonucleic acid (RNA) isolated from the infarct zone after the
acute phase protocol using Porcine 1.0 ST microarrays. (The Online
Appendix presents details.) All raw and processed data from this
microarray analysis can be accessed under the Gene Expression
Omnibus accession number GSE108644. Quantitative polymerase chain
reaction (PCR) and Western blot analysis confirmed expression of
significantly regulated genes and their activation in altered
pathways.
[0106] LV tissue samples were obtained from the center of the
infarct zone, washed and fixed with 3% glutaraldehyde in phosphate
buffer, and then embedded in epoxy resin. Electron micrographs were
acquired and analyzed for cardiomyocyte injury, including
mitochondrial swelling and integrity.
[0107] A-2. Quantification of SDF-1.alpha. and CXCR4 Levels
[0108] Total protein was extracted from tissue homogenates,
isolated as previously described (22-24). SDF-1.alpha. protein
levels were quantified in LV tissue isolated from sham-operated
animals and infarct zones using Western blot analysis and an
enzyme-linked immunosorbent assay. Circulating serum levels of
SDF-1.alpha. were quantified by using an enzyme-linked
immunosorbent assay (R&D Systems, Minneapolis, Minn.). CXCR4
levels in LV tissue isolated from sham-operated animals and infarct
zones were quantified by Western blot analysis (Abcam, Cambridge,
United Kingdom). Immunoblot analysis was then performed as
previously described.
[0109] A-3. Quantification Of MMP-2, MMP-9, and DPP-4 Levels and
Activity
[0110] MMP-2 and MMP-9 activities in homogenates of heart tissues
were determined by zymography as previously described. Briefly,
gelatin zymography was performed with sodium dodecyl sulfate
polyacrylamide gel electrophoresis gels containing 1 mg/ml of
porcine gelatin. Samples were prepared under nonreducing
conditions. Gel electrophoresis was performed at 150 V for 1 h.
After electrophoresis, the gel was washed in 2.5% Triton X-100
solution with gentle agitation for 6 h at room temperature,
followed by replacement with developing buffer containing 50 mM
Tris-HCl (pH 7.5), 0.2 M NaCl, 5 mM CaCl.sub.2, and 0.2% Brij-35.
The gel was agitated at room temperature for 30 min, placed into
fresh developing buffer, and incubated at 37.degree. C. overnight.
The following morning, gels were stained with 0.5% Coomassie
Brilliant Blue R-250 in 40% methanol and 10% acetic acid for 2 to 4
h and destained in 40% methanol and 10% acetic acid at room
temperature. Gelatinolytic bands were quantified by scanning
densitometry with ImageJ software (National Institutes of Health,
Bethesda, Md.). DPP-4 protein levels were quantified by
immunoassay, and activity levels were measured by using a
commercially available activity assay kit (MilliporeSigma,
Burlington, Mass.).
[0111] A-4. Quantification of Apoptotic Signaling Pathways
[0112] Immunoblot analysis was performed by using antibodies
against porcine B-cell lymphoma (BCL)-2 (Cell Signaling Technology,
Danvers, Mass.), BAX (Cell Signaling Technology), B-cell
lymphoma-extra-large (BCL-XL) (Cell Signaling Technology),
caspase-3 (Cell Signaling Technology), and
glyceraldehyde-3-phosphate dehydrogenase. Expression of apoptosis
regulatory protein levels were normalized to both total protein
levels and glyceraldehyde-3-phosphate dehydrogenase. TUNEL staining
was performed by using 10-mm thick sections obtained from the
peri-infarct zone fixed in 4% paraformaldehyde/phosphate-buffered
saline for 20 min. Slides were permeabilized on ice with 0.1%
Triton X-100 in 0.1% sodium citrate, and sections were labeled in
the dark at 37.degree. C. for 60 min. Slides were rinsed with
phosphate-buffered saline, and nuclei were labeled with ProLong
Gold Antifade with DAPI (Life Technologies, Grand Island, N.Y.).
Images were acquired by using an Eclipse E800 fluorescence
microscope (Nikon Corporation, Tokyo, Japan) and Openlab version 5
software (Perkin Elmer, Waltham, Mass.). TUNEL-positive cells were
counted at 10.times.magnification by an investigator blinded to
experimental group and are expressed as a percentage of all
nuclei.
[0113] A-5. Other
[0114] For all cell-based real-time PCR experiments, total RNA was
extracted directly with Trizol (Thermo Fisher Scientific, Waltham,
Mass.) and converted to complementary deoxyribonucleic acid with a
High Capacity cDNA Reverse Transcription Kit (Thermo Fisher
Scientific). For all real-time PCR experiments, samples were
quantified in triplicate by using 40 cycles performed at 94.degree.
C. for 30 s, 60.degree. C. for 45 s, and 72.degree. C. for 45 s
with an ABI Prism 7900 Sequence Detection System (Thermo Fisher
Scientific) using appropriate primers.
[0115] Results are presented as mean.+-.SD. An unpaired Student's
t-test or one-way analysis of variance was used to compare
continuous variables between groups. All data within groups over
time were analyzed by using nonparametric 2-way repeated measures
analysis of variance. Simple linear regression analysis was used to
evaluate for a correlation between two parameters. All statistical
analyses were performed with GraphPad Prism (GraphPad Software, La
Jolla, Calif.). An alpha-level of p<0.05 was considered to
indicate a significant effect or between-group difference.
[0116] B. Results
[0117] B-1. LV Unloading for 30 Min Before Reperfusion Reduces
Acute Infarct Size Compared with Reperfusion Alone
[0118] LV unloading for 30 min before reperfusion reduced
myocardial infarct size compared with reperfusion alone (33.3.+-.5%
vs. 62.2.+-.1.7% infarct/area-at-risk, group 3 vs. group 1,
respectively; p<0.01) (see FIG. 6B). LV unloading followed by
rapid reperfusion within 15 min (group 2) or after reperfusion
(group 4) failed to reduce myocardial infarct size compared to
P-reperfusion alone.
[0119] B-2. LV Unloading Induces a Global Shift in Gene Expression
Associated with Reduced Injury within the Infarct Zone After
AMI
[0120] To begin exploring cardioprotective mechanisms associated
with LV unloading before reperfusion, we analyzed whole
transcriptomes from within the infarct zone among sham controls,
group 1, and group 3 to identify genes that were differentially
expressed between treatment groups. A heat map of all
differentially regulated genes showed that compared with sham
controls, LV unloading for 30 min before reperfusion attenuates
changes in the gene expression associated with reperfusion alone
(see FIG. 7A).
[0121] Relative to reperfusion alone, LV unloading for 30 min
before reperfusion limited down-regulation of genes associated with
mitochondrial function and cellular respiration (see Table 5
below). Consistent with these observations, real-time PCR of LV
tissue samples from the infarct zone confirmed that compared with
group 1, group 3 exhibited increased messenger ribonucleic acid
(mRNA) levels of key genes associated with cellular respiration, as
shown in FIG. 7B. Electron microscopy further showed loss of
mitochondrial integrity within the infarct zone from group 1 (but
not group 3), as shown in FIG. 7C. These findings identify that
compared with reperfusion alone, LV unloading for 30 min before
reperfusion triggers a broad shift in gene expression within the
infarct zone, with significant protection of genes associated with
mitochondrial function.
[0122] B-3. LV Unloading Limits SDF-1.alpha. Degradation in AMI
[0123] Given the importance of SDF-1.alpha./CXCR4 signaling in
cardioprotection during ischemia-reperfusion injury, SDF-1.alpha.
and CXCR4 protein levels were quantified within the infarct zone.
We observed that compared with sham controls, reperfusion alone
(group 1), LV unloading for 15 min (group 2), or LV unloading after
reperfusion (group 4) were associated with reduced protein levels
of SDF-1.alpha. within the infarct zone (see FIGS. 8A and 8B). In
contrast, compared with sham controls, only LV unloading for 30 min
before reperfusion (group 3) maintained SDF-1.alpha. protein levels
within the infarct zone. CXCR4 levels remain unchanged across all 4
study groups compared with sham controls.
[0124] To determine whether increased SDF-1.alpha. levels are
transcriptionally regulated, we quantified mRNA expression by using
real-time PCR between groups and observed no difference in
SDF-1.alpha. or CXCR4 gene expression (see FIGS. 8C and 8D).
Because SDF-1.alpha. is highly regulated by proteolytic
degradation, we next explored expression of key proteases known to
degrade SDF-1.alpha.. Compared with sham controls, reperfusion
alone increased MMP-2 and MMP-9 activity levels, but LV unloading
for 30 min before reperfusion did not (see FIGS. 8E and 8F).
Reperfusion alone increased DPP-4 expression and activity levels
within the infarct zone compared with sham controls (see FIGS. 8G
and 8H). LV unloading for 30 min before reperfusion limited
up-regulation of DPP-4 expression and activity. These data suggest
that LV unloading for 30 min before reperfusion may preserve
SDF-1.alpha. protein levels by limiting the activity of proteases
known to degrade SDF-1.alpha..
[0125] B-4. Loss of SDF-1.alpha./CXCR4 Activity Attenuates the
Cardioprotective Effect of LV Unloading
[0126] To explore whether SDF-1.alpha./CXCR4 signaling is necessary
for the cardioprotective effect of LV unloading, in a separate
group of animals, we blocked CXCR4 activity using intracoronary
delivery of AMD3100. Compared with vehicle-treated controls
subjected to LV unloading for 30 min before reperfusion, loss of
CXCR4 activity increased infarct size and reduced cardioprotective
signaling via the RISK pathway, including Akt,
extracellular-regulated kinase, and glycogen synthase kinase 3b
(see FIGS. 8I and 8J). These findings suggest that
SDF-1.alpha./CXCR4 signaling is required for the cardioprotective
effect of LV unloading before reperfusion.
[0127] B-5. LV Unloading Limits Proapoptotic Signaling
[0128] To further explore whether LV loading for 30 min reduces
levels of proteins associated with apoptosis within the infarct
zone, we observed that compared with sham controls, reperfusion
alone (group 1) increased levels of proapoptotic proteins,
including BAX and active caspase-3, and further reduced levels of
antiapoptotic proteins, including BCL-2 and BCLXL (see FIGS. 9A to
9C). Compared with group 1, group 3 exhibited reduced levels of BAX
and active caspase-3 and increased levels of the antiapoptotic
BCL-2 and BCL-XL proteins. Compared to P-reperfusion, P unloading
reduced the number of TUNEL-positive cells within the infarct zone
(see FIGS. 9D and 9E).
[0129] B-6. Compared with Primary Reperfusion, Primary Unloading
Reduces Myocardial Infarct Size and Preserves Cardiac Function 28
Days After AMI
[0130] To confer clinically relevant cardioprotection, the observed
effect of P-unloading on infarct size reduction must be maintained
beyond the acute treatment phase. To test this theory, adult male
swine were treated with either P-reperfusion or P-unloading, and LV
scar size, LV function, and molecular changes associated with heart
failure were quantified 28 days after MI. Fourteen animals
completed the ischemiareperfusion phase of the protocol. Two
animals in the P-reperfusion group died within 6 h after
reperfusion and 12 animals survived to 28 days (6 per group).
[0131] Compared with P-reperfusion, P-unloading reduced LV scar
size quantified by using LGE (3.9.+-.3.2% vs. 9.+-.3.7%; p=0.03)
and anatomic pathology (7.2.+-.4.9% vs. 14.9.+-.4.1%; p=0.02) (FIG.
5A). Histological planimetry of infarct size correlated directly
with percentage LGE from CMR (R2=0.85) (see FIGS. 10B to 10D).
Using CMRderived volumes, end-diastolic volume and endsystolic
volume were similar between groups (enddiastolic volume: 152.+-.29
ml vs. 142.+-.14 ml; P reperfusion vs. P-unloading [p=NS];
end-systolic volume: 86.+-.26 ml vs. 74.+-.6 ml; P-reperfusion vs.
P-unloading [p=NS]). CMR-derived LV mass did not differ between
groups (90.4.+-.10.6 g vs. 84.4.+-.8.6 g; P-reperfusion vs.
P-unloading [p=NS]). Compared with P-reperfusion, hemodynamic
analysis using LV conductance catheters showed that P-unloading was
associated with higher stroke volume (54.+-.7 ml vs. 40.+-.6 ml;
p=0.02), cardiac output (3.9.+-.0.6 l/min vs. 2.5.+-.0.2 l/min;
p=0.006), and stroke work (3,075.+-.339 ml.times.mm Hg vs.
2,195.+-.307 ml.times.mm Hg; p=0.008) (see Table 5 below).
TABLE-US-00005 TABLE 5 Hemodynamic Variables 28 Days After Acute
Myocardial Infarction Primary Primary Reperfusion Unloading p Value
Heart rate, beats/min 63 .+-. 9 73 .+-. 12 NS LV EDV, ml 190 .+-.
13 248 .+-. 54 NS LV ESV, ml 150 .+-. 15 195 .+-. 47 NS LV stroke
volume, ml 40 .+-. 6 54 .+-. 7 0.02 LV cardiac output, 1/min 2.5
.+-. 0.2 3.9 .+-. 0.6 0.006 LV stroke work, ml .times. mmHg 2,195
.+-. 307 3,075 .+-. 339 0.008 LV systolic pressure, mmHg 79 .+-. 3
78 .+-. 10 NS LV end-diastolic 11.3 .+-. 2.5 7.4 .+-. 1.5 0.02
Values are mean .+-. SD EDV = end-diastolic volume; ESV =
end-systolic volume; LV = left ventricular; NS = not
significant
[0132] B-7. Primary Unloading Increases Circulating and Tissue
Levels of SDF-1.alpha. Levels Acutely and 28 Days After AMI
[0133] Compared with P-reperfusion, P-unloading increased
circulating SDF-1.alpha. levels during the 28 days after AMI with a
peak SDF-1.alpha. level 1 week after AMI (see FIG. 10E). In
contrast, P-reperfusion failed to increase circulating SDF-1.alpha.
levels at any time point after AMI. Compared with sham controls,
P-reperfusion decreased SDF-1.alpha. protein levels within the
infarct zone of the left ventricle, but P-unloading did not.
Circulating SDF-1.alpha. levels on day 28 after AMI correlated
inversely with LV scar size (see FIGS. 10F and 10G).
[0134] B-8. Primary Unloading Limits Maladaptive Cardiac
Remodeling
[0135] Compared with P-reperfusion, P-unloading reduced circulating
levels of B-type natriuretic peptide (BNP) 28 days after AMI (see
FIG. 11A). Compared with sham controls, P-reperfusion increased BNP
mRNA and protein levels within the noninfarct zone (see FIGS. 11B
and 11C). In contrast, P-unloading attenuated any increase in
tissue levels of BNP within the noninfarct zone of the left
ventricle. Compared with P-reperfusion, P-unloading increased mRNA
levels of sarcoplasmic/endoplasmic reticulum calcium ATPase and
reduced levels of calcineurin and type I collagen without affecting
levels from the noninfarct region of the left ventricle (see FIGS.
11D to 11F).
[0136] C. Discussion
[0137] The central finding of this example is that P-unloading for
30 min before reperfusion alters several key biological pathways
involving cellular respiration and post-translation regulation of
SDF-1.alpha. levels, thereby reducing acute infarct size, as shown
in FIG. 12. Furthermore, P-unloading reduced LV scar size and
improved cardiac function 28 days after AMI. Specifically, we
report that: 1) 30 min of P-unloading is necessary and sufficient
before reperfusion to limit infarct size; 2) P-unloading triggers a
global shift in gene expression associated with protection of
mitochondrial integrity within the infarct zone; 3) compared with
P-reperfusion, P-unloading for 30 min preserves SDF-1.alpha.
protein levels without changing SDF-1.alpha. mRNA levels within the
infarct zone and further promotes a shift toward antiapoptotic
signaling within the infarct zone; 4) P-unloading reduces activity
levels of proteases known to degrade SDF-1.alpha.; and 5)
P-unloading reduces LV scar size, preserves cardiac output, reduces
BNP expression, and limits expression of genes and proteins
associated with maladaptive remodeling within the noninfarct zone
28 days after AMI. This data identifies P-unloading as a novel
approach to enhance cardioprotective mechanisms that may preserve
cardiac function after AMI.
[0138] It was identified that 30 min of mechanical LV unloading
with a TV-pump before, not after, reperfusion limits acute infarct
size. This observation suggests for the first time that LV
unloading itself may be a therapy as opposed to simply an adjunct
supportive approach for a dysfunctional left ventricle. One
potential explanation for the beneficial effects of 30 min of
mechanical LV unloading before reperfusion is that LV unloading
biologically primes the myocardium for reperfusion. A potential
explanation of the impact of unloading the LV is that it can reduce
infarct size and increase protein levels of SDF-1.alpha. within the
infarct zone.
[0139] Using a genomics approach, it was identified that compared
with P-reperfusion, P-unloading for 30 min differentially alters
expression of >600 genes within the infarct zone. Pathway
analysis identified that P-unloading preserved expression of genes
associated with cellular respiration and mitochondrial integrity.
It was confirmed that these observations with direct quantification
of select genes from each component of the electron transport chain
involved in cellular respiration. The findings of this study
indicate that initiation of LV unloading before reperfusion may
limit the impact of ischemiareperfusion injury on mitochondrial
integrity, thereby promoting cardiomyocyte survival.
[0140] In this study, it was observed that compared with
P-reperfusion, P-unloading failed to increase SDF-1.alpha. mRNA
levels within the infarct zone. However, it was observed that
compared with sham controls, P-reperfusion reduced SDF-1.alpha.
protein levels within the infarct zone. In contrast, LV unloading
for 30 min before reperfusion preserved SDF-1.alpha. protein
levels.
[0141] Because SDF-1.alpha. levels are highly regulated by
proteases associated with inflammation, we next explored whether
protein and activity levels of key regulatory proteases such as
MMP-2, MMP-9, or DPP-4 were altered by P-reperfusion and
P-unloading. It was observed that compared with sham controls,
P-reperfusion increases, but P-unloading attenuates, activity of
these proteases. To further establish the downstream effect of
P-unloading, we also observed reduced expression of proteins
associated with apoptosis within the infarct zone. These findings
suggest for the first time that 30 min of P-unloading limits
protease activity within the infarct zone, which limits
SDF-1.alpha. degradation in the setting of an AMI.
[0142] A preclinical study was designed in which animals were
assigned to P-reperfusion or P-unloading and then quantified LV
scar 28 days later by using cardiac MRI. It was observed for the
first time that P-unloading reduced infarct scar size as blindly
quantified by LGE-CMR, which tightly correlated with anatomic
measurements of myocardial scar size. Well-established molecular
markers of maladaptive remodeling in the noninfarct zones were then
quantified where the bulk of compensatory remodeling would occur in
response to a large anterior MI. It was observed that compared with
P-reperfusion, P-unloading reduced calcineurin, beta myosin heavy
chain, and BNP levels, while preserving sarcoplasmic/endoplasmic
reticulum calcium ATPase levels 28 days after AMI. Furthermore,
circulating and LV tissue levels of a clinically relevant biomarker
of heart failure, BNP, were reduced after P-unloading but not after
P-reperfusion. These findings are the first to identify that use of
a transvalvular pump at the time of AMI has durable effects on both
LV scar size and markers of maladaptive remodeling 28 days later.
For decades, immediate reperfusion in AMI was the main focus;
however, these data suggest for the first time that the
"pre-reperfusion time period" is a critical moment that may allow
for interventions such as LV unloading and delayed reperfusion to
have a durable effect on late-term cardiac remodeling.
[0143] Finally, SDF-1.alpha. levels after AMI were quantified and
an increase in circulating and LV tissue levels of SDF-1.alpha.
levels 28 days after P-unloading but not after P-reperfusion was
observed. Circulating SDF-1a levels correlated inversely with LV
scar size. These findings identify that in addition to providing an
acute reduction in infarct size after MI, P-unloading promotes a
more durable reduction in LV scar size, improves cardiac function,
and limits maladaptive remodeling after AMI. By using clinically
relevant biomarkers of myocardial injury, including CMR and
circulating BNP levels, the findings of this study suggests a
strong translational potential for P-unloading as an approach to
limit ischemic heart failure after AMI.
[0144] D. Findings
[0145] The findings of this study show that activation of a
transvalvular, micro-axial flow pump for 30 min before reperfusion,
as in the method 200 of FIG. 2 described in the foregoing, limits
both acute infarct size and subsequent scar size compared with
P-reperfusion alone. The results of this study provide a new
mechanistic insight into the biological impact of myocardial
unloading and activation of cardioprotective pathways within the
infarct zone.
[0146] The foregoing is merely illustrative of the principles of
the disclosure, and the apparatuses can be practiced by other than
the described implementations, which are presented for purposes of
illustration and not of limitation.
[0147] Variations and modifications will occur to those of skill in
the art after reviewing this disclosure. The disclosed features may
be implemented, in any combination and subcombination (including
multiple dependent combinations and subcombinations), with one or
more other features described herein. The various features
described or illustrated above, including any components thereof,
may be combined or integrated in other systems. Moreover, certain
features may be omitted or not implemented.
[0148] Examples of changes, substitutions, and alterations are
ascertainable by one skilled in the art and could be made without
departing from the scope of the information disclosed herein. All
references cited herein are incorporated by reference in their
entirety and made part of this application.
* * * * *