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Non-Blood Contacting Biventricular Mechanical Actuation for the Failing Heart

2

Authors

Curtis J. Wozniak MD

Aaron M. Campbell

Anthony J. Pothoulakis MD

Lawrence J. Prochaska PhD

Rebecca J. Darner

Shawn M. Gargac

Mark P. Anstadt MD

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Background

Direct Mechanical Ventricular Actuation (DMVA) is a unique, non-blood contacting, biventricular assist device that is being developed for support of the failing heart (Myotech Circulatory Support System (CSS)). The device is contoured to fit over the heart and attaches to the ventricular myocardium by an atraumatic vacuum seal (Figure 1). A pneumatic drive is then used to deliver positive (systolic) and negative (diastolic) actuating forces to the ventricular surface. DMVA has been shown to be effective in both laboratory and clinical applications for supporting the fibrillating, asystolic or severely failing heart. Current research is focused on utilizing a rabbit model of heart failure.

Figure 1. Schematic of DMVA actuating

the failing heart

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Purpose

To determine the effects of the Myotech CSS on maladaptive molecular signals and ventricular dynamics that characterize heart failure. Initial experiments have examined cell membrane disruption (a mechanism of cell signaling), matrix metalloproteinases (central to collagen breakdown), myocardial heat shock protein expression ( an indicator of cellular stress), and regional LV wall motion.

Figure 2. Cell membrane disruption is important for myocardial cell signaling and varies with mechanical myocardial stress. Albumin crosses these transient membrane disruptions, and therefore, is a useful static measure of this cellular process.

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Methods

New Zealand white rabbits are anesthetized, undergo median sternotomy, and instrumented for hemodynamic monitoring. A transesophageal probe is positioned for echocardiographic interrogation. Esmolol is titrated to achieve a cardiac output of approximately 50 percent baseline. Animals are then either observed as unsupported heart failure (HF) controls or supported with DMVA application.

Figure 3. A transesophageal probe placed in the esophagus for ventricular imaging.

Figure 4. DMVA actuating the failing heart. Drive lines exit caudal. Aortic and pulmonary flow probes cephalad

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Results

Intracellular Albumin

0

1

2

3

4

Left Ventricle Septum Right Ventricle

Wall Location

Ce

ll D

isru

pti

on

G

rad

e

Control Failure HF + DMVA

Figure 5. Intracellular albumin was increased in all myocardial regions during HF. However, DMVA support decreased intracellular albumin in all these regions compared to unsupported HF, suggesting DMVA attenuates plasma membrane disruption.

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Results

Figure 6. Micrographs (200X) stained for albumin indicated by pink-red. The right depicts moderate to severe (grade 3 to 4), the left, trace to mild (grade 1 to 2) membrane disruption.

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Results

Cardiac Output

0

50

100

150

200

250

Baseline Failure Recovery

Experiment Time-course

Car

dia

c O

utp

ut

(ml/m

in)

Heart Failure (HF) HF + DMVA

Figure 7. Mean cardiac output at baseline, failure, and recovery. During recovery, hearts supported by DMVA exhibited improved function.

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Results

Figure 8. A transesophageal echo probe is used to capture real-time echocardiographic images of DMVA actuating the failing heart. End-systolic actuation is shown in this image.

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Results

Left Ventricular MMP Activity

0

20

40

60

80

Control 30 min HF 120 min HFTime

MM

P A

ctiv

ity

(Pix

els)

Control Heart Failure Heart Failure & DMVA

Figure 9. Attenuation of LV matrix metalloproteinase (MMP) activity following 30 and 120 minutes of DMVA vs. unsupported HF.

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Results

HSP-70 Expression

0

10

20

30

40

50IO

D P

ixel

s +

/- S

EM

Heart Failure Heart Failure & DMVA

Figure 10. Attenuation of heat-shock protein (HSP-70) expression following 30 minutes of DMVA vs. unsupported HF.

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Summary and Conclusions

A rabbit model of acute heart failure has been successfully developed for assessing DMVA. The primary focus of these experiments is to determine how DMVA affects myocardial wall stress and maladaptive cell signaling characteristic of the failing heart. Current results indicate that DMVA can significantly augment the failing heart while reducing myocardial stress. These findings suggest that DMVA can provide adequate hemodynamic support while favorably altering the maladaptive pathophysiology of heart failure.

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Future Studies

Ongoing studies are further evaluating DMVA’s impact on maladaptive cellular responses which characterize HF including anti- and pro-apoptotic cell signaling, plasma membrane disruptions and collagen turnover. Mitochondrial function and detailed analysis of regional myocardial wall motion are also under investigation. Findings are expected to determine if and how DMVA favorably alters pathologic remolding of the failing heart.

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Postscript

Funding provided in part by Myotech, LLC and NIH/NHLBI (#2 T35 HL007805-11 )

Dr. Anstadt is a consultant for Myotech, LLC.