Hemodynamic Assessment Series by Transonic -- Part 1: PV Loop Case Study

Craig Emter, PhD

Assistant Professor, University of Missouri,

Columbia

Robert Hamlin, PhD

DVM, DACVIM, DSPS QTest Labs and The Ohio

State University

Timothy Hacker, PhD

Director, Cardiovascular Physiology Core Facility UW-Madison

Filip Konecny, PhD

Applications Scientist,

Transonic Systems

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Integrating Coronary

Vascular & Myocardial

Function in Mini-swine

with Heart Failure Craig A. Emter, Ph.D.

Assistant Professor

University of Missouri, Columbia

Scientific Application

• I am interested in evaluating the impact of exercise

and novel pharmacological strategies to assess

their efficacy in treating HFpEF

• My laboratory uses an aortic-banding model in

mini-pigs that displays numerous characteristics of

heart failure with preserved ejection fraction

including the following…

① Depressed LV Contractile Reserve

② Diastolic Dysfunction

③ LV Fibrosis

④ LV Hypertrophy

⑤ Increased BNP levels

⑥ Impaired LV Bioenergetics

Scientific Application

Classic treatment strategies

utilized for heart failure patients

with resting systolic dysfunction

do not improve outcomes for

HFpEF patients

Why do we care?

In the present study, we tested

two hypotheses in treadmill

trained aortic-banded Yucatan

miniature swine:

① Chronic low-intensity interval training

preserves normal myocardial oxygen

supply/demand balance

② Training-dependent attenuation of LV

fibrotic remodeling improves

diastolic function

Scientific Study

① Pressure-Volume loops

② Echocardiography

③ Coronary blood flow

④ Myocardial blood gas

PV loops are essential to providing a comprehensive examination of both systolic & diastolic function in vivo

They provide key measures allowing my lab to assess the functional integration of the myocardium, blood flow, and

metabolism

What methods did we use?

Brachiocephalic Artery

Band

Descending Aorta

Ascending Aorta

Heart

Aortic-Banding Location and Hemodynamics

Coronary Flow

Probe (LAD)

P-V Loop Catheter

(apical insertion)

Custom Venous

Catheter

Here we use the P-V loop to

integrate blood flow &

metabolism

0

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100 U

ntw

isti

ng

- P

ea

k G

lob

al E

R

ota

tio

n R

ate

(d

eg

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/se

c)

CON

HF

HF-TR

y = -0.3286x + 102.37 R = -0.45 P = 0.05

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twis

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tau Glantz (msec)

CON

HF

HF-TR

y = -0.3131x + 102.78 R = -0.61 P < 0.05

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/se

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LVESV (mL)

*

Marshall K D et al. J Appl Physiol 2013;114:131-147

Here we use P-V loops to

integrate diastolic function &

LV volumes with ultrasound

exercise

exercise

Here we use the P-V loop to assess LV contractile reserve

① Chronic low-intensity interval exercise training prevented diastolic impairment assessed by multiple integrated measures (pressure, volume, ultrasound)

② Chronic low-intensity interval exercise training improved cardiac efficiency

③ Chronic low-intensity interval exercise training preserved LV systolic functional reserve

What were we able to conclude?

PV loops allowed us to integrate functional and hemodynamic data

from multiple methodologies to provide a comprehensive look into global cardiovascular coupling in a large animal setting of heart failure

Meaningful results…

PV loops are essential to providing a

comprehensive examination of both systolic &

diastolic function in vivo and provide key measures

allowing my lab to assess the functional integration

of the myocardium, blood flow, and metabolism…

What is the lab doing next?

We’re currently planning to examine exercise of different intensities and if exercise

benefits can are preserved in the presence of some clinical therapies that have recently

seen an increase in use for heart failure patients…

Summary & Next Steps

What are the

properties of

this compound? Robert Hamlin, PhD

DVM, DACVIM, DSPS

QTest Labs and The

Ohio State University

http://www.qtestlabs.com/

Global Concepts and Objectives

1. All properties affected by a test article that may

translate to morbidity and/or mortality must be

explored to protect patients (lives) and the

manufacturer's reputation

2. Determine potential therapeutic and/or harmful

effects of test articles; determine putative

mechanism(s) of action

1. Electrocardiography and cardiac electrography (recording from the heart itself)

including electrophysiological testing with programmed electrical stimulation

2. Recording of pressure pulses and their derivatives from all cardiac chambers

using fluid-filled and solid state devices

3. Recording of cardiac output and regional blood flows and vascular resistances

4. Measuring myocardial contractility and both static and dynamic ease of filling

5. Calculating function of high- and low-pressure baroreceptors

6. Calculating venous volume and reactivity

7. Quantifying heart rate variability and other expressions of autonomic tone

8. Myocardial energetics: determinants of oxygen demand and oxygen delivery

Essential Measurements

Remember…

A "good" animal model shares, with man, the physiology

and pathophysiology of target diseases, and molecular

targets of the test articles.

Different models may be required for differing targets;

variability of species and/or strains is essential to optimize

chances of having appropriate polymorphisms of targets.

"One man is not even a good surrogate for another!"

What properties does this drug have?

dose

Inotrope?

What properties does this drug have?

Arteriolar

Vasoconstrictor,

Vasodilator?

Energetic Imbalance or Balance?

Chronotrope? Lusitrope?

Arterial

Vasoconstrictor,

Vasodilator?

How about dLVP/dt?

If you aren’t sure, what else do

you want to know?

Remember… a change in any

one of these may kill!

What

more do

you

know

now?

The Value of PV Loops

• Two families of PV loops

were generated during

heterometric

autoregulation (temporary

decreased LV EDV)

• Fit ESPVR

• Slope of LV filling relates

with stiffness – the

reciprocal of lusitrope

Now what do we know? P

ressu

re (

mm

Hg

)

Volume (uL)

Inotrope?

Arteriolar

Vasoconstrictor,

Vasodilator?

Energetic Imbalance or Balance?

Chronotrope? Lusitrope?

Arterial

Vasoconstrictor,

Vasodilator? P

ressu

re (

mm

Hg

)

Volume (uL)


Inotrope

Class of Drug: Inodilator!

Arteriolar

Vasodilator

Energetic Balance

Chronotrope Lusitrope

Arterial

Vasoconstrictor

Stroke Volume

Pre

ssu

re (

mm

Hg

)

Volume (uL)

Preload

• Quantifying inotrope and lusitrope (dynamic and static).

• Measuring stroke volume and cardiac output, end-diastolic volume and end-systolic volume

• Quantifying aortic and mitral regurgitation, shunt through

• interventricular septal defect, quantifying dilated and hyper-trophic cardiomyopathy

• Calculating determinants of myocardial oxygen consumption


The Bigger Picture in Pharma

• PV loop data can affect your decision(s) to advance test

articles.

• Top administrators, clinical investigators, and venture

capitalists want it.

• Don’t subjects or patients deserve it?

• What does it require

(technology, surgical competency, time & effort)

Time = 2 days ; Cost < $18,000/£12,000

So, is this a Good or Bad investment?

The Utility of

Right Ventricular

PV Loops Timothy Hacker, PhD

Director of Cardiovascular

Physiology Core Facility

University of Wisconsin-

Madison

Pulmonary Arterial Hypertension (PAH)

• Marked by arterial remodeling (stiffening) and occlusion (small distal arterioles)

• Median survival of PAH is 2.8 years

• Current treatment targets vascular changes, but outcomes are poor.

Image from J Am Coll Cardio 2013:62(25_s)

• What are the molecular

mechanisms that

govern the transition

from RV adaptation to

RV maladaptation and

failure in PAH?

Critical Knowledge Gap

Develop a model of PAH that transitions from

compensatory RV remodeling to right heart

failure

Measure PV Loops

Develop a mathematical

model to examine the RV/pulmonary vascular

interactions

Methods…

1. Mice

– Normobaric hypoxia (10% oxygen) for 14, 21 or 28 days

– Treated with SUGEN (SU5416, Sigma) (20 mg/Kg, IP once weekly)

2. Hemodymanics

– Right ventricular pressure-volume analysis

3. Echocardiography

– Wall thickness, tricuspid regurgitation, pulmonary artery blood velocity

4. Ex vivo

– Arterial viscoelastic measurements

– Isolated myocyte cross bridge kinetics

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ure

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mH

g)

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Normoxia

28 HySu

Right Ventricular Pressure-Volume Loops

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1.0

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2.0

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Ees

(mm

Hg

/µl)

Normoxia14 HySu21 HySu28 HySu

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)


A B C

*

**

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Eje

ctio

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(%

)


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Ea


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tota

l PV

R (

mm

Hg/

mL

· m

in)


A

†*

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21% O2 8% O2

Ea (

mm

Hg

/µl)


B

*C

Discussion

• Only PV analysis shows when the RV starts to fail – PV analysis shows an initial increase in contractility (Ees,

PRSW), then decreases

– Initial increases in ventricular vascular coupling (Ees/Ea) then decreases

• Other measurements do not show the transition – Continual increase in RV pressure

– Continual decline in ejection fraction

– Continual increase in RV mass

– By Echo » No changes in tricuspid regurgitation

» Continual increases in RV wall thickness

» Continual increases in PA velocity acceleration

Normoxia

14 HySu 21 HySu 28 HySu

Discussion

Mathematical modeling

• Of the 26 different inputs, most gathered from the PV data, a significant increase in the stiffness of the right free wall must be added to the above model to make it work as compared to the value at 14 or 21 days

• May be due to the increased RV collagen accumulation found experimentally Mathematical

Front Physiol. 2013

Dec 11;4:355

http://www.ncbi.nlm.nih.gov/pubmed/24376421




Summary

PV loops are critical to determining the change

from compensated to decompensated RV function

Echocardiography did not have a similar

delineation

Next Steps: Compare global function by PV data to

ex-vivo vascular and isolated myocyte changes

Synergy of

Pressure-Volume

Technology with

Left Ventricular

Assisted Devices Filip Konecny, DVM PhD

Application Scientist

Transonic

Essential Parts:

1. pump

2. controller

3. tubing carrying blood out of heart

chamber(s) to controller

4. tubing carrying blood to artery(ies)

5. power source

What is a Ventricular Assist Device (VAD)?

Types:

• Continuous flow & Pulsatile flow

• LVAD (LV to aorta or artery ; e.g. Fem. Subclavian)

• RVAD (RV to PA; only short term)

• Bi VAD or TAH (total artificial heart; replaces both

chambers with pumps )

VADs based on placement:

• percutaneous: pump and power source outside body

• implantable

• mobile

When VAD is used?

• peri or post surgery e.g. (post-cardiotomy, arrhythmias)

• bridge to transplant

• destination therapy

What is a Ventricular Assist Device (VAD)?

There are two broad research divisions:

1. Pre-clinical testing: early stage testing to characterize the device and

optimize performance

2. Post-clinical testing: evaluation of approved devices for continuous

improvement and study in specific disease models

In both cases, the main objective is to study the following:

• ventricle unloading of injured myocardium

• sustained end-organ perfusion

• blood oxygenation and diuresis

Global Challenge and Objectives

GOAL IS BALANCED HEMODYNAMIC SUPPORT WITH MINIMAL HEART ENERGY DEMAND

Systems to monitor LVAD

1. Flow Probe in & outflow measurements

2. Pressure Catheters central & peripheral systems

3. Swan-Ganz approximate CO and pressures

(CVP, RAP, RVP, PAP, and PAOP or PCWP)

4. EKG valve function & timing

5. Continuous PV Loops real-time hemodynamics

and load-independent measures of function

You are about to influence

hemodynamic parameters –

it is warranted to monitor central and

peripheral pressure and volume to

prevent suction on the system and/or

blood stasis and congestion.

LVAD Challenges

Ideally a VAD provides perfect balance -- in reality, resulting hemodynamics will fall

somewhere between “under-accomplished” and “excessive” support, and will vary

depending on heart and device function…

Inadequate Unloading Ao Regurgitation,

haemolysis, thrombosis, infection,

LVAD failure

Excessive Unloading Possible suction, may lead to post LVAD right HF

Balanced Condition

encourage cardiac recovery, decrease apoptosis, reduce

infarct size

PV Loops: Disease Progression to LVAD

• Total CO *

• ESP (mmHg)

• EDV

• SV (ml)

• SW (Joule)

• ESP (BSL>Injury>Unloaded)

• SV (BSL>Injury>Unloaded)

• EDV (Injury>Unloaded>BSL)

• SW (BSL>Injury>Unloaded) LV Volume (ml)

LV p

ress

ure

(m

mH

g)

Post ACUTE injury

BASELINE

UNLOADED LV with LVAD

Not unloaded FAILING

*sum of native cardiac and LVAD, based on position of suction (unloading) cannula

* PVA by quadratic fit (Joule)

Volume (ml)

Pre

ssu

re (

mm

Hg)

PV Loops: Disease Progression to LVAD

•PVA (MVO2)

•Post-injury>BSL>Unloaded

Seminar Summary

For the HFpEF, PV loops are essential for interrogating both systolic and diastolic function

PV loops allow us to elucidate complex drug interactions through load independent measurements

For the right heart, PV loops provide insight into functional compensation through various stages of pulmonary distress

Through transient load restriction and cycle to cycle assessment, LVAD testing can be improved

Seminar Resources

Slide-Deck and Recording for Review

Question & Answer Report

Five Part Pressure-Volume eBook Series Technology and Theory

Equipment Needs & Protocol Considerations

Application Overviews

Detailed Surgical Guides

Data Analysis Review

*over 100 pages of PV Loop application and technology information

http://insidescientific.com/events/past-events/item/336-hemodynamic-assessment-series-by-transonic-part-1-pv-loop-case-study

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Hemodynamic Assessment Series by Transonic -- Part 1: PV Loop Case Study

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Transcript of Hemodynamic Assessment Series by Transonic -- Part 1: PV Loop Case Study