1. PV loops provide a comprehensive examination of cardiac function by integrating measurements of pressures, volumes, flows, and metabolism. 2. The presenter uses PV loops in mini-pigs to evaluate the impacts of exercise and pharmacological therapies on heart failure with preserved ejection fraction. 3. PV loops allow the integration of data from multiple methodologies to assess global cardiovascular function and the effects of treatments. The presenter is planning to next examine different exercise intensities and combinations with therapies.

2. 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

3. InsideScientific is an online educational environment designed
for life science researchers. Our goal is to aid in the sharing and
distribution of scientific information regarding innovative
technologies, protocols, research tools and laboratory services.

4. Integrating Coronary
Vascular & Myocardial
Function in Mini-swine
with Heart Failure
Craig A. Emter, Ph.D.
Assistant Professor
University of Missouri, Columbia

5. 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…

6. ① Depressed LV Contractile Reserve
② Diastolic Dysfunction
③ LV Fibrosis
④ LV Hypertrophy
⑤ Increased BNP levels
⑥ Impaired LV Bioenergetics
Scientific Application

7. Classic treatment strategies
utilized for heart failure patients
with resting systolic dysfunction
do not improve outcomes for
HFpEF patients
Why do we care?

8. 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

9. 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?

10. Brachiocephalic Artery
Band
Descending Aorta
Ascending Aorta
Heart
Aortic-Banding Location and Hemodynamics

11. Coronary Flow
Probe (LAD)
P-V Loop Catheter
(apical insertion)
Custom Venous
Catheter

12. Here we use the P-V loop to
integrate blood flow &
metabolism

13. 0
10
20
30
40
50
60
70
80
90
100Untwisting-PeakGlobalE
RotationRate(degree/sec) CON
HF
HF-TR
y = -0.3286x + 102.37
R = -0.45
P = 0.05
0
20
40
60
80
100
120
0 20 40 60 80 100
Untwisting-PeakGlobalE
RotationRate(degree/sec)
tau Glantz (msec)
CON
HF
HF-TR
y = -0.3131x + 102.78
R = -0.61
P < 0.05
0
20
40
60
80
100
120
0 50 100 150
Untwisting-PeakGlobalE
RotationRate(degree/sec)
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

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

15. 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?

16. 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…

17. 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

18. What are the
properties of
this compound?
Robert Hamlin, PhD
DVM, DACVIM, DSPS
QTest Labs and The
Ohio State University

19. 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

20. 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

21. 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!"

22. What properties does this drug have?
dose

23. Inotrope?
What properties does this drug have?
Arteriolar
Vasoconstrictor,
Vasodilator?
Energetic Imbalance or Balance?
Chronotrope? Lusitrope?
Arterial
Vasoconstrictor,
Vasodilator?

24. 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!

25. What
more do
you
know
now?

26. 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?
Pressure(mmHg)
Volume (uL)

27. Inotrope?
Arteriolar
Vasoconstrictor,
Vasodilator?
Energetic Imbalance or Balance?
Chronotrope? Lusitrope?
Arterial
Vasoconstrictor,
Vasodilator?
Pressure(mmHg)
Volume (uL)
The Value of PV Loops

28. Inotrope
Class of Drug: Inodilator!
Arteriolar
Vasodilator
Energetic Balance
Chronotrope Lusitrope
Arterial
Vasoconstrictor
Stroke Volume
Pressure(mmHg)
Volume (uL)
Preload

29. • 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 Value of PV Loops

30. 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?

31. The Utility of
Right Ventricular
PV LoopsTimothy Hacker, PhD
Director of Cardiovascular
Physiology Core Facility
University of Wisconsin-
Madison

32. 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.

33. 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

34. 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

35. 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

36. 0
10
20
30
40
50
60
0 10 20 30 40 50
Pressure(mmHg)
Volume (µL)
Normoxia
28 HySu
Right Ventricular Pressure-Volume Loops

37. 0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
21% O2 8% O2
Ees(mmHg/µl)
Normoxia
14 HySu
21 HySu
28 HySu
0
5
10
15
20
25
30
35
40
45
21% O2 8% O2
Preloadrecruitablestrokework
(mmHg)
Normoxia
14 HySu
21 HySu
28 HySu
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
21% O2 8
dP/dtmax(mmHg/s)
Normoxia
14 HySu
21 HySu
28 HySu
A B C
*
*
*

38. 20
25
30
35
40
45
50
55
60
65
70
21% O2 8% O2
EjectionFraction(%)
Normoxia
14 HySu
21 HySu
28 HySu
2
3
4
5
6
7
8
9
10
11
12
21% O2 8% O2
CardiacOutput(mL/min)
Normoxia
14 HySu
21 HySu
28 HySu
A B

39. 0.0
0.2
0.4
0.6
0.8
1.0
1.2
21% O2
Ees/Ea
Normoxia
14 HySu
21 HySu
28 HySu
0
1
2
3
4
5
6
7
8
21% O2 8% O2
totalPVR(mmHg/mL·min)
Normoxia
14 HySu
21 HySu
28 HySu
A
†*
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
21% O2 8% O2
Ea(mmHg/µl)
Normoxia
14 HySu
21 HySu
28 HySu
B
*
C

40. 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

41. 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

42. 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

43. Synergy of
Pressure-Volume
Technology with
Left Ventricular
Assisted Devices
Filip Konecny, DVM PhD
Application Scientist
Transonic

44. 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 )

45. 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)?

46. 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

47. 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

48. 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.

49. 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

50. 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)
LVpressure(mmHg)
Post
ACUTE
injury
BASELINE
UNLOADED LV with LVAD
Not
unloaded
FAILING
*sum of native cardiac and LVAD, based on position of suction (unloading) cannula

51. * PVA by quadratic fit (Joule)
Volume (ml)
Pressure(mmHg)PV Loops: Disease Progression to LVAD
•PVA (MVO2)
•Post-injury>BSL>Unloaded

52. 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

53. 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

54. Thank you for taking part in this event. We encourage all attendees to
register at www.insidescientific.com for notifications about future webinars.
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by Indus Instruments
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