In this exclusive webinar sponsored by Millar, Dr. Navin Kapur, Assistant Professor and Assistant Director of the Interventional Cardiology Center at Tufts Medical Center, discusses how PV loop data can translate over from mouse to man and provide a confident approach to evaluating drug studies, device validation and treatments outcomes. Hemodynamics and measurements of cardiac function from the research bench-top are presented along with findings from the clinical research settings. Furthermore, Dr. Kapur provides perspective on how PV Loops can be used as a tool for the interventional cardiologist and during the evaluation of advanced heart failure. Dr. Navin Kapur's research interests include the molecular basis of cardiac fibrosis, transforming growth factor-beta signaling in cardiac fibroblasts, and novel imaging modalities of myocardial perfusion.

1. Understanding the
Translational Value
of PV Loops from
Mouse to Man

2. InsideScientific is an online educational
environment designed for life science researchers.
Our goal is to aid in the sharing and distribution of
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3. Navin K. Kapur, MD, FACC, FSCAI
Director, Acute Circulatory Support Program
Director, Interventional Research Laboratories
Investigator, Molecular Cardiology Research Institute
Boston, MA
Translational Hemodynamics
The Role of Pressure Volume Loop Analysis
MCRI

4. 1. Heart Disease in 2015
2. Pressure and Volume Govern Cardiovascular Physiology
3. The Conductance Catheter Method
4. Preclinical Applications: Experimental Biology
5. Translational Applications: Mechanical Pump Physiology
6. Clinical Applications: A New Age for Invasive Hemodynamics
Disclosures: Research Funding from Abiomed, Cardiac Assist, Maquet, Heartware
Speaker/Consultant Honoraria from Abiomed, Cardiac Assist, Maquet, Heartware, Thoratec, Millar
We will be discussing off-label devices and device use.
Translational Hemodynamics

5. Heart Disease: A True Pandemic
Lancet 2014

6. Heart Disease: An American Problem
#1 cause of US deaths
1 in every 4 deaths
735,000 heart attacks/yr
5-7 million individuals with
heart failure in the US
Expenditure on CVD by
2030 estimated to be
> 800 billion USD

7. Activation of:
SNS, RAAS, ET-1, and TGFb Systems
Maladaptive Hypertrophy
Cardiac Fibrosis
Disrupted Angiogenesis
Systemic Vasoconstriction
Decline in Cardiac Output
Remodeling and
progressive
worsening of
LV & RV Function Venous Congestion &
Decreased Organ Perfusion
Myocardial Infarction
Hypertension
Primary Cardiomyopathy
Valvulopathy
Fall in LV Performance
Morbidity and mortality
Pathophysiology of the Failing Heart
JACC 2005

8. Goodlin. JACC 2009;54:386
Initial Presentation Cardiogenic Shock
The Clinical Spectrum of Heart Failure
Recurrent Heart
Failure

9. The Clinical Spectrum of Heart Failure
Goodlin. JACC 2009;54:386
Initial Presentation Cardiogenic Shock
Recurrent Heart
Failure

10. Primary Target of Heart Failure Therapy: Reduce LV Wall Stress
Normal
Acute
Load
Compensatory
Hypertrophy
Systolic
Failure
Dilated
Cardiomyopathy
Pressure and Volume Govern Cardiac Function
Pressure x Radius Pressure x Volume
2 x Wall Thickness LV Mass
Laplace’s Law: Wall stress = =
Wall Stress

11. Pressure
Volume
Arterial Elastance (Ea)
Stroke
Volume
Stroke Work
Potential
Energy
End-Systolic Elastance (Ees)
Contractility
Ea =ESP
SV
Afterload = Wall Stress =
ESP x Radiusej
2 x hej
Arterial elastance (Ea) is not ‘Afterload’
Mean Arterial Pressure is not ‘Afterload’
Plumbing 101: Ventricular ‘Loading’ Conditions

12. Pressure
Volume
Arterial Elastance (Ea)
Stroke
Volume
Stroke Work
Potential
Energy
End-Systolic Elastance (Ees)
Contractility
Ventriculo-Arterial Coupling =
Ea
Ees
Plumbing 201: Ventriculo-Arterial Coupling

13. StrokeVolume
LVEDP or LVEDV
1
3
4
2
Volume
Ees
Pressure
1
2 3
4
Condition 1: ‘Normal’
Condition 2: AMI
Condition 3: Compensated HFrEF
Condition 4: Cardiogenic Shock (AMI or HFrEF)
Clinical Rounds with Frank and Starling

14. Volume
Pressure
Ea
Ees
>> 1
Ea
Ees
= 1
Uncoupling of VA-Coupling in Heart Failure

15. Volume
Pressure
Goal of Medical Therapy: Re-Couple VA-Coupling
Ea
Ees
>> 1
Ea
Ees
= 1
1. Preload
2. Inotropy
3. Afterload

16. Clinical Tools to Evaluate Hemodynamic Status
Excellent for values in the pressure-time domain
Provide only an estimate of stroke volume
Pulmonary Artery Catheter Langston Catheter

17. Clinical Tools to Evaluate Hemodynamic Status
Non-invasive measures of LV and RV volume
Provide surrogate measures of cardiac pressure
3D Echocardiography Cardiac MRI

18. The Conductance Catheter Method
Solid State
Pressure Sensor
Volume measured
across electrode pairs
Total and Segmental
Changes Measured

19. The Conductance Catheter Method
Segmental PV Loops in Man

20. The Conductance Catheter Method
Integrating Pressure and Volume

21. The Conductance Catheter Method
Integrating Pressure and Volume

22. The Conductance Catheter Method
Integrating Pressure and Volume in Real Time

23. The Conductance Catheter Method
Systolic and Diastolic Function
IVC Occlusion (Preclinical)

24. The Conductance Catheter Method
Load Independent Variables

25. Circulatory Support Device EvaluationThe Conductance Catheter Method
Biventricular Interdependence
LV RV

26. RV LV
The Conductance Catheter Method
Biventricular Interdependence
Hypertonic Saline Calibration

27. • SV, HR, EF, CO
• ESV, EDV, SW
• ESP, EDP, MDP
• +dP/dt, -dP/dt, Tau
• Ees, PRSW, SCI
• EDPVR, end-diastolic stiffness
• PER, PFR
• Segmental PV loops
• Dyssynchrony quantification
The Conductance Catheter Method
Primary Variables Acquired from One Study

28. The Conductance Catheter Method
Preclinical Applications

29. Thoracic Aortic Constriction
(Left Heart Failure)
From Bench to Bedside
Murine Models of Heart Failure

30. Smad2/3  pSmad2/3
Hypertrophy
Fibrosis
Smad1/5/8  pSmad1/5/8
Anti-fibrotic
Angiogenesis
TB
R2
ALK5 ALK1
BMP
R2
TGFb1 BMP-7 (Zeisberg Nat Med 2007)
(Kass JCI 2011)
(Kuwahara Circ 2003)
Eng
“Pathologic”“Physiologic”
(Kapur Circ 2012)
Dissecting the Functional Role
of Specific Ligands and Receptors

31. Reduced Endoglin Expression Improves Survival
after TAC-induced Heart Failure
Kapur et al Circulation 2012

32. 4wk TAC PV Loops
Reduced Endoglin Expression Preserves Cardiac
Function Despite Chronic Pressure Overload
Hemodynamics correlate with echocardiography

33. Global Deletion of the ALK-1 Receptor
Worsens Mortality and Cardiac Function
Is this traditional maladaptive remodeling?
Kapur Lab

34. c
cKO-ALK1
- Tam + TamA
B
C
D
Colonic
Hemorrhage
Global Deletion of ALK-1 Triggers
Development of Arteriovenous Malformations
Kapur LabOh P et al JCI 2008

35. High Output Heart Failure due to AVMs
Let the hemodynamic data guide your
interpretation and conclusions
Kapur Lab

36. What about the Right Ventricle?
Right Heart Failure Always Worsens Mortality
Ghio et al Am J Card 2011
Van de Veerdonk et al JACC 2011

37. Haddad and Hunt et al. Circulation 2008;117;1717-1731
The LV and RV: A Hemodynamic Odd Couple
1. Higher afterload
2. Isovolumic phases
3. Rising ejection phase
4. Higher stroke work
1. Lower afterload
2. Non-isovolumic phases
3. Falling ejection phase
4. 1/6th of LV stroke work
Left Ventricle Right Ventricle
Haddad and Hunt et al. Circulation 2008;117;1717-1731

38. Haddad and Hunt et al. Circulation 2008;117;1717-1731
Greater impact of acute RV pressure overload on stroke volume.
The LV and RV: A Hemodynamic Odd Couple
Haddad and Hunt et al. Circulation 2008;117;1717-1731

39. Pulmonary
Artery
Constriction
Murine Models of RV Pressure Overload

40. Thoracic Aortic Constriction
(Left Heart Failure)
Secondary RVPO
Pulmonary Artery Constriction
(Right Heart Failure)
Primary RVPO
Murine Models of RV Pressure Overload

41. Biventricular Catheterization in Murine Models
Kapur et al. PLOS One 2013
Mouse Surgeon
Mark Aronovitz

42. Biventricular Uncoupling due to RVPO
Kapur NK PLOS One 2013
Chronic 1o RVPO
Chronic 2o RVPO

43. RV LV
Biventricular Coupling Index
Ea
Ees
Ea
Ees
=
(RV)
(LV)
Biventricular Coupling Ratios:
Ventriculo-Ventricular Coupling IndexBiventricular Uncoupling due to RVPO

44. 1. Heart Disease in 2015
2. Pressure and Volume Govern Cardiovascular Physiology
3. The Conductance Catheter Method
4. Preclinical Applications: Experimental Biology
5. Translational Applications: Mechanical Pump Physiology
6. Clinical Applications: A New Age for Invasive Hemodynamics
Translational Hemodynamics
The Role of Pressure Volume Loop Analysis

45. The Tsunami of Advanced Heart Failure
300 Million (Total US Population)
2.6% with HF = 7.8 Million
50% with Systolic HF
(3.9 Million)
Class IIIB = 350,000
Class IV = 200,000
Class IIIB and IV < age 75
 350,000
50% with
Non-Systolic HF
(3.9 Million)
NYHA Class
I = 35%
II = 35%
III = 25% (IIIb=10%)
IV = 5%
Potential
LVAD
Candidates
Adapted from Miller LW Circ 2011
<2500 OHTx

46. Circulatory Support Options are Rapidly Expanding
Surgical VADs Percutaneous MCS Devices
Next Gen: Minimally Invasive VADs
Synergy PHP

47. Circulatory Support Device Evaluation

48. The ‘Unloading’ Profile of a Continuous-flow LVAD
Reduced LV-ESP and LV-EDV = Reduced Wall Stress
Reduced PV-Area = Reduced LV Stroke Work

49. Novel Device Development: LV Apical Cannulation for
Continuous Flow Pumps

50. Hemodynamic Analysis of Next Generation
Continuous-Flow LVADs
Kapur and Pham et al. ISHLT 2013

51. Hemodynamic Analysis of Next Generation
Continuous-Flow LVADs
Kapur and Pham et al. ISHLT 2013

52. Device Speed Modulation Impacts
LV Stroke Work and dP/dT-max
Conductance Catheter Langston Pigtail Catheter
Kapur and Pham et al. ISHLT 2013

53. Percutaneous Circulatory Support Pumps
Intra-aortic Balloon Pump
JIC 2012
JTCVS 1999

54. Augmented Diastolic
Pressure: 122 mmHg
Assisted Systolic
Pressure: 75 mmHg
Unassisted Systolic
Pressure: 98 mmHg
Unassisted Diastolic
Pressure: 58 mmHg
Proximal Aorta

55. Pressure
Volume
Ea1
Ees
Ea2 =
LVSP
SVEa2
1) Reduced Ea
2) Reduced Wall Stress (Afterload)
IABP: A Volume-Displacement Pump

56. Schreuder J et al. Ann Thorac Surg 2005;79:872-880
Percutaneous Pulsatile: Standard IABP
Ea
Ea

57. Percutaneous LA  FA Bypass Pump
TandemHeart Unloading Characteristics
pLA-FA Bypass
Circ Arrhythm Electrophysiol. 2012 Dec;5(6):1202-6

58. pLA-FA Bypass
Ea1
Ea2
LVPressure
LV Volume
1) Increased Ea
2) Reduced Wall Stress (Afterload)
Percutaneous LA  FA Bypass (TandemHeart):
Unloading Characteristics

59. Percutaneous Axial Flow Catheter
Impella “LV-Direct” Unloading Characteristics

60. J Cardiovasc Transl Res. 2009 Jun;2(2):168-72.
Axial Flow Catheter (Impella):
Unloading Characteristics
Ea1
Ea2
1) Increased Ea
2) Reduced Wall Stress (Afterload)
Impella 2.5
Impella CP
Impella 5.0

61. Kapur et al ASAIO 2014
Head-to-Head Device Comparisons
Left Atrial vs Left Ventricular Unloading

62. Kapur et al ASAIO 2014
Mechanical Unloading: Targeting the LV or the LA

63. Veno-Arterial ECMO
(RA  FA Bypass + Oxygenator)
Veno-Arterial Extracorporeal Membrane Oxygenation
RA  FA Bypass Pump

64. Pressure
Volume
Ea1
Veno-Arterial ECMO
Ea2
1) Increased Ea
2) Increased Wall Stress (Afterload)

65. VA-ECMO: LV Loading

66. VA-ECMO
TandemHeart
Impella 5.0
Distinct Effects of Circulatory Support Devices on
LV Wall Stress

67. Hemodynamic Decision-Making
LV
Baseline VA-ECMO
Started
LV Loading
(10 mins)
Langston Catheter VA-ECMO +
Impella CP

68. EC-PELLA : VA-ECMO + Impella CP VA-ECMO without CP
LV Venting: ECPELLA

69. Pressure
Volume
Rationale for Venting the LV with VA-ECMO
Ea2
VA-ECMO
+
LV VENT
Ea3
1) Unchanged Ea
2) Reduced Wall Stress (Afterload)

70. Hemodynamics Guide Clinical Decision Making
JACC 2015

71. Hemodynamics of a Heart Attack
Current Treatment Paradigm: Restore Oxygen Supply

72. Baseline Occlusion
Ischemia-Reperfusion Injury in the Pressure-Volume Domain
Reperfusion

73. Closed-Chest Model of Mechanical Unloading
In Acute Myocardial Infarction
Hypothesis: First Unload the LV, then Reperfuse
Kapur et al Circulation 2013

74. Baseline Occlusion Reperfusion
Occlusion
Baseline
Reperfusion
+ Unloading
Hypothesis: First Unload the LV, then Reperfuse

75. Correlating PV Loop Indices with 3D-Strain Echo

76. Hypothesis: First Unload the LV, then Reperfuse
Reduced Infarct Size

77. DTB DTU
Translational Feasibility: Smaller, Powerful Pump
Kapur et al AHA 2014

78. Kapur et al AHA 2014
Mechanical Unloading Reduces Infarct Size

79. Hemodynamic Data Driving Clinical Paradigms

80. Audience Polling

81. A New Age for Invasive Hemodynamics
Conductance Catheters in Clinical Practice

82. Conductance Catheters in Clinical Practice

83. Conductance Catheters in Clinical Practice
Saline Calibration 0.025 wire loading
Wire-loaded pigtail into
vascular sheath

84. Conductance Catheters in Clinical Practice
0.025 wire ahead of the
pigtail catheter
Over-the-wire across the
aortic valve into the LV
Catheter positioning
along the long axis of
the LV

85. PV Loops in Pressure Overload
Transcatheter Aortic Valve Replacement
Pre-TAVR Pre-TAVR
Ea1 Ea1
Ea2
Bern

86. PV Loops in Volume Overload
Mitral Valve Regurgitation
Degenerative MR Functional MR

87. PV Loops in Volume Overload
Mitral Valve Therapy (Mitra-Clip)
Zurich
Pre-MitraClip Post-MitraClip
Ea1
Ea1
Ea2

88. Hemodynamic Insights into Clinical Outcomes
Gaemperli and Corti et al. Circulation 2013

89. Epicardial left ventricular lead placement for CRT:
Optimal pace site selection with pressure-volume loops
Dekker et al J Thorac Cardiovasc Surg 2004;127:1641-1647
PV Loops in the Electrophysiology Lab
Dyssynchronous RV and LV Contraction

90. The Conductance Catheter Method
Clinical Applications
FDA Approved for Hemodynamic Interrogation
Diagnostic Evaluation:
Ventricles  Systolic and Diastolic Heart Failure
Valves  Any valvular disorder (stenosis or regurgitation)
Vessels  Ischemic heart disease
Congenital Heart Disease
Therapeutic Evaluation:
Ventricles:
Short and long-term effect off drug or cell-based therapies
Durable and Non-durable mechanical assist devices
Cardiac Resynchronization Therapy
Septal ablation for Hypertrophic Obstructive Cardiomyopathy
Valves:
Pre-and Post-transcatheter ANY valve therapy
Vessels:
Pre- and Post-percutaneous coronary intervention

91. Coming soon to a location near you…

92. Conclusions:
• Pressure and volume govern cardiac physiology.
• The conductance catheter provides a powerful
platform for analysis of preclinical and clinical
hemodynamics at the level of :
– Experimental Biology and Physiology
– Device and Drug Development
– Clinical Evaluation of Therapeutic Interventions
• Time for a fresh look at invasive hemodynamics.
Current hemodynamic clinical practice is restricted
to the pressure-time domain.

93. MCRI Team:
• Mark Aronovitz
• Kevin Morine
• Vikram Paruchuri
• Xiaoying Qiao
• Lyanne Buiten
• Suzy Wilson
• Adil Yunis
• Emily Mackey
• Gerard Daly
• Keshan Ughreja
• Jonathan Levine
SIRL Team
• Barbara Murphy
• Lara Reyelt
• Courtney Boggins
• Corinna Bealle
• George Perides
Cath Lab Leadership:
• Carey Kimmelstiel
• Richard Botto
• Jen Eaton
Industry Sponsors:
Cardiac Assist
Abiomed
Maquet
Heartware
Funding Sources:
NIH KO8 Award
AHA Martin Leon Award
Mentors:
• Richard Karas
• David Kass
• James Udelson
• Marvin Konstam
Acknowledgements

94. Thank You!
For additional information on both pre-clinical
and clinical applications of PV Loop
measurements please visit:
http://www.millar.com/
nkapur@tuftsmedicalcenter.org