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Understanding the
Translational Value
of PV Loops from
Mouse to Man
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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
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
Heart Disease: A True Pandemic
Lancet 2014
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
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
Goodlin. JACC 2009;54:386
Initial Presentation Cardiogenic Shock
The Clinical Spectrum of Heart Failure
Recurrent Heart
Failure
The Clinical Spectrum of Heart Failure
Goodlin. JACC 2009;54:386
Initial Presentation Cardiogenic Shock
Recurrent Heart
Failure
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
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
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
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
Volume
Pressure
Ea
Ees
>> 1
Ea
Ees
= 1
Uncoupling of VA-Coupling in Heart Failure
Volume
Pressure
Goal of Medical Therapy: Re-Couple VA-Coupling
Ea
Ees
>> 1
Ea
Ees
= 1
1. Preload
2. Inotropy
3. Afterload
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
Clinical Tools to Evaluate Hemodynamic Status
Non-invasive measures of LV and RV volume
Provide surrogate measures of cardiac pressure
3D Echocardiography Cardiac MRI
The Conductance Catheter Method
Solid State
Pressure Sensor
Volume measured
across electrode pairs
Total and Segmental
Changes Measured
The Conductance Catheter Method
Segmental PV Loops in Man
The Conductance Catheter Method
Integrating Pressure and Volume
The Conductance Catheter Method
Integrating Pressure and Volume
The Conductance Catheter Method
Integrating Pressure and Volume in Real Time
The Conductance Catheter Method
Systolic and Diastolic Function
IVC Occlusion (Preclinical)
The Conductance Catheter Method
Load Independent Variables
Circulatory Support Device EvaluationThe Conductance Catheter Method
Biventricular Interdependence
LV RV
RV LV
The Conductance Catheter Method
Biventricular Interdependence
Hypertonic Saline Calibration
• 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
The Conductance Catheter Method
Preclinical Applications
Thoracic Aortic Constriction
(Left Heart Failure)
From Bench to Bedside
Murine Models of Heart Failure
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
Reduced Endoglin Expression Improves Survival
after TAC-induced Heart Failure
Kapur et al Circulation 2012
4wk TAC PV Loops
Reduced Endoglin Expression Preserves Cardiac
Function Despite Chronic Pressure Overload
Hemodynamics correlate with echocardiography
Global Deletion of the ALK-1 Receptor
Worsens Mortality and Cardiac Function
Is this traditional maladaptive remodeling?
Kapur Lab
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
High Output Heart Failure due to AVMs
Let the hemodynamic data guide your
interpretation and conclusions
Kapur Lab
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
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
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
Pulmonary
Artery
Constriction
Murine Models of RV Pressure Overload
Thoracic Aortic Constriction
(Left Heart Failure)
Secondary RVPO
Pulmonary Artery Constriction
(Right Heart Failure)
Primary RVPO
Murine Models of RV Pressure Overload
Biventricular Catheterization in Murine Models
Kapur et al. PLOS One 2013
Mouse Surgeon
Mark Aronovitz
Biventricular Uncoupling due to RVPO
Kapur NK PLOS One 2013
Chronic 1o RVPO
Chronic 2o RVPO
RV LV
Biventricular Coupling Index
Ea
Ees
Ea
Ees
=
(RV)
(LV)
Biventricular Coupling Ratios:
Ventriculo-Ventricular Coupling IndexBiventricular Uncoupling due to RVPO
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
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
Circulatory Support Options are Rapidly Expanding
Surgical VADs Percutaneous MCS Devices
Next Gen: Minimally Invasive VADs
Synergy PHP
Circulatory Support Device Evaluation
The ‘Unloading’ Profile of a Continuous-flow LVAD
Reduced LV-ESP and LV-EDV = Reduced Wall Stress
Reduced PV-Area = Reduced LV Stroke Work
Novel Device Development: LV Apical Cannulation for
Continuous Flow Pumps
Hemodynamic Analysis of Next Generation
Continuous-Flow LVADs
Kapur and Pham et al. ISHLT 2013
Hemodynamic Analysis of Next Generation
Continuous-Flow LVADs
Kapur and Pham et al. ISHLT 2013
Device Speed Modulation Impacts
LV Stroke Work and dP/dT-max
Conductance Catheter Langston Pigtail Catheter
Kapur and Pham et al. ISHLT 2013
Percutaneous Circulatory Support Pumps
Intra-aortic Balloon Pump
JIC 2012
JTCVS 1999
Augmented Diastolic
Pressure: 122 mmHg
Assisted Systolic
Pressure: 75 mmHg
Unassisted Systolic
Pressure: 98 mmHg
Unassisted Diastolic
Pressure: 58 mmHg
Proximal Aorta
Pressure
Volume
Ea1
Ees
Ea2 =
LVSP
SVEa2
1) Reduced Ea
2) Reduced Wall Stress (Afterload)
IABP: A Volume-Displacement Pump
Schreuder J et al. Ann Thorac Surg 2005;79:872-880
Percutaneous Pulsatile: Standard IABP
Ea
Ea
Percutaneous LA  FA Bypass Pump
TandemHeart Unloading Characteristics
pLA-FA Bypass
Circ Arrhythm Electrophysiol. 2012 Dec;5(6):1202-6
pLA-FA Bypass
Ea1
Ea2
LVPressure
LV Volume
1) Increased Ea
2) Reduced Wall Stress (Afterload)
Percutaneous LA  FA Bypass (TandemHeart):
Unloading Characteristics
Percutaneous Axial Flow Catheter
Impella “LV-Direct” Unloading Characteristics
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
Kapur et al ASAIO 2014
Head-to-Head Device Comparisons
Left Atrial vs Left Ventricular Unloading
Kapur et al ASAIO 2014
Mechanical Unloading: Targeting the LV or the LA
Veno-Arterial ECMO
(RA  FA Bypass + Oxygenator)
Veno-Arterial Extracorporeal Membrane Oxygenation
RA  FA Bypass Pump
Pressure
Volume
Ea1
Veno-Arterial ECMO
Ea2
1) Increased Ea
2) Increased Wall Stress (Afterload)
VA-ECMO: LV Loading
VA-ECMO
TandemHeart
Impella 5.0
Distinct Effects of Circulatory Support Devices on
LV Wall Stress
Hemodynamic Decision-Making
LV
Baseline VA-ECMO
Started
LV Loading
(10 mins)
Langston Catheter VA-ECMO +
Impella CP
EC-PELLA : VA-ECMO + Impella CP VA-ECMO without CP
LV Venting: ECPELLA
Pressure
Volume
Rationale for Venting the LV with VA-ECMO
Ea2
VA-ECMO
+
LV VENT
Ea3
1) Unchanged Ea
2) Reduced Wall Stress (Afterload)
Hemodynamics Guide Clinical Decision Making
JACC 2015
Hemodynamics of a Heart Attack
Current Treatment Paradigm: Restore Oxygen Supply
Baseline Occlusion
Ischemia-Reperfusion Injury in the Pressure-Volume Domain
Reperfusion
Closed-Chest Model of Mechanical Unloading
In Acute Myocardial Infarction
Hypothesis: First Unload the LV, then Reperfuse
Kapur et al Circulation 2013
Baseline Occlusion Reperfusion
Occlusion
Baseline
Reperfusion
+ Unloading
Hypothesis: First Unload the LV, then Reperfuse
Correlating PV Loop Indices with 3D-Strain Echo
Hypothesis: First Unload the LV, then Reperfuse
Reduced Infarct Size
DTB DTU
Translational Feasibility: Smaller, Powerful Pump
Kapur et al AHA 2014
Kapur et al AHA 2014
Mechanical Unloading Reduces Infarct Size
Hemodynamic Data Driving Clinical Paradigms
Audience Polling
A New Age for Invasive Hemodynamics
Conductance Catheters in Clinical Practice
Conductance Catheters in Clinical Practice
Conductance Catheters in Clinical Practice
Saline Calibration 0.025 wire loading
Wire-loaded pigtail into
vascular sheath
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
PV Loops in Pressure Overload
Transcatheter Aortic Valve Replacement
Pre-TAVR Pre-TAVR
Ea1 Ea1
Ea2
Bern
PV Loops in Volume Overload
Mitral Valve Regurgitation
Degenerative MR Functional MR
PV Loops in Volume Overload
Mitral Valve Therapy (Mitra-Clip)
Zurich
Pre-MitraClip Post-MitraClip
Ea1
Ea1
Ea2
Hemodynamic Insights into Clinical Outcomes
Gaemperli and Corti et al. Circulation 2013
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
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
Coming soon to a location near you…
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.
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
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

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Understanding the Translational Value of PV Loops from Mouse to Man

  • 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 scientific information regarding innovative technologies, protocols, research tools and laboratory services.
  • 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
  • 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
  • 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)
  • 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
  • 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