understanding the translational value of pv loops from mouse to man
TRANSCRIPT
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
Pre
ssu
re
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
Pre
ssu
re
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
Str
oke V
olu
me
LVEDP or LVEDV
1
3
4
2
Volume
Ees
Pre
ssure
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
Pre
ssu
re
Ea
Ees >> 1
Ea
Ees = 1
Uncoupling of VA-Coupling in Heart Failure
Volume
Pre
ssu
re
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 Evaluation
The 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 + Tam A B
C
D Colonic
Hemorrhage
Global Deletion of ALK-1 Triggers
Development of Arteriovenous Malformations
Kapur Lab Oh 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 Index Biventricular 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
Pre
ssu
re
Volume
Ea1 Ees
Ea2 = LVSP
SV Ea2
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
LV
Pre
ssure
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
Pre
ssu
re
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
Pre
ssu
re
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/