Understanding the Translational Value of PV Loops from Mouse to Man

Understanding the Translational Value of PV Loops from Mouse to Man

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.

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


Segmental PV Loops in Man


Integrating Pressure and Volume


Integrating Pressure and Volume


Integrating Pressure and Volume in Real Time


Systolic and Diastolic Function

IVC Occlusion (Preclinical)


Load Independent Variables

Circulatory Support Device Evaluation


Biventricular Interdependence

LV RV

RV LV


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


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



Greater impact of acute RV pressure overload on stroke volume.

The LV and RV: A Hemodynamic Odd Couple


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


Device Speed Modulation Impacts

LV Stroke Work and dP/dT-max

Conductance Catheter Langston Pigtail Catheter


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


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


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


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


Correlating PV Loop Indices with 3D-Strain Echo


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



Saline Calibration 0.025 wire loading Wire-loaded pigtail into

vascular sheath


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/

[email protected]

http://www.millar.com/

http://www.insidescientific.com/

Science

Understanding the Translational Value of PV Loops from Mouse to Man