3/14/2009

1

The Imaging of the RV-PA unit

Evangelos Michelakis, MD, FACC, FAHAProfessor of Medicine (Cardiology)

University of Alberta

UCSF - March 15 2009

RA

PA

A L

Nor

mal

Com

pens

atio

nF

ailu

re

Right Ventricle Pulmonary Arteries

Thin RVHealthy PA endotheliumThin walled-relaxed PAsLarge capillary network

Hypertrophied RVAbnormal PA endotheliumConstricted-stiff PAsLoss of microvessels

Dilated RVCell proliferation in the PA wallObliterative PA remodeling

Normal CONormal PVRNormal perfusion

Normal COMild increase in PVRModerate decrease in perfusion

Severe decrease in COSevere increase in PVRSevere decrease in perfusion

Circulation, 2009 - in press

“…And I ask, as the lungs are so close at hand, and in continual motion, and the vessel that supplies them is of such dimensions, what is the use or meaning of this pulse of the right ventricle? and why was nature reduced to the necessity of adding another ventricle for the sole purpose of nourishing the lungs?”

William Harvey “Exercitatio Anatomica de Motu Cordi s et Sanguinis in Animalibus”, 1628

RV LV

The RV and the LV are embryologically different

The molecular and metabolic profile of the normal RV is significantly different compared to RVH

Zaffran et al, Circ Res 2004.

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Control PAH + DCA

x40

Control

PAH

+ DCA

50

30

20

mm

Hg

0.5 sec

+DCAPAH

125x

Mitochondrial Membrane Potential

Circulation, 2002CircRes 2004Circulation 2007

DCA reverses established vascular remodeling in rat PAH

DCA

Con

trol

(n

on s

mal

l ce

ll lu

ng c

ance

r)D

CA

-tre

ated

(non

sm

all

cell

lung

can

cer)

CT scan(reconstructed tumor in blue)

PET(glucose uptake)

Mitochondrialmembrane potential

TMRM: redDAPI: blue

TMRM: redDAPI: blue Nagendran et al, JTCS, 2008

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Pressure Transducer

Inflow

Balloon

Aortic Cannula

Outflow

Silk Tie

Main PA

RV LVCoronary Sinus

Modified Langendorff isolated perfused heart

Nagendran et al, JTCS, 2008

DCA: a positive RVH inotrope

Normal RV

Pt#

1

Pt#

6

RVH

SMA

MHC

40X

PDE5

PDE5

SMA+PDE5+DAPI

MHC+PDE5+DAPI

Pt#

5

Pt#

7

SMA

PDE5

PDE5

MHC MHC+PDE5+DAPI

SMA+PDE5+DAPI

Nagendran et al, Circulation 2008

10 m

mH

g10

mm

Hg

1 min

1 min

0.1 sec

baseline MY-5445 10-6M

0.1 sec

10 m

mH

g10

mm

Hg

MY-5445 10-6M

Sildenafil: a positive RV inotrope in RVH

nRV

RVH

-400

-300

-200

-100

0

100

200

300

400

-400

-300

-200

-100

0

100

200

300

400

dP/d

t (m

mH

g/se

c)

1st derivative

Nagendran et al, Circulation 2008

sildenafilsildenafil

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PDE5A Inhibitor Treatment of Persistent Pulmonary HypertensionAfter Mechanical Circulatory Support

Tedford et al, Circulation: Heart Failure, Nov 2008

Sildenafil improves RV contractility in patients with persistent PAH post LVAD

ETR-A is up-regulated in Human RVH

RVH

nRV

ETR-A MHC Merge

MHC MergeETR-A

ET-1 is expressed in Human RVH

MHC Merge

MHC Merge

ET-1

ET-1

The ET axis is up-regulated in human RVH(representative of 16 patients)

ET-A receptor(48 kDa)

RV RVH

GAPDH

RV RVH

GAPDH

Endothelin-1(24 kDa)

10 min

20

40

0

Endothelin Receptor Antagonists Decrease Contractility in RVH

Bosentan 10-6M

Sildenafil 10-6M

Krebs Krebs

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5

0

20

40

60

80

100

120

ECHO RVSP

0 100 200 300 400 500 600

6 min walk

0

20

40

60

80

100

120

140

PAAT

0 100 200 300 400 500 600

6 min walk

LV endocardialcontour

LV epicardial contourRV epicardial contour

RV endocardialcontour

0

100

200

300

400

500

600

0 100 200 300 400 500 600 700

PVRi

P<0.02

dynes.sec/cm5.m2 100

200

300

400

500

600

6 min walk

20 40 60 80 100 120

rv mass/bsa

P<0.001

gm/m2

van Wolferen, S. A. et al. Eur Heart J 2007 28:1250 -1257.

Prognostic Significance ofCMR Derived RV Measures

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Interstudy Reproducibility of CMR

Grothues F et al AHJ 2004

N=60Mean Difference

±±±± SD

Coefficient of Variability

(%)

RVEDVi (ml/m2) 0.9 ± 4.7 6.2

RVSVi (ml/m2) 0.6 ± 6.7 8.2

RVEF (%) -0.1 ± 4.9 8.3

RV mass i (g/m2) -0.2 ± 2.9 8.7

Advantage of True Volumes

Adapted from Strohm et al. JMRI 2001.

LV Mass Method Sample Size to Detect a 10% Difference

P value

2-D Echo Teicholz 2443

2-D Echo Biplanar 898 <0.01

CMR 35 <0.001

LA

LV

AoRV

Measuring Cardiac Output with MRI

3 Chamber View

Perpendicular imaging plane is prescribed to capture the vessel cross-section

Aortic Valve Plane (Magnitude)

Aortic Valve Plane (Velocity)

PA Stiffness

Diastole Systole

Gan et al. Chest 2007;132:1906-12.

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PA Stiffness

Gan et al. Chest 2007;132:1906-12.

RV Pressure Volume Loops

MRI

CathPH vs control

Kuehne et al. Circulation 2004;110:2010-16.

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RA

PA

Severe PAH Moderate PAH

Normal

A 54 year old man with hemophilia and HIV-induced PAH. He presented with a rapidly worsening CHF and was found

to have PA pressure of 100/45 with a PAWP of 9 mmHg.

RA

PA

MR Perfusion ImageMR Angiogram Low FlowRegion

High FlowRegion

Ohno, Y. et al. Am. J. Roentgenol. 2007;188:48-56

NORMAL PPH

Lung Perfusion:CMR Derived Peak Blood Flow

Ohno, Y. et al. Am. J. Roentgenol. 2007;188:48-56

r = -0.79

PBF Correlation with Cath

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Contrast Time Intensity Curves1 2 3 4 5MRA – Coronal MIP

Upper Right LungNo Visible Arteries

?

Right Lung (slice 2) Left Lung (Slice 4)

Time 1(35 seconds)

1 2 3 4 5

?

MRI Lung Perfusion: Pre-Thromboarterectomy (Dec 02, 2008) 1 2 3

4 5

Slice Orientation

Summary: Upper right lung and middle left lung near the chest have a significant delay in the onset of contrast arrival – left lung region also have reduced upslope and peak value (i.e. significantly reduced perfusion). Note the delay in the green curve on the left figure and the red curve in the right hand figure.

Dr. Richard Thompson, Department of Biomedical Engineering

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1 2 3 4 5MRA – Coronal MIP

Upper Right LungVessels Now Visible

1 2 34 5

Slice Orientation

MRI Lung Perfusion: Post-Thromboarterectomy (Dec 19, 2008)

Time 1(35 seconds)

1 2 3 4 5

Contrast Time Intensity CurvesRight Lung (slice 2) Left Lung (Slice 4)

Dr. Richard Thompson, Department of Biomedical Engineering

Summary: All contrast arrival delays were corrected by surgery. Left lung now has uniform and good perfusion. Lower chest on right lung now has a new significant flow abnormality (red curve on left figure directly above). Note the arterial input function is sharper than pre surgery - may imply that impedance is reduced.

1 2 34 5

Slice Orientation

MRI Lung Perfusion: Post-Thromboarterectomy (March 11/09)

Time 1(35 seconds)

1 2 3 4 5

Pre- Post-

CMR Cost

Picano E. Cardiovasc Ultrasound 2005

Unit Cost

Echocardiography 1

CT 3.1

SPECT 3.27

CMR 5.51

PET 14.03

Cardiac cath 19.96 MRI PET

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Before AfterTherapy with Flolan decreases RV glucose uptake

Increased lung glucose uptake in iPAH patients

RV

LV

RV

LV

Increased RV glucose uptake in iPAH

Oikawa et al, JACC 2005

Xu et al, PNAS, 2007

Thank youStephen Archer, MDLinda Webster, NPSebastien Bonnet, PhDSean McMurtry, MD, PhDJayan Nagendran, MDGopi Sutendra, MScAl Haromy, BScSandra Bonnet, MScKyoko Hashimoto, BSc

Richard Thompson, PhDIan Paterson, MD

Ballarina II, Joan Miro, 1925