Disclosures VASCULATURE AND Hemodynamic Core lab for Merck Research - - PowerPoint PPT Presentation

6/22/2013 1

THE PULMONARY VASCULATURE AND ASSESSMENT OF THE RIGHT VENTRICLE

6th International Neonatal and Childhood Pulmonary Vasculature Disease Conference, San Francisco, CA

Ryan J. Tedford, MD

Heart Failure, Mechanical Circulatory Support, and Cardiac Transplantation Division of Cardiology, Department of Medicine Johns Hopkins School of Medicine June 22nd, 2013

Disclosures

Hemodynamic Core lab for Merck Research

Laboratories

Heart Failure Core Lab for Women’s Health

Initiative Heart Failure Study

NIH sponsored research

RV Afterload

“Load” the RV must eject blood against Most precisely, afterload is related to wall stress (σ)

that occurs during ejection:

P = ventricular pressure; r = ventricular radius; h = wall

thickness

r is a relatively small number, h is constant so: Afterload RV PressureEJ RVEJ pressure ~ PAEJ pressure in most cases

EJ EJ EJ EJ

Afterload on the PV loop

60 80 100 120 140 10 20 30 40 50

RV Volume (mL) RV Pressure (mmHg)

PV opens PV closes

Afterload ~ Sum of RV systolic pressure throughout ejection

6/22/2013 2

What are the components of afterload?

Mean resistance (resistance to blood flow during

steady state) (i.e. PVR or TPR)

Compliance of the vascular system Blood storage capacity of the vessels Arterial wave reflections due to pulsatile blood

flow

Pulse wave velocity (timing) affected by compliance Inertance of blood during ejection

Three Element Windkessel Model

Am J Physiol Heart Circ Physiol 291: H1731–H1737, 2006.

Pulmonary Artery Input Impedance

• Comprehensive description of the RV vascular load and takes

into account:

• Resistance of the pulmonary bed
• Pulse wave reflections
• Inertance of blood that is accelerated during ejection
• Ability of vessels to accommodate ejected blood bolus

(compliance properties)

Piene H. Physiol Rev. 1986 Jul;66(3):606-52

Pulmonary Artery Impedance

• Fourier analysis of

simultaneous measures of pressure and flow

• Forms a graph of modulus

(amplitude of pressure divided by amplitude of flow) and phase (delay between flow and pressure) plotted against frequency (typically, multiples of heart rate).

Milnor WR et al. Circ Res. 1966 Sep;19(3):467-80.

6/22/2013 3

Pulmonary Impedance Spectra

Frequency (Hz)

Z0 (mean pressure/mean flow) = Total Pulmonary Resistance Characteristic Impedance (Zc) = ratio of blood mass inertia to proximal vessel compliance; Sum of high frequency impedance (~2-12 Hz) First Zmin = function of pulse wave velocity and the distance to the major site(s)

• f wave reflection

Z1 = low frequency impedance; Large portion of total blood flow and important fraction

• f total hydraulic load; large influence by wave reflections

Milnor et al. Circ Res. 1966 Sep;19(3):467-80

Pulmonary Impedance Spectra

Separate and study individual components of RV

vascular load

Additionally it allows for calculation of: Reflection coefficients Ratio of forward to reflective waves Total hydraulic power Integrating product of pressure and flow Oscillatory power (total – mean) Impedance spectrum shifts toward the right with PAH; Zo

and Z1 increase; Zmin occurs at higher frequencies

Kussmaul WG et al. J Appl Physiol. 1993 Jan;74(1):161-9. Chesler NC et al. Conf Proc IEEE Eng Med Biol Soc. 2009

Do we have to measure impedance to understand afterload in pulmonary hypertension? Maybe not!

Afterload in the Systemic Circulation

Large Vessel Compliance (~80%) Small Vessel Compliance (~20%) Vascular Resistance Wave Reflection Aging Stiffening of the aorta Lower Large Vessel Compliance Increased Pulse Wave Velocity

Elevation of Left Ventricular Afterload

Enhanced

Lower compliance independent of resistance

6/22/2013 4

Calculating components of afterload in the pulmonary circulation

Pulmonary Vascular Resistance = (mPAP – PCWP) /

Cardiac output

Compliance can best estimated a number of ways

including: (stroke volume / pulse pressure)

“Lumped” parameter that also takes into account

contributions of wave reflections

As wave reflections return during RV systole, RV systolic

pressure increases increasing pulse pressure and lowering “Compliance”

Pulmonary R-C relationship

Tedford RJ et al. Circulation. 2012;125:289-297

PCWP < 15 mmHg

Systemic R-C relationship

Tedford RJ et al. Circulation. 2012;125:289-297

PCWP < 15 mmHg

Pulmonary RC time vs. Systemic RC time

Tedford RJ et al. Circulation. 2012;125:289-297

6/22/2013 5

Afterload in the Pulmonary Circulation

Compliance is more

evenly distributed across the pulmonary bed and the peripheral or distal vessels are responsible for most of the pulmonary vascular compliance

Sauoti et al. 2009; 297: H2154-H2160.

Vascular Resistance Large Vessel Compliance (~20%) Small Vessel Compliance (>50%)

Peripheral compliance in the lung: Why might this occur?

In the lungs, there are ~8-10 times more peripheral

vessels than in the systemic tree

Total # of pulmonary arterioles with a length of 2mm and

diameter of 8 µm is ~ 4 x 109

One such arteriole has a compliance of 0.5 x 10-9

mL/mmHg

Total peripheral compliance is 2 mL/mmHg Total pulmonary arterial system has a compliance < 4

mL/mmHg

Saouti N et al. Eur Respir Rev 2010; 19: 117, 197–203

How does PH treatment effect?

Lankhaar JW et al. Eur Heart J. 2008 Jul;29(13):1688-95.

Before After n=62

Consequences of the pulmonary RC relationship

Main determinant of compliance is PVR, and therefore

PVR a major determinant of pulsatile load

Saouti et al have suggested the oscillatory power –

power required to account for pulsatile load – is constant fraction of total power (~23%)

Sauoti et al. AJRCCM 2010 Nov 15;182(10):1315-20

High IPAH: PA mean >58mmHg (median) Mod IPAH: PA Mean <58mmHg

6/22/2013 6

Back to our Windkessel Model

Am J Physiol Heart Circ Physiol 291: H1731–H1737, 2006.

Characteristic Impedance (pulmonary circulation)

Am J Physiol Heart Circ Physiol 291: H1731–H1737, 2006.

Because Z is higher in the IPAH (distal small vessel dz) than CTEPH (proximal large vessel narrowing +/- small vessel dz), very proximal arterial narrowing does not appear have a large affect on Zc. (n) NONPH (10) CTEPH (10) IPAH (9) mPAP 18 ±4 45±14 58±14

• Higher mPAP lead to a decrease in total C and

proximal C, the later of which is the main determinant of Zc.

Am J Physiol Heart Circ Physiol 291: H1731–H1737, 2006.

Characteristic Impedance and RV afterload Does the pulmonary RC relationship ever change?

6/22/2013 7

Aging Alters the Relationship - Slightly

Tedford RJ et al. Circulation. 2012;125:289-297

Does Severe Interstitial Fibrosis Alter The Relationship?

All DLCO <41%

Tedford RJ et al. Circulation. 2012;125:289-297

Systemic Sclerosis – No!

Tedford et al. Circulation: Heart Failure, 2013, in press

PCWP large affect on Compliance

Tedford et al. Circulation. 2012;123:2414-2422

6/22/2013 8

Effect of Aging vs. PCWP on Compliance

Age 18-51 Age 52-63 Age 64-87

AGE PCWP

PVR=3 WU

Quantifying PCWP effect

If PCWP is used as a continuous variable:

[Log Pulm C = 0.112 - (0.553 * log Pulm R) - (0.0122 * PCWP); R2 = 0.70, p<0.001]

At a resistance of 3 Wood unit, compliance is be lowered from 3.34 to 1.65 to 0.82 mL/mmHg as PCWP increases from 0 to 25 to 50 mmHg respectively Range of 2.52 ml/mmHg or a 75% decline in compliance (Age 0.49 mL/mmHg or a 19% decline over 70 years)

Tedford RJ et al. Circulation. 2012;125:289-297

Proportional To PCWP Elevation

P<0.001

Tedford RJ et al. Circulation. 2012;125:289-297

Implications for PCWP

Increasing PCWP substantially lowers pulmonary

vascular compliance for a given pulmonary vascular resistance and lowers the RC time

Lower compliance leads to increased pulsatile

afterload and therefore total RV afterload

6/22/2013 9

Does the PCWP effect translate to clinical outcomes in heart failure?

Dupont M et al. Circ Heart Fail. 2012;5:778–785.

• PAC was a stronger predictor of RV dysfunction and all cause mortality
• r transplantation than PVR
• PAC bundles the effects of PVR and left-sided filling pressures on RV afterload

Even in PH, RC is not completely constant

Mean Pulmonary Artery Pressure (mmHg)

20 40 60 80 100

Pulmonary RC time (seconds)

0.0 0.5 1.0 1.5 2.0 2.5

Slight overall increase in RC time as mPAP rises

How can we assess RV function independent of afterload?

Human RV Pressure Volume Analysis

• Conductance based volume estimations could be made in the RV

Bishop A et al. International Journal of Cardiology 58 (1997) 211–221

6/22/2013 10

Clinical Applications

10 patients with CAD

Bishop A et al. Heart 1997;78:480–487 Bishop A et al. International Journal of Cardiology 58 (1997) 223–228

RCA Occlusion LAD Occlusion 19 patients undergoing angioplasty

Pressure Volume Loops in PAH

No PAH

20 50 80 110 140 170 200 20 40 60 80

RV Pressure (mm Hg)

20 40 60 80 100 20 40 60 80

RV Pressure (mm Hg)

60 90 120 150 180 10 20 30 40

RV Volume (mL) RV Pressure (mm Hg) RV Volume (mL) RV Volume (mL)

IPAH SScPAH

Slope of Blue Line = Effective Arterial Elastance (Ea) = Pes/SV

End-Systolic Pressure Volume Relationship

Slope of Red Line = End-Systolic Elastance (Ees) Ratio of Ees/Ea = measure of RV-PA coupling

100 150 200 250 300 30 60 90 120

RV Volume (mL)

20 40 60 80 100 20 40 60 80

RV Volume (mL)

60 80 100 120 20 40 60

RV Volume (mL)

IPAH SScPAH

20 50 80 110 140 170 20 40 60 80

RV Pressure (mm Hg) RV Volume (mL) RV Pressure (mm Hg) RV Pressure (mm Hg) RV Pressure (mm Hg)

30 60 90 120 150 30 60 90 120 150

RV pressure (mm Hg) RV Volume (mL)

20 40 60 80 100 120 20 40 60 80 100

RV Volume (mL) RV Pressure (mm Hg)

Tedford et al. Circulation: Heart Failure, 2013, in press

PRSW = Slope of the stroke work versus end-diastolic volume relation

Preload Recruitable Stroke Work (PRSW)

IPAH SScPAH

6/22/2013 11

SScPAH vs. IPAH

Tedford et al. Circulation: Heart Failure, 2013, in press

SScPAH vs. IPAH

Tedford et al. Circulation: Heart Failure, 2013, in press

Preload Reduction Techniques

Tedford et al. Circulation:Heart Failure, 2013, in press

Valsalva Effect on Preload

Wang Z et al. PLoS One. 2013;8(1):e53917. Epub 2013 Jan 14.

6/22/2013 12

A non-invasive method?

Brimioulle S et al. Am J Physiol Heart Circ Physiol 284: H1625–H1630, 2003.

A more simplified version?

Trip P et al. J Heart Lung Transplant 2013;32:50–55

IPAH patients with MRI based ESV and RHC derived mPAP: assumes V0=0.

A more simplified version?

Trip P et al. J Heart Lung Transplant 2013;32:50–55

Ees,V0=0 significantly understimated Ees V0 ≠ 0 in the RV in PAH

V0≠0

Tedford et al. Circulation: Heart Failure, 2013, in press

6/22/2013 13

Conclusions

The pulmonary vasculature and the afterload it imposes on the

RV is quite different from the systemic circulation.

The predictable inverse hyperbolic relationship of the

resistance-compliance relationship, and constant RC time, implies the factors that contribute to RV afterload are all dependent on

• ne other (and can be predicted from one another).

Elevations in left sided filling pressures lead to increased RV

load independent of resistance.

Measuring load independent RV function is possible in humans;

these techniques may improve our understanding of the effect

• f PH on the RV as well as allow us to develop better non-

invasive measures of RV afterload and contractility.

Thank you

What measures of RV load are known to predict prognosis in pulmonary arterial hypertension? Prognosis: Hemodynamic predictors in PAH

Transplant free survival – multivariate predictors Cardiac index (HR 0.41, p=0.026) Acute vasoreactivity (HR 0.13, p=0.046)

2Kawut et al. Am J Cardiol 2005;95:199–203. 1D’Alonzo GE et al. Ann Intern Med. 1991 Sep 1;115(5):343-9.

• 1194 patients in NIH PPH registry
• Idiopathic PAH and Heritable PAH only;
• Before PAH specific therapies

6/22/2013 14

Data from REVEAL

Benza RL. Circulation. 2010;122:164-172

Summary of resting hemodynamic predictors

Saggar R et al. Am J Cardiol 2012;110[suppl]:9S–15S.

Compliance in PAH

Mahapatra S. J Am Coll Cardiol 2006;47:799–803)

Compliance (estimated by SV/PP), blood storage capacity of the vessel: “Lumped” parameter that takes into arterial stiffness and wave reflection

Prognosis – PH in HF

Post-treatment assessment

• f PAP

, PCWP , and PVR in 242 patients with ADHF who received a PAC catheter (VMAC trial)

Six-month mortality: Reactive group (48.3%) Passive group (21.8%) No PH group (8.6%). Most observational studies

report an approximate two- fold increase in mortality in patients with pulmonary hypertension and elevated PVR.

Aronson D et al. Circ Heart Fail. 2011;4:644-650. Di Salvo TG. Curr Opin Cardiol 2012, 27:262–272.

6/22/2013 15

In Acute And Chronic PCWP elevation

Tedford RJ et al. Circulation. 2012;125:289-297

High and Low Flow Lungs due to CTE Disease

n=23

Saouti N et al. Am J Physiol Heart Circ Physiol 297: H2154–H2160. 2009.

Implications for PH Treatment

0.0 0.2 0.4 0.6 0.8 1.0 2 4 6 8 10

Treprostinil Sildenafil Derived Curve in PH/SPH cohort

Pulmonary Vascular Resistance (mmHg*S*mL-1) Pulmonary Vascular Compliance (mL*mmHg-1)

Sildenafil in PAH1: Avg pre-tx R = 0.62 (mmHg*s*mL-1) Avg post-tx R = 0.50 (mmHg*sec/mL) Treprostinil in PAH2: Avg pre-tx R = 0.77 (mmHg*sec/mL) Avg post-tx R = 0.71 (mmHg*sec/mL)

1N Engl J Med 2005;353:2148-57; 2AJRCCM 2002; 165: 800-804; 3N Engl J Med. 1996; 334: 296-301.

PVR = 3 Wood Units IV Prostacyclin in PAH3: Avg pre-tx R = 0.96 (mmHg*sec/mL) Avg post-tx R = 0.63 (mmHg*sec/mL) IV Prostacyclin

Does Aging Alter The Relationship?

Tedford RJ et al. Circulation. 2012;125:289-297

6/22/2013 16

Stroke Volume Removed

Tedford RJ et al. Circulation. 2012;125:289-297

Stroke Volume Removed

Tedford RJ et al. Circulation. 2012;125:289-297