Disclosures. Afterload on the PV loop. RV Afterload THE PULMONARY VASCULATURE AND ASSESSMENT OF THE RIGHT VENTRICLE

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1 THE PULMONARY VASCULATURE AND ASSESSMENT OF THE RIGHT VENTRICLE Ryan J. Tedford, MD Heart Failure, Mechanical Circulatory Support, and Cardiac Transplantation Division of Cardiology, Department of Medicine Johns Hopkins School of Medicine Disclosures Hemodynamic Core lab for Merck Research Laboratories Heart Failure Core Lab for Women s Health Initiative Heart Failure Study NIH sponsored research June 22 nd, th International Neonatal and Childhood Pulmonary Vasculature Disease Conference, San Francisco, CA RV Afterload Afterload on the PV loop 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 Pressure EJ RV EJ pressure ~ PA EJ pressure in most cases EJ EJ EJ EJ RV Pressure (mmhg) PV closes PV opens Afterload ~ Sum of RV systolic pressure throughout ejection 1

2 What are the components of afterload? Three Element Windkessel Model 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 Am J Physiol Heart Circ Physiol 291: H1731 H1737, 26. Pulmonary Artery Input Impedance Pulmonary Artery 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) 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). Piene H. Physiol Rev Jul;66(3):66-52 Milnor WR et al. Circ Res Sep;19(3):

3 Pulmonary Impedance Spectra Pulmonary Impedance Spectra Z (mean pressure/mean flow) = Total Pulmonary Resistance Characteristic Impedance (Z c ) = ratio of blood mass inertia to proximal vessel compliance; Sum of high frequency impedance (~2-12 Hz) Frequency (Hz) Z 1 = low frequency impedance; Large portion of total blood flow and important fraction of total hydraulic load; large influence by wave reflections Milnor et al. Circ Res Sep;19(3):467-8 First Z min = function of pulse wave velocity and the distance to the major site(s) of wave reflection 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; Z o and Z 1 increase; Z min occurs at higher frequencies Chesler NC et al. Conf Proc IEEE Eng Med Biol Soc. 29 Kussmaul WG et al. J Appl Physiol Jan;74(1): Afterload in the Systemic Circulation Do we have to measure impedance to understand afterload in pulmonary hypertension? Maybe not! Increased Pulse Wave Velocity Enhanced Wave Reflection Large Vessel Compliance (~8%) Aging Stiffening of the aorta Lower Large Vessel Compliance Elevation of Left Ventricular Afterload Small Vessel Compliance (~2%) Vascular Resistance Lower compliance independent of resistance 3

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 PCWP < 15 mmhg Systemic R-C relationship Pulmonary RC time vs. Systemic RC time PCWP < 15 mmhg 4

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 Large Vessel Compliance (~2%) Small Vessel Compliance (>5%) Vascular Resistance Peripheral compliance in the lung: Why might this occur? In the lungs, there are ~8-1 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 1 9 One such arteriole has a compliance of.5 x 1-9 ml/mmhg Total peripheral compliance is 2 ml/mmhg Total pulmonary arterial system has a compliance < 4 ml/mmhg Sauoti et al. 29; 297: H2154-H216. Saouti N et al. Eur Respir Rev 21; 19: 117, How does PH treatment effect? Consequences of the pulmonary RC relationship n=62 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%) Before After High IPAH: PA mean >58mmHg (median) Mod IPAH: PA Mean <58mmHg Lankhaar JW et al. Eur Heart J. 28 Jul;29(13): Sauoti et al. AJRCCM 21 Nov 15;182(1):

6 Back to our Windkessel Model Characteristic Impedance (pulmonary circulation) 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. Am J Physiol Heart Circ Physiol 291: H1731 H1737, 26. Am J Physiol Heart Circ Physiol 291: H1731 H1737, 26. Characteristic Impedance and RV afterload (n) NONPH (1) CTEPH (1) IPAH (9) mpap 18 ±4 45±14 58±14 Does the pulmonary RC relationship ever change? 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, 26. 6

7 Aging Alters the Relationship - Slightly Does Severe Interstitial Fibrosis Alter The Relationship? All DLCO <41% Systemic Sclerosis No! PCWP large affect on Compliance Tedford et al. Circulation: Heart Failure, 213, in press Tedford et al. Circulation. 212;123:

8 Effect of Aging vs. PCWP on Compliance Quantifying PCWP effect AGE Age Age Age PVR=3 WU PCWP If PCWP is used as a continuous variable: [Log Pulm C = (.553 * log Pulm R) - (.122 * PCWP); R 2 =.7, p<.1] At a resistance of 3 Wood unit, compliance is be lowered from 3.34 to 1.65 to.82 ml/mmhg as PCWP increases from to 25 to 5 mmhg respectively Range of 2.52 ml/mmhg or a 75% decline in compliance (Age.49 ml/mmhg or a 19% decline over 7 years) Proportional To PCWP Elevation Implications for PCWP P<.1 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 8

9 Does the PCWP effect translate to clinical outcomes in heart failure? Even in PH, RC is not completely constant 2.5 Pulmonary RC time (seconds) PAC was a stronger predictor of RV dysfunction and all cause mortality or transplantation than PVR PAC bundles the effects of PVR and left-sided filling pressures on RV afterload Mean Pulmonary Artery Pressure (mmhg) Slight overall increase in RC time as mpap rises Dupont M et al. Circ Heart Fail. 212;5: Human RV Pressure Volume Analysis How can we assess RV function independent of afterload? Conductance based volume estimations could be made in the RV Bishop A et al. International Journal of Cardiology 58 (1997)

10 Clinical Applications Pressure Volume Loops in PAH 8 IPAH 8 SScPAH RCA Occlusion RV Pressure (mm Hg) RV Pressure (mm Hg) patients with CAD Bishop A et al. Heart 1997;78: Bishop A et al. International Journal of Cardiology 58 (1997) patients undergoing angioplasty LAD Occlusion RV Pressure (mm Hg) 4 No PAH Slope of Blue Line = Effective Arterial Elastance (Ea) = Pes/SV End-Systolic Pressure Volume Relationship Preload Recruitable Stroke Work (PRSW) RV Pressure (mm Hg) RV Pressure (mm Hg) IPAH RV pressure (mm Hg) Tedford et al. Circulation: Heart Failure, 213, in press Slope of Red Line = End-Systolic Elastance (E es ) Ratio of E es /E a = measure of RV-PA coupling RV Pressure (mm Hg) RV Pressure (mm Hg) SScPAH RV Pressure (mm Hg) IPAH SScPAH PRSW = Slope of the stroke work versus end-diastolic volume relation 1

11 SScPAH vs. IPAH SScPAH vs. IPAH Tedford et al. Circulation: Heart Failure, 213, in press Tedford et al. Circulation: Heart Failure, 213, in press Preload Reduction Techniques Valsalva Effect on Preload Tedford et al. Circulation:Heart Failure, 213, in press Wang Z et al. PLoS One. 213;8(1):e Epub 213 Jan

12 A non-invasive method? A more simplified version? IPAH patients with MRI based ESV and RHC derived mpap: assumes V =. Brimioulle S et al. Am J Physiol Heart Circ Physiol 284: H1625 H163, 23. Trip P et al. J Heart Lung Transplant 213;32:5 55 A more simplified version? V Ees,V = significantly understimated E es V in the RV in PAH Trip P et al. J Heart Lung Transplant 213;32:5 55 Tedford et al. Circulation: Heart Failure, 213, in press 12

13 Conclusions Thank you 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 one 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 of PH on the RV as well as allow us to develop better noninvasive measures of RV afterload and contractility. Prognosis: Hemodynamic predictors in PAH What measures of RV load are known to predict prognosis in pulmonary arterial hypertension? patients in NIH PPH registry Idiopathic PAH and Heritable PAH only; Before PAH specific therapies Transplant free survival multivariate predictors Cardiac index (HR.41, p=.26) Acute vasoreactivity (HR.13, p=.46) 1 D Alonzo GE et al. Ann Intern Med Sep 1;115(5): Kawut et al. Am J Cardiol 25;95:

14 Data from REVEAL Summary of resting hemodynamic predictors Benza RL. Circulation. 21;122: Saggar R et al. Am J Cardiol 212;11[suppl]:9S 15S. Compliance in PAH Prognosis PH in HF Compliance (estimated by SV/PP), blood storage capacity of the vessel: Lumped parameter that takes into arterial stiffness and wave reflection Post-treatment assessment of 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 twofold increase in mortality in patients with pulmonary hypertension and elevated PVR. Mahapatra S. J Am Coll Cardiol 26;47:799 83) Aronson D et al. Circ Heart Fail. 211;4: Di Salvo TG. Curr Opin Cardiol 212, 27:

15 In Acute And Chronic PCWP elevation High and Low Flow Lungs due to CTE Disease n=23 Saouti N et al. Am J Physiol Heart Circ Physiol 297: H2154 H Implications for PH Treatment Does Aging Alter The Relationship? Pulmonary Vascular Compliance (ml*mmhg -1 ) PVR = 3 Wood Units IV Prostacyclin Treprostinil Sildenafil Derived Curve in PH/SPH cohort Pulmonary Vascular Resistance (mmhg*s*ml -1 ) Sildenafil in PAH 1 : Avg pre-tx R =.62 (mmhg*s*ml -1 ) Avg post-tx R =.5 (mmhg*sec/ml) Treprostinil in PAH 2 : Avg pre-tx R =.77 (mmhg*sec/ml) Avg post-tx R =.71 (mmhg*sec/ml) IV Prostacyclin in PAH 3 : Avg pre-tx R =.96 (mmhg*sec/ml) Avg post-tx R =.63 (mmhg*sec/ml) 1 N Engl J Med 25;353: ; 2 AJRCCM 22; 165: 8-84; 3 N Engl J Med. 1996; 334:

16 Stroke Volume Removed Stroke Volume Removed 16