3/12/2019 Conflict of Interest Disclosure Enhanced Assessment of - PDF document

3/12/2019 Conflict of Interest Disclosure Enhanced Assessment of Right Ventricular Function in Preterm Infants with Chronic Pulmonary Hypertension Philip T. Levy Philip T. Levy MD • I have no financial relationships with a Assistant Professor of Pediatrics commercial entity producing healthcare- Harvard Medical School Division of Newborn Medicine related products and/or services. Boston Children’s Hospital March 7 th , 2019 12 th International Conference Neonatal & Childhood Pulmonary Vascular Disease What are we actually looking at… Learning objectives Adult Adult Term Premature I. Explore the (patho) physiologic relationship between the RV and its Female Heart Male Heart Heart Heart load in chronic PH (e.g. morphology, afterload, contractility) II. Identify emerging non-invasive quantitative indices of RV mechanics in preterm infants with chronic PH. III. Review the neonatal literature that utilizes these measures to screen, diagnosis, & test the efficacy of management strategies. IV. Future initiatives (Composite score, coupling, 3D echocardiography) 250 grams 290 grams 20 grams 4 -15 grams 1

3/12/2019 Cellular homeostasis Cellular homeostasis The value of the right heart Right heart/lung interactions “It is not the size of the man, but the size of his right SVR BP Determinants of function heart that matters… ” - Circulatory System Preload Afterload amount of blood the resistance against RV performance Cardiac output present in the ventricle which the ventricle Lymphatics Cardiovascular at end diastole. muscle must contract - Evander Holyfield (1996) CO = SV x HR CO = SV x HR Sats Hgb Work Length-tension Force-velocity Stroke relationship relationship volume Blood O 2 Blood O 2 Heart Vasculature Blood (pump) (transport network) (transport vehicle) delivery consumption Contractility “ Great beauty, great strength, and great riches are really the intrinsic ability of the myocardium to contract Right Right Left Arteries, veins, capillaries Pulmonary vasculature Target organ and truly of no great use; a RIGHT HEART exceeds all…” (Target organ flow) Force-frequency relationship  Embryology C o u p l Morphology e d Pulmonic Pulmonic Systemic  Morphology Heart - Benjamin Franklin (1776 ) Cellular  Genetic rate  Performance Metabolism Courtesy of McNamara and El-Khuffash RV-PA axis formation Hemodynamic profile of the right ventricle and its load in chronic PH Coupling mechanisms Coupled Coupling Maintained Uncoupling Stage 1 Stage 2 Stage 3 Coupling = Δ Energy = Work RV-PA axis RV Contractility RV Afterload Uncoupling RV Afterload (PVR, PAP, compliance) RV failure RV Performance RV Contractility Right RV-PA (Contractility) = Ventricle Coupling RV Afterload RV Morphology (Volume/thickness) Adapted from. J Am Coll Cardiol 2017;69:236–43 2

3/12/2019 RV performance and PH RV afterload Right heart/lung interactions External factors that oppose contraction 1. Opposition by the pulmonary valve (RV outflow tract) Low RV Impaired RV High RV preload contractility afterload 2. Load imposed by the pulmonary vasculature tree 3. Blood (pressure and viscosity) RV dysfunction Right ventricle Pulmonary valve Optimize RV preload Augment RV function Reduce RV afterload Jain et al. Seminars in Fetal & Neonatal Medicine 2015 RV afterload RV afterload 3 element Windkessel model Constant ( τ ) = Resistance x Compliance Early PVD Established PH a. Resistance (R) Static ( 75%) ce 15 • Mild increase in PVR/PAP • Significantly increased PVR/PAP n • Proximal artery and distal arteries/arterioles (% total afterload) ita • Normal RV performance • Abnormal RV performance • Large decrease in • Compliance depleted, small • PVR = (mPAP – PCWP) / CO c a compliance decrease p a • Clinically silent • Symptomatic l c 10 b. Compliance (C) ) Pulsatile (25 %) g ria H m / m • Storage capacity of vasculature (elasticity) rte L (m  Pulsatile • Entire system (small arteries > large) a ry 5  Static • PAC = Stroke volume / pulse pressure a  Pulsatile n o lm  Static 1% c. Characteristic impedance (Z) u P 0 • Proximal artery 0 2 4 6 8 10 Pulmonary vascular resistance • Z = blood mass / compliance (woods units - mmHg - S/mL) Eur Heart J 2008;29:1688 –95. Am J Physiol. 1999;277:H725-31 3

3/12/2019 RV afterload RV contractility Constant ( τ ) = Resistance x Compliance Myocardial muscle fiber orientation N = 125 children Right Left ce 15 n (n=36 with PH, mPAP > 20, PVRi > 3) ita c Early PVD a p a l c 10 ) g ria H m / m τ = R x C rte L (m a ry 5 Established PH a n o lm u P 0 0 2 4 6 8 10 Superficial Superficial Pulmonary vascular resistance Layer 3 Layer 2 Layer 1 B Layer 1 A oblique oblique (woods units - mmHg - S/mL) Longitudinal Circumferential (subendocardium) (subepicardium) Courtesy of N. Silverman, Stanford Levy & Patel et al. J Am Soc Echocardiogr 2016;29:1056-65. RV contractility RV contractility Myocardial muscle fiber orientation Peristaltic contraction patterns Dominant pattern Fiber orientation Right Ventricle Left Ventricle 1. Contraction of longitudinal (% of wall thickness) fibers pull the tricuspid valve towards apex. Base Layer 1 Superficial oblique (25%) Superficial oblique (20%) 2. Inward movement of the RV free wall . Layer 2 Middle longitudinal (20%) Deep longitudinal (80%) RV Layer 3 Deep circumferential (60%) 3. Traction of RV free wall from connection to LV free Apex wall at the Apex . Dominant layer longitudinal circumferential Courtesy of Professor RH Anderson 4

3/12/2019 Validation of quantitative measures Echocardiographic evaluation of RV mechanics 3- step approach SVR BP I. Reliability testing Determinants of function Simultaneous cath & Echo Preload Afterload amount of blood the resistance against • Feasibility RV performance present in the ventricle which the ventricle at end diastole. muscle must contract CO = SV x HR Sats Hgb Work • Reproducibility (compare to gold standard) 1. RV Areas 1. Pressure-dependent 1. Pressure-dependent 1. RV contractility 1. RV contractility 1. RV Areas 1. IVC (?) Length-tension Force-velocity Stroke relationship • TR velocity jet • TR velocity jet relationship • dp/dt • dp/dt • Systolic • Systolic volume Blood O 2 Blood O 2 II. Mechanistic approach 2. Volumes (?) Clinical and Preclinical studies • Septal wall motion • Septal wall motion • Strain rate • Strain rate • Diastolic • Diastolic delivery consumption Contractility • RA / RV morphology • RA / RV morphology • 4-ch / 3-ch • 4-ch / 3-ch 2. RV systolic function 2. RV systolic function the intrinsic ability of the • Tell a story ? (react to changes in management) myocardium to contract • LV eccentricity index • LV eccentricity index • FAC / MPI / Strain • FAC / MPI / Strain Pulmonary vasculature • Maturational changes / Reference values • Shunts / directions • Shunts / directions • TAPSE / Strain • TAPSE / Strain (Target organ flow) 2. Dimensions 2. Dimensions Force-frequency relationship • RV inflow 3. RV diastolic function 3. RV diastolic function • RV inflow III. Therapeutic Models 2. PA acceleration time 2. PA acceleration time • RV outflow • RV outflow Clinical disease modeling • Tissue Doppler velocities • Tissue Doppler velocities Heart rate Morphology RV-PV • Strain rate • Strain rate • PAAT / RVET • PAAT / RVET • Efficacy a patient management strategies Metabolism Courtesy of McNamara • Make a clinical difference and El-Khuffash RV afterload : PA acceleration time RV afterload Constant ( τ ) = Resistance x Compliance RV systolic time intervals Afterload (PVR, PAP) a. Resistance (R) Static ( 75%) Normal PH Compliance • Proximal artery and distal arteries/arterioles (% total afterload) • PVR = (mPAP – PCWP) / CO b. Compliance (C) Pulsatile (25 %) RVET RVET • Storage capacity of vasculature (elasticity) • Entire system (small arteries > large) • PAC = Stroke volume / pulse pressure 1% c. Characteristic impedance (Z) • Proximal artery • Z = blood mass / compliance PAAT PAAT PAAT = 120 msec PAAT = 74 msec RVET = 250 msec RVET = 280 msec Am J Physiol. 1999;277:H725-31 PAAT:RVET = 0.48 PAAT:RVET = 0.26 5

3/12/2019 RV afterload RV afterload Preterm infants with chronic PH Preterm infants with chronic PH For detection of chronic PH: • PAAT < 47 msec • PAAT:RVET < 0.28 At 32 weeks PMA resulted in a sensitivity of 89% and a specificity of 93% with a combined AUC of 0.9306 (CI 0.89-0.97) Patel et al. JASE 2019 (In review) Clinical significance RV afterload Novel insights: PVD at 1 year corrected age Eccentricity index * P < 0.01 120 120 PA acceleration time * P < 0.01 RV afterload 100 100 80 80 60 60 40 40 Preterm, + cPH Preterm, No cPH Term, Healthy N= 12 n= 68 n=100 RV, right ventricle LV, left ventricle IVS, interventricular septum J Pediatr 2018; 197:48-56.e2 www.tnecho.com (Images) Animations, Malcom and Evans 24 6