INVASIVE MEASUREMENT:THE NEW GOLD STANDARD FOR DIAGNOSIS OF HFpEF?Susanna Mak MD, PhDDirector, Anna Prosserman Heart Function Clinic Harold & Esther Mecklinger and The Posluns Families Cardiac Catheterization Clinical Research LaboratorySinai Health System, University of TorontoMay 11, 2019

INVASIVE MEASUREMENT:THE NEW GOLD STANDARD FOR DIAGNOSIS OF HFpEF?Susanna Mak MD, PhDDirector, Anna Prosserman Heart Function Clinic Harold & Esther Mecklinger and The Posluns Families Cardiac Catheterization Clinical Research LaboratorySinai Health System, University of TorontoMay 11, 2019 Disclosures and Funding•No off-label use of pharmaceuticals will be discussed•Speakers honoraria previously received from Actelion, Johnson & Johnson, Bayer •In-Kind contributions to research from Thornill Research Institute, Ergoline•Relevant research funding obtained from the Ontario Research Fund, HSFC, PMCC Innovation Fund•Philanthropic contributions from the Daniels Family, The Mecklinger Family, The Posluns Family 2 Discuss the current diagnostic algorithms for the diagnosis of HFpEFUnderstand the rationale and methodology for invasive exercise stress testing for the diagnosis of HFpEFDiscuss the role of invasive exercise testing in the context of other stimuli or non-invasive testing Objectives Current Diagnostic Algorithms for HFpEF 4 Current Definitions for the Diagnosis of HFpEF Evidence of HF syndrome “Preserved” Ejection Fraction HFpEF 5 CCS (2017)HFpEF > 50%HFmEF 41-49%“recovered EF” > 40%ESC (2016)HFpEF > 50%HFmrEF 41-49%AHA/ACC (2013)HFpEF >50%HFpEF borderline 41-49%Improved > 40% SIGNS + SYMPTOMSBNPECHOCARDIOGRAPHY Canadian Journal of Cardiology, Volume 33, Issue 11, November 2017 Pager 1342-13European Heart Journal, Volume 37, Issue 27, 14 July 2016, Pages 2129–2200, https://doi.org/10.1093/eurheartj/ehw128Circulation, Volume 128, Issue 16, October 2013 Figure1 Canadian Journal of Cardiology2017 33, 1342-1433DOI: (10.1016/j.cjca.2017.08.022) Copyright © 2017 Canadian Cardiovascular SocietyTerms and Conditions Symptoms and Signs of Heart Failure Additional Diagnostics Relevant to HFpEFEvaluation of IschemiaStress testing, cathEvaluation for infiltrationMRI, iron studies/light chains, biopsy?CPETNatriuretic PeptidesEchocardiography European Heart Journal, Volume 37, Issue 27, 14 July 2016, Pages 2129–2200, https://doi.org/10.1093/eurheartj/ehw128The content of this slide may be subject to copyright: please see the slide notes for details. Figure4.1 Diagnostic algorithm for a diagnosis of heart failure of non-acute onset Symptoms and Signs of Heart Failure EchocardiographyNatriuretic Peptides Rationale for additional criteria to demonstrate HF pathophysiology in HFpEFType of HFHFrEFHFmrEFHFpEF CRITERIA 1Symptoms and Signs*Symptoms and Signs*Symptoms and Signs*2LVEF < 40%LVEF 40-49%LVEF >50% 31.Elevated levels of natriuretic peptides2.At least 1 additional criteriona.Relevant structural heart disease (LVH and/or LAE)b.Diastolic dysfunction 1.Elevated levels of natriuretic peptides2.At least 1 additional criteriona.Relevant structural heart disease (LVH and/or LAE)b.Diastolic dysfunction 8 * Signs may not be present in the early stages of HF (especially in HFpEF) and in patients treated with diureticsEuropean Heart Journal, Volume 37, Issue 27, 14 July 2016, Pages 2129–2200, https://doi.org/10.1093/eurheartj/ehw128, Table 3.1The content of this slide may be subject to copyright: please see the slide notes for details. In the absence of a validated gold standard for HFpEF, there is a continuum of confidence for the diagnosisUNCERTAIN•73y F HTN, “mild asthma”•Hx of dyspnea on exertion (NYHA 2-3), bending over•BNP 50•Echo: LVEF 60%, RVSP 40 mmHg, normal LV mass, E:e’ 8•?Deconditioning•?COPD•?Early HFpEF LESS CERTAIN•78y F HTN, angina•Hx of dyspnea on exertion (NYHA 2-3), treatment includes lasix•BNP 130•Echo: LVEF 55%, mild LAE, RVSP 47 mmHg, E:e’ 13•?HFpEF•?PAH CERTAIN•84y F HTN, DM, AFib•Hospital admission, pulmonary edema, eGFR 40, requiring diuretics•BNP 500•Echo: LVEF 72%, LVH, LAE, mod MR•Rx CHFpEF AHA stage CAHA stage D Supporting evidence of relevant structural heart disease or diastolic dysfunction: Echocardiography•Left atrial volume index >34ml/m2•Left ventricular mass index >115 g/m2, >95 g/m2•E/e’ >13, mean e’ septal and lateral <9 cm/s•TR jet velocity •Upwards of 80% HFpEF exhibit PH•Overlap: PAH versus PH-LHD 10European Heart Journal, Volume 37, Issue 27, 14 July 2016, Pages 2129–2200, https://doi.org/10.1093/eurheartj/ehw128, Table 3.1The content of this slide may be subject to copyright: please see the slide notes for details. Supporting evidence of abnormal cardiac chamber physiology: Role of Cardiac Catheterization•“In cases of uncertainty, a stress test or invasively measured elevated LV filling pressure may be needed to confirm the diagnosis” •ESC HF Guidelines •“Right heart catheterization (RHC) is required to make the diagnosis of PAH” (and differentiate from PH-LHD)•ESC PH Guidelines 11 Updated Hemodynamic Definitions for PH-LHDHemodynamic classificationDefinitionUpdatesClinical Group(s)PHmPAP>25 mmHgmPAP > 20 mmHgAllPre-capillary PHmPAP >25 mmHgPAWP < 15 mmHgmPAP > 20 mmHgPAWP < 15Group 1,3-5Post capillary PH Isolated post-capillary PHCombined post-capillary and pre-capillaryPH mPAP>25 mmHgPAWP >15 mmHgLVEDP > 15 mmHgDPG < 7 mmHg and/or PVR <3WUDPG >7 mmHg and/or PVR > 3 WU mPAP > 20mmHgPAWP >15 mmHgLVEDP > 15mmHgPVR <3WU PVR > 3 WU Group 2 PH-LHD Galie et al, Guidelines for diagnosis and treatment of pulmonary hypertension, Eur Heart J 2016 January 1;37(1):67-119, Eur Resp J 2019 Methodology and Interpretation of Invasive Hemodynamic Assessment 13 “Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction” Borlaug, Circulation HF2010:3:588 •Dyspnea of unknown origin•Normal BNP and echo•Subgroup with “exaggerated” PAWP response to even slight exercise•Hypothesized to reflect diastolic impairment as a cause of dyspnea 5thWorld PH Symposium 2013: Significant Knowledge Gaps Preclude Recommendation of Exercise Hemodynamics•Exercise hemodynamics likelyto be useful, however exercise criteria cannot be reintroduced at the present time•Prognostic and therapeutic implications of exercise-induced hemodynamic responses unclear•Refinement of exercise stress protocol (position, type, intensity) required•Age adjusted “normal” values or reference ranges in health are unknown Improving Standardization of Exercise Hemodynamic Testing Maron BA et al, Circulation. 2013;127:1157-1164Wright et al, Heart 2016; 102:438-443 Design of the Exercise Challenge: Necessary Elements •Cycle Ergometry Preferred•Upright positioning•Supported body weight•Measurable workloads•Maximal or submaximal protocols•Disadvantages –submaximal efficiency•+/-metabolic testing •Ensure 2-3 minute warmup to avoid sampling early after initiation or escalation of workrate Wright et al, Heart 2016; 102:438-443 Hemodynamic Interpretation in Exercising Older Adults PAWP > 25 mmHg considered as ULN in adults > 40years PAWP 25 mmHgPAWP 25 mmHg Wright et al, Heart 2016Wolsk et al, JACC HF 2017 Additional Criteria: Increase in PAWP adjusted for the Increase in CO < 2mmHg/L/min Reflects early ↑in PAWP vs moderate ↑ in CO within initial exercise stageAs exercise duration and intensity ↑, PAWP ↔ or ↓ with further↑ in CO Esfandiari et al, Med Sci Sports Ex 2017 Towards Increasing Acceptance“In patients presenting exercise intolerance, in which noninvasive and resting invasive measurements are inconclusive, provocative testing in the cardiac catheterization laboratory should be considered to determine the presence of a cardiac etiology. Cycle ergometry exercise is the most physiologically relevant and sensitive stressor and is preferred over other maneuvers such as saline loading or arm exercise” Sorajja, P., Borlaug, B. A., Dimas, V. V., Fang, J. C., Forfia, P. R., Givertz, M. M., Kapur, N. K., Kern, M. J. and Naidu, S. S. (2017), SCAI/HFSA clinical expert consensus document on the use of invasive hemodynamics for the diagnosis and management of cardiovascular disease. Cathet. Cardiovasc. Intervent., 89: E233–E247 The Society of Cardiovascular Angiography and InterventionsHeart Failure Society of America Clinical Utility in HFpEF and Alternatives Exercise versus Saline Challenge•Exercise is a classic physiologic stressor that reproduces symptoms and the patient experience•More potent hemodynamic stress compared with saline 22 Andersen et al, Circ Heart Fail 2015;8:41-48 HFpEFControl SalineExercise Non-Invasive Diagnostic Modalities In Situations of Uncertain HFpEF•Diastolic Stress Echocardiography•Limitations of measuring E:e’ during exercise•Limitations of assessment of TR jet velocity•Studies directly comparing invasive and non-invasive diastolic stress testing limited•Cardiopulmonary Exercise Testing (CPET)•Useful screen for exercise intolerance related to cardiac and pulmonary vascular limitation•+ RHC, invasive CPET23 Invasive Hemodynamic Exercise Testing: A New Therapeutic Target for HFpEF Feldman et al, Circulation 2018;137:364-375 Inclusion CriteriaExercise PAWP > 25mmHgPAWP:RA difference > 5mmHgPrimary endpointExercise PAWP Clinical Trials for HFpEF Rx using Exercise Hemodynamic Entry Criteria are Currently Enrolling Patients 25 AgentStudy DesignSponsorAZD4831Phase 2 RCTAstra ZenecaMetforminPhase 2 CrossoverNIHMyeloperoxidase inhibitorPhase 1 RCTMayo ClinicSaccubitril-ValasartanOpen label follow upMayo Clinic, NIHDapagliflozinRCTSt. Luke’s Health SystemOral NitrateParallel designNIHPotassium NitrateRCTUniversity of Pennsylvania/NorthwesternClinicaltrials.gov search terms HFpEF, intervention, actively recruiting, accessed March 14, 2019 Reddy et al, A simple, evidence-based Approach to Help Guide Diagnosis of Heart Failure With Preserved Ejection Fraction. Circulation 2018;138:861-870Clinical VariablesValues PointsH2HeavyBody mass index > 30 kg/m22Hypertensive2 or more antihypertensive medications1FAtrial FibrillationParoxysmal or Persistent3PPulmonary HypertensionDoppler Echocardiographic estimated Pulmonary Artery Systolic Pressure > 35 mmHg 1EElderAge > 60 years1FFilling PressureDoppler Echocardiographic E/e’ > 91H2FPEF scoreSum (0-9)26