Long-Term Management: Preventing Progression. Daniel Burkhoff Cardiovascular Research Foundation and Columbia University

Transcription

1 Long-Term Management: Preventing Progression Daniel Burkhoff Cardiovascular Research Foundation and Columbia University

2 Disclosure Unrestricted institutional (CRF) educational grant from Abiomed

3 Left Ventricular Pressure Heart Failure Progression Summarized by PV Analysis: LV Remodeling Explained Acute NH Activation Chronic NH Activation, Inflammation Remodeling Normal CHF Left Ventricular Volume

4 Degree of Remodeling Relates to Size of Infarct (3 months follow-up) Pfeffer JM, Pfeffer MA, Braunwald E: Circ Res 1985;57:84

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6 INFARCT SIZE LV REMODELING HEART FAILURE

7 Vicious Cycle of HFrEF Remodeling Apoptosis Remodeling Hypertrophy Hypertrophy Dilation / MR Dilation / MR Dyssynchrony Dyssynchrony Arrhythmias (+) Maladaptive Myocyte Loss And Weakness Afterload Preload HR Contractility LV Pump Function Adaptive Sympathetic Activation NE Epi DA (-) CO BP Renal Hypoperfusion Renin AngII Aldo Na/H 2 O Retention Cytokines Compensatory Mechanisms (Adaptive / Maladaptive) Stress ANP BNP

8 Preventing/minimizing heart failure and subsequent disease progression: It all comes down to limiting infarct size Better to prevent/minimize remodeling than to try to reverse it

9 Timilol

10 BHAT Study Propranolol

11 Brivet et al

12 Pharmacologic Unloading Attenuates Remodeling Sham Captopril Control Captorpil Reduces Preload (EDP) Pfeffer JM, Pfeffer MA, Braunwald E: Circ Res 1985;57:84

13 The Larger the Infarct, the Less the Prevention of Remodeling Pfeffer JM, Pfeffer MA, Braunwald E: Circ Res 1985;57:84

14 SAVE Pfeffer et al, NEJM 1992

15 Current Guidelines for STEMI Include: B-blockers + ACEi/ARB unless heart failure, hypotension, etc 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction JACC 2013

16 Improved regional myocardial blood flow, left ventricular unloading and infarct salvage using an axial-flow, transvalvular left ventricular assist device: A comparison with intra-aortic balloon counterpulsation and reperfusion alone in a canine infarction model Smalling et al Circulation1992;85: *LV assistance was maintained during the entire period of occlusion and reperfusion

17 Why is unloading so important? Left ventricular unloading by cathetermounted axial flow pump reduces infarct size Meyns et al, JACC 2003;41: Area at risk (AAR) % AAR Infarcted Control (reperfusion alone) Unloading During Isch & Reperfusion Unloading during Reperfusion Partial Unloading during Reperfusion

18 Necroptosis, Apoptosis and Autophagy Play Role in Peri- and Post-infarct Remodeling

19 Mechanical Pre-Conditioning With Acute Circulatory Support Before Reperfusion Limits Infarct Size in Acute Myocardial Infarction Kapur et al. J Am Coll Cardiol HF 2015;3:873 82

20 LV Unloading before reperfusion promotes functional recovery after AMI Esposito, Kapur, et al. JACC 2018

21 Acute Mechanisms and Factors that lead to Remodeling Loss of Myocytes Necroptosis Apoptosis Autophagy Inflammation Collagen breakdown Physical Forces that stretch the infarct zone Increased diastolic wall stress End-diastolic pressure All of these factors and mechanisms are activated at the time of AMI; remodeling begins essentially immediately

22 Preventing/minimizing heart failure and subsequent disease progression: It all comes down to limiting infarct size Better to prevent/minimize remodeling than to try to reverse it

23 AHA/ACC/HFSA Guidelines are all Geared to Preventing Progression

24 LV Reverse Remodeling Therapy Comparisons* Enalapril Carvedilol CRT CONSESUS et al Konstam et al. 1 year Doughty et al Packer et al 1 Year Abraham et al 6 months MV Repair MV Replace Acker et al. N Eng J Med year MITRA-FR 1 year MitraClip COAPT 2 year Δ EF% ? Δ ESV (ml) ml (EDV) Mortality (% risk reductio n) 31% 65% 10% Not Evaluated Not Evaluated No Effect ~40% Death or HF Hosp 50% 27% 18% Not Evaluated Not Evaluated No Effect ~50% *Medical therapies turn back the clock, but remodeling progresses

25 Summary Remodeling starts immediately with AMI The larger the infarct the more the subsequent remodeling Remodeling can be reduced by pharmacologic (bblockers, ACEi/ARBs) and by mechanical unloading The relevant pharmacologic therapies are not applicable in CS Molecular mechanisms underlying necroptosis, apoptosis and autophagy being clarified Molecular impact of mechanical unloading starting to be understood Once remodeling is present, reversal is difficult and disease progression is inevitable Minimizing infarct size is the key to preventing heart failure and minimizing disease progression

26 Impella ASAP RHC to guide therapy

27 Door-to-Unload Study Door To Unload: Kapur, O Neill, STEMI DTU Safety Investigators & Feasibility Trial Anterior STEMI Referred for Primary PCI (WITHOUT SHOCK) ENROLLMENT INCLUSION CRITERIA COMPLETED Age years First Myocardial Infarction May 2018 Acute STEMI (anterior ST elevation 2 mm in 2 contiguous or 4 mm ST-sum) Within 1 to 6 hours of symptom onset LV Unloading, Then Immediate PCI Reperfusion (U-IR Group) Informed Consent Enrollment and Randomization LBCT Presentation at Impella CP Insertion + Activation AHA Scientific Sessions LV Unloading for 30 minutes, Then Delayed Reperfusion (U-DR Group) November Chicago Explant Impella CP after a minimum of 3 hours support