Inflammation as a Driver of Progressive Cardiac Deterioration

Inflammation as a Driver of Progressive Cardiac Deterioration Following AMI Stephen E. Epstein, MD Dror Luger, Ph. D Michael J Lipinski MD Med. Star Heart and Vascular Institute Washington Hospital Center

Stephen Epstein, MD I have no relevant financial relationship.

Progressive deterioration in LV function and adverse remodeling post AMI (murine AMI model) LVEF ** LVEDV LVESV Luger, Lipinski, Epstein et al. 2017

Change in LVEDV index from the measurement obtained during the first week post-AMI to 4 months later = Major adverse cardiac events (death, MI, HF) 9% of pts 23% of pts (11/47) (4/43) develop >20% increase in LVEDV From the value measured <1 week post-AMI, by 4 months, 17% of patients experience a >20% increase in LVEDV. Westman, Lipinski, Luger, Waksman, Bonow, Wu, Epstein. JACC 2016

What are the mechanisms responsible for this gradual deterioration in LV function?

Cellular and cytokine response to AMI Westman, Lipinski, Luger, Waksman, Bonow, Wu, Epstein. JACC 2016

Cellular and cytokine response to AMI Hypothesis: The inflammatory responses of some patients are excessive and persistent, leading to progressive inflammation-induced myocardial dysfunction.

Evidence that inflammation plays an important role in the progressive decrease in LV function occurring following AMI…

The Cardiosplenic Axis Injury signal Change in immune/inflammatory cell populations Generation of Immune/inflammatory responses Release of immune/inflammatory cells that then home to the injured tissue

Effects of AMI on NK cells in the spleen and myocardium. NK cells in the Spleen 6 P=0. 045 7 days post AMI P<0. 001 P=0. 048 Splenic NK cells (%) 5 AMI increases NK cells in the spleen and myocardium. 4 3 2 1 0 Naïve Sham MI MI+ MSCs NK cells are major orchestrators of inflammation, having effects on many cellular players involved in inflammation. Luger, Lipinski, Epstein et al. 2017

If inflammation plays a key causal role in the progressive myocardial dysfunction that occurs following AMI, then decreasing NK cells—a key marker of inflammation—should prevent the progressive myocardial dysfunction…

Effects of NK cell depletion (via an anti NK cell antibody) on LV infarct size, LV function, and adverse remodeling B LV Infarct (%) Ejection Fraction (%) A Control Baseline NK Depletion Day 7 Day 20 C D Baseline Day 7 Day 20 Baseline NK cell depletion decreases infarct size and improves both LV function and adverse remodeling. Luger, Lipinski, Epstein et al. 2017

Neutrophils are immediate responders to injury and contribute importantly to adverse myocardial remodeling post MI. 12 Myocardial Neutrophils (%) 10 8 AMI increases myocardial neutrophil content. 6 4 2 0 Naive 24 h 7 days Post AMI Luger, Lipinski, Epstein et al. 2017

• NK cells and neutrophils exert cross-regulatory actions on each other. • We therefore determined whether NK cell reduction reduces myocardial neutrophil content.

Effects of NK cell depletion on neutrophil infiltration of infarcting myocardium Heart Neutrophils (%) 12 P=0. 045 10 8 6 4 NS 2 0 t rc e Pr -i a nf . 1. 1 no K 1 N N titi. An An 24 h . 1. 1 no K 1 N N ti ti. An An 7 Days Post infarction NK cell depletion decreases neutrophils in the heart early post AMI, an effect that likely attenuates the deleterious infects an excessive inflammatory response has on injured myocardium. Luger, Lipinski, Epstein et al. 2017

Pathways by which persistent inflammation causes progressive functional deterioration of the myocardium in patients with AMI or with cardiomyopathy Inflammatory and immune responses reactive fibrosis ROS replacement fibrosis Microvascular Mitochondrial dysfunction Apoptosis Decreased energy microvascular-induced availability ischemia Matrix metalloproteinases Increased interstitial collagen deposition Parenchyma loss Dysfunctional myocardium Progressive myocardial dysfunction Heart Failure

Acute Myocardial Infarction Small Infarct ~ 10 % ~ 25 % Large Infarct ~ 75 % ~ 90 % Appropriate Inflammatory Response Excessive/ Persistent Inflammatory Responses Stable LV Function Adverse LV Remodeling Further Adverse LV Remodeling Heart Failure Appropriate Inflammatory Response Frank-Starling Induced LV Dilatation Stable LV Dilatation

This formulation raises the possibility currently being tested in several clinical trials, that interventions having the potential to exert antiinflammatory effects may improve outcomes in patients with AMI and those with ischemic or with non-ischemic cardiomyopathy.