Claudio Borghi, FESC, FAHA Dipartimento di Scienze Mediche e Chirurgiche

Università di Bologna

Quando tutto è in fiamme

The burning environment

Proportion of all deaths due to major causes in Europe

Nichols M et al. Eur Heart J 2014;35:2950-2959

…..a safe pathogenetic harbour

An inflammatory approach…......

The “elementary” CV inflammatory cascade

Pro-inflammatory triggers

Acute/chronic inflammation

Oxidative

stress Cytokines

production

Proteolytic matrix

degradation

Auto-immunity

CV injury, Fibrosis

Dysfunction

Heart Failure

Theroretical pathway of inflammatory-immune

activation in HF

Anker S & von Haehling S. Heart 2004

The net effect of the cytokine network in HF: balance between pro-inflammatory and anti-inflammatory mediators

Gullestad L et AL., Am J Cardiol 2005;95(suppl):17C–23C

Inflammatory

TNF-α

Fas/FasL

IL-β

IL-1, IL-6

IL-18, IL-33

Cardiotrophin-1

Chemochines

Anti-Inflammatory

IL-10

TNF-β

sTNFRs

IL-1α

IL-1β

IL-4

IL-13

Additional Inflammation mediators in HF

• Cytokines receptors

• sTNFR1, sTNFR2 (TNF)

• Transmembrane glicoprotein 130 (IL-6)

• Soluble ST2 receptors IL-33 (sT2)

• Adesion molecules

• Inducible (macrophage-derived) Nitric Oxide

• Galectin-3 (+/-)

• Pentraxin-3 (++)

The NLRP3 intracellular inflammasome

NLRP3 inflammasome is composed of 3 proteins: NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and proecaspase-

1. NRLP3 has 3 domains: leucine-rich repeats (LRRs), NACHT domain, and N-terminal pyrin domain (PYD). The adaptor protein ASC pairs with NLRP3 via PYD

domains and with proecaspase-1 via CARD (caspase activation and recruitment domain). Danger-associated molecular pattern (DAMP) activation via LRR triggers

transcription of NLRP3 and proeinterleukin (IL)-1b. The fully assembled NRLP3 inflammasome activates caspase-1, leading to the activation and release of IL-1b and

IL-18.

Butts B et Al., J Cardiac Fail 2015;21:586e593

Won Suk Jahng J et Al., Experimental & Molecular

Medicine 2016;48,e217

Elevated circulanting levels of TNF in severe chronic

CHF and the relationship with PRA

Levine B et Al., NEJM 1990:323:236-241

The marked and consequential role of monocyte/macrophage type

and function along the continuum to HF

Glezeva N et Al., Journal of Molecular and Cellular Cardiology 2015;89:136–145

Inflammation and CHF

“Burning” questions

• Is inflammation associated with HF?

Deleterious Effects of Inflammatory Mediators in HF

Modified from Kapadia S, et Al. The role of cytokines in the failing human heart.

In: Crawford M, ed. Cardiology Clinics. Philadelphia, Pa: WB Saunders; 1998:645– 656, by permission

Left ventricular dysfunction

Pulmonary edema in humans

Cardiomyopathy in humans

Reduced skeletal muscle blood flow

Endothelial dysfunction

Anorexia and cachexia

Receptor uncoupling from adenylate cyclase

experimentally

Activation of the fetal gene program experimentally

Cardiac myocyte apoptosis experimentally

TNF-α levels in patients with NYHA class I to IV

Seta Y et al, 1996

HF Rates According to the Number of Elevated Inflammatory Markers at Baseline.

The Health ABC (Health, Aging, and Body Composition) Study

Kalogeropoulos A et Al., JACC 2010;55(19):2129–37

Inflammatory biomarkers and incident HF. Individual and pooled effect

Kalogeropoulos A et Al., JACC 2010;55(19):2129–37

Inflammatory biomarkers and incident HF with

death as a competing risk

Kalogeropoulos A et Al., JACC 2010;55(19):2129–37

Summary of study of the effect of CRP genotype combination on

risk of ischemic cerebrovascular disease

Zacho J et Al., NEJM 2008;359(18):1897-1908

Odds ratios of significant associations between inflammatory mediators with the primary

outcome measure (freedom from 1) HF hospitalization or 2) death and a 3) decrease in

echocardiographic End SV of >15% at 12 m) on univariate and/or multivariate analysis

(pts with advanced HF receiving cardiac resynchronization therapy)

Belperio J et Al., Am J Cardiol 2016;117:617-

625

Co-morbidities, inflammation and myocardial dysfunction

in HEpEF

Paulus WJ et Al., JACC 2013;62(4):263–71

Myocardial Dysfunction and Remodeling in HFPEF, HFREF,

and Advanced HFREF

Paulus WJ et Al., JACC 2013;62(4):263–71

Inflammation and CHF

“Burning” questions

• Is inflammation associated with HF?

• Is inflammation directly related to HF/CVD?

IL-6 levels and CHD risk

(Danesh et Al, Plos Medicine 2008)

Inflammation and CHF

“Burning” questions

• Is inflammation associated with HF?

• Is inflammation directly related to HF/CVD?

• Is inflammation affecting the outcome of HF?

Levels of cytokines and survival in HF in the VEST study

Deswal A et al, Circulation 2011

Relationships between the production of monocyte TNF-α and IL-6,

serum levels of lipids and cardiac events in CHF patients

Nakagomi A et Al., Intern Med 2014;53: 2415-2424

LVEF, IL-10/TNFα ratio and CV mortality

over 10 years in patients with CAD

Patients with a low LV-EF as well as patients with a low IL-10/TNFα ratio showed an increased CV mortality over 10 years (both p<0.05).

The IL-10/TNFα ratio is decreased in patients with low EF and poor prognosis. The reduced heart function correlates with an increased

proinflammatory state (low monocytic IL-10/TNFα ratio) in patients with CAD. This observed imbalance of IL-10 and TNFα in monocytes might

explain pathophysiological processes in atherosclerosis and HF.

Dopheide JF et Al., Inflammation 2015;38(2):911-922

Association between inflammatory cytotoxic CD4+CD28null

cell and all-cause and CV mortality in CHF patients

Koller L et Al., Atherosclerosis 2013;30:414-416

Association between baseline concentrations of pentraxin-3

(PTX3) and mortality in the CORONA and GISSI-HF trials

Latini R et Al., European Journal of Heart Failure 2012;14,:92–999

All-cause mortality CV mortality

The association between baseline PTX3 concentration and all-cause mortality or CV mortality in the pooled population

was assessed by regression splines. The solid lines indicate estimated hazard ratios (with 95% confidence intervals as

dashed lines) and the vertical lines indicate the tertile cut-off points

Kaplan-Meier analysis for the probability of CV and PTX3 levels (A), PTX3 levels

plus BNP (B), and subgroups of NYHA class II patients (C) in HFNEF

Matsubara J et Al., J Am Heart Assoc

2014;3:e000928

All

NYHA-II

PTX-3+BNP

Baseline detectable IL-13 and hospitalized HF survival (pts with advanced HF receiving cardiac resynchronization therapy)

Belperio J et Al., Am J Cardiol

2016;117:617-625

Inflammation and CHF

“Burning” questions

• Is inflammation associated with HF?

• Is inflammation directly related to HF/CVD?

• Is inflammation affecting the outcome of HF?

• Is anti-inflammatory approach beneficial in HF?

RCT of TNF-α inhibitors

• Etanercept (TNFR-2 fusion protein)

• RENEWAL Program (2048 pts) • RENAISSANCE (US)

• RECOVER (Europe)

• Infliximab (chimeric antibody TNF-α)

• ATTACH (150 pts)

(Dixon et Al, Arthritis & Rheum 2007)

(Atherosclerosis 2011)

Effects of IL-1 blockade with anakinra on exercise

parameters and CRP plasma levels in CHF patients

Van Tassell B W et Al., Am J Cardiol 2014;113:321e327

Initial clinical experience with anakinra: completed clinical trials

Van Tassell BW et Al., Curr Heart Fail Rep 2015;12:33–41

Ongoing clinical trials of anakinra in HF

Van Tassell BW et Al., Curr Heart Fail Rep 2015;12:33–41

Antinflammatory approach to HF

Therapeutic targets

• Cytokines

• Pentraxins (PTX3)

• TNF-α and receptors

• Immunomodulation strategies

• Immunoglobulin or Interferon

• Immunoabsorption (autoantibodies)

• Antioxidant compounds

• PI3Kγ-inhibitors

• Matrix metalloproteinase modulation

• Mannose-binding lectins

Circ Res, 2009