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