Il rischio cardiovascolare. Claudio Borghi Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna

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1 Il rischio cardiovascolare Claudio Borghi Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna

2 Age-adjusted death rates for diseases of the heart, cerebrovascular disease, and chronic lower respiratory disease by year. USA to 2010 Lackland D et Al., Stroke 2013;45:

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5 Complessità del rapporto NAFLD/NASH e malattie CV NAFLD, NASH MS si/no, DM si/no Tipo di studio (Retr,Prosp,CS,Pop) Outcome (MCV, Mort- CV, CHD, LVH, IMT..) Smple size Modalità valutazione epatopatia (US,Biops,Lab.Index)

6 Principal studies of the association between NAFLD and the incidence of major CV events Luo J et Al., Eur J Gastroenterology & Hepatology 2015, 27:

7 Fatty Liver Index and risk of CHD Gastaldelli A et al, Hepatology (5):

8 Distribution of the percentage of patients having coronary stenosis of greater than 70% on a 4-point vessel scoring Arch Turk Soc Cardiol 2008;36(6):

9 Risk of CVD, CHD and CV target organ damage in patients with/without NAFLD/NASH (US,Histology,Liver enzyme) Event Type of studies Evidence CV mortality Retrospective Increased risk Prospective Increased risk CHD/CVD Population-based Increased risk LV structure Retrospective (1 Pr.) Increased LVH/AF Carotid IMT Cross-sectional Increased IMT/ATS Fargion S et Al., World J Gastroenterol 2014 ; 20(37): Ballestri S et Al., World J Gastroenterol 2014;20(7):

10 Increased arterial stiffness in nonalcoholic fatty liver disease: the Cardio-GOOSE study. Salvi, Paolo; Ruffini, Raffaele; Agnoletti, Davide; Magnani, Elena; Pagliarani, Gabriele; Comandini, Giulia; Pratico, Antonino; Borghi, Claudio; Benetos, Athanase; Pazzi, Paolo Journal of Hypertension. 28(8): , August 2010.

11 Logistic regression analyses of factors associated with incident CVD events among DM2 patients Multivariate model adjusted for age, sex, smoking, diabetes duration, Hb A 1C, LDL-C, GGT, use of medications (i.e., hypoglycemic, antihypertensive, lipidlowering, or antiplatelet drugs), presence of MS Targher G et al. Diabetes 54: , 2005

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13 Quali meccanismi sono implicati nei rapporti tra NAFLD/NASH e rischio CV?

14 NAFLD e rischio CV: possibili meccanismi Effetti primitivi della epatopatia

15 Forest plot of meta-analysis of fully adjusted study results of the association of GGT with incident CHD or stroke Fraser A et al. Arterioscler. Thromb. Vasc. Biol. 2007;27;

16 NAFLD e rischio CV: possibili meccanismi Effetti primitivi della epatopatia Effetti della sindrome metabolica associata

17 Adverse Prognostic Implications of Metabolic Syndrome Population-based observational study in 1209 men without DM in the Kuopio Ischaemic Heart Disease Risk Factor Study Metabolic syndrome present Metabolic syndrome absent Coronary Heart Disease Morality Cardiovascular Disease Morality All-Cause Mortality Cumulative Hazard (%) RR (95% CI): 3.77 ( ) RR (95% CI): 3.55 ( ) RR (95% CI): 2.43 ( ) Follow-up (y) Lakka H-M, et al. JAMA. 2002;288:

18 The prevalence of subjects with or without the MS among 1874 men and 514 women with NFALD Hamaguchi H et Al., World J Gastroenterol 2012; 18(13):

19 Increased arterial stiffness in nonalcoholic fatty liver disease: the Cardio-GOOSE study. Salvi, Paolo; Ruffini, Raffaele; Agnoletti, Davide; Magnani, Elena; Pagliarani, Gabriele; Comandini, Giulia; Pratico, Antonino; Borghi, Claudio; Benetos, Athanase; Pazzi, Paolo Journal of Hypertension. 28(8): , August PWV, IMT and carotid plaques in patients with NAFLD and/or MS

20 NAFLD e rischio CV: possibili meccanismi Effetti primitivi della epatopatia Effetti della sindrome metabolica associata Effetti delle resistenza insulinica/iperinsulinemia

21 Fatty liver index and insulin resistance Glucose disposal (mmol/min Kg ffm ) ng/ml Peripheral insulin sensitivity Adiponectin * FLI<20 FLI<60 FLI>60 * * * Fasting EGPxInsulin (mmol/min Kg ffm x pmol/l) Insulin concentration (pmol/l) Hepatic Insulin resistance * * FLI<20 FLI<60 FLI>60 Fasting Insulin * * 0 FLI<20 FLI<60 FLI>60 0 FLI<20 FLI<60 FLI>60 *p<0.001 after correcting for age, center, gender, alcohol intake and physical activity Gastaldelli A et al, Hepatology (5):

22 Risk of Major CHD Event Associated With High Insulin Levels in Nondiabetic Men 1.00 Kaplan-Meier Survival Curve 0.95 Proportion without major CHD event Log rank: Overall P=.001 Q5 vs Q1 P<.001 Q1 Q2 Q3 Q4 Q Years Q1 to Q5=quintiles of area under the curve (AUC) insulin (Q1=lowest quintile; Q5=highest quintile). Pyörälä M et al. Circulation 1998;98:

23 NAFLD, Insulin resistance and CV diseases: Possible Links NAFLD. Insulin Resistance Compensatory Hyperinsulinemia Glucose Uptake Functional and structural vascular involvement Heightened Sympathetic Neural Activity Exaggerated Salt and Water Retention RAS activation

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25 NAFLD e rischio CV: possibili meccanismi Effetti primitivi della epatopatia Effetti della sindrome metabolica associata Effetti delle resistenza insulinica/iperinsulinemia Effetti della interazione Ins-Res/RAAS (AT 1 R)

26 Clinically overlapping effects of Insulin and angiotensin II Townsend RR. Current Hypertension Reports 2003, 5: The boxes enclosed with dashed lines are overlapping effects of Insulin and Ang II The solid enclosed box is an effect of insulin only

27 Effects of insulin on AT 1 receptor mrna expression in rat aortic SMC Nickenig G et al, Basic Res Cardiol 1998

28 SURFACE AREA STAINING FOR AT 1 RECEPTOR AND DEGREE OF ATHEROSCLEROSIS (stary grade) IN HUMAN CORONARY ARTERIES Gross MC et al, basic res cardiol 2002

29 Effect of AT 1 angiotensin receptor antagonist on luminal surface area of atherosclerotic lesion in the aorta of Apo-E KO mice. Kato M et Al., J Cardiovasc Pharmacol 2006;47:

30 Working hypothesis on the possible interactions between NAFLD, RAS activation, angio-ii and CV diseases Insulin resistance Hyperinsulinemia NAFLD AT 1 receptor expression Functional vascular damage ATS & CV disease

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32 Hystological sections of right atrial free wall from a sham dog, a fifth week rapid pacing dog, and a fifth week rapid pacing dog with candesartan Kumagai K et Al., JACC 2003

33 Prevalence of excessive fibrosis in atenolol- and losartan-treated patients at baseline and after 36 week treatment Atenolol Losartan Baseline 57% 69% Therapy 61% 48% Ciulla MM. Hypertension. 2004; 110:

34 Evidenze e prospettive I pazienti con NAFLD presentano un rischio elevato di malattie CV. Tale elevata probabilità è legata alla presenza di un eccesso di fattori di rischio CV associati alla presenza di di insulino-resistenza. La presenza di NAFLD è associata alla presenza di una condizione pro-aterogena e caratterizzata da resistenza insulinica (70%), SM e profilo pro-infiammatorio. Il particolare profilo di rischio CV della NAFLD potrebbe conseguire alla iperattività del sistema nervoso simpatico e/o del sistema RAS che potrebbero spiegare lo sviluppo di ATS, l aumento del rischio CV e anche contribuire alla progressione del danno epatico (?) ed influenzare le scelte terapeutiche.