Claudio Borghi Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna

Il rischio cardiovascolare

Age-adjusted death rates for diseases of the heart, cerebrovascular disease, and chronic lower respiratory disease by year.

Lackland D et Al., Stroke 2013;45:315-353

USA- 1900 to 2010

Complessità del rapporto NAFLD/NASH e malattie CV

NAFLD, NASH

Tipo di studio (Retr,Prosp,CS,Pop)

Smple size

Modalità valutazione epatopatia

(US,Biops,Lab.Index)

Outcome (MCV, Mort-CV, CHD, LVH, IMT..)

MS si/no, DM si/no

Principal studies of the association between NAFLD and the incidence of major CV events

Luo J et Al., Eur J Gastroenterology & Hepatology 2015, 27:193–199

Fatty Liver Index and risk of CHD

Gastaldelli A et al, Hepatology. 2009 49(5):1537-442008

Arch Turk Soc Cardiol 2008;36(6):376-381

Distribution of the percentage of patients having coronary stenosis of greater than 70% on a 4-point vessel scoring

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): 13306-13324 Ballestri S et Al., World J Gastroenterol 2014;20(7): 1724-1745

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):1699-1707, August 2010.

Logistic regression analyses of factors associated with

incident CVD events among DM2 patients

Multivariate model adjusted for age, sex, smoking, diabetes duration, Hb A1C, LDL-C, GGT, use of medications (i.e., hypoglycemic, antihypertensive, lipid-lowering, or antiplatelet drugs), presence of MS

Targher G et al. Diabetes 54:3541–3546, 2005

……..

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

NAFLD e rischio CV: possibili meccanismi

• Effetti primitivi della epatopatia

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;2729-2735

NAFLD e rischio CV: possibili meccanismi

• Effetti primitivi della epatopatia

• Effetti della sindrome metabolica associata

Population-based observational study in 1209 men without DM in the Kuopio Ischaemic Heart Disease Risk Factor Study

Lakka H-M, et al. JAMA. 2002;288:2709-2716.

Coronary Heart Disease Morality

Cardiovascular Disease Morality

All-Cause Mortality

Cum

ulat

ive

Haz

ard

(%)

20

15

10

5

0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 2 4 6 8 10 12

Follow-up (y)

RR (95% CI): 3.55 (1.96–6.43) RR (95% CI): 2.43 (1.64–3.61) RR (95% CI): 3.77 (1.74–8.17)

Metabolic syndrome present Metabolic syndrome absent

Adverse Prognostic Implications of Metabolic Syndrome

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): 1508-1516

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):1699-1707, August 2010.

PWV, IMT and carotid plaques in patients with NAFLD and/or MS

NAFLD e rischio CV: possibili meccanismi

• Effetti primitivi della epatopatia

• Effetti della sindrome metabolica associata

• Effetti delle resistenza insulinica/iperinsulinemia

Fatty liver index and insulin resistance

*p<0.001 after correcting for age, center, gender, alcohol intake and physical activity

* *

Peripheral insulin sensitivity

* *

Adiponectin

0

2

4

6

8

10

12

FLI<20 FLI<60 FLI>60

Glu

cose

dis

posa

l (m

mol

/min

Kg f

fm) *

*

Hepatic Insulin resistance

0

200

400

600

800

FLI<20 FLI<60 FLI>60

Fast

ing

EG

PxI

nsul

in

(mm

ol/m

in K

g ffm

x p

mol

/l)

0

10

20

30

40

50

60

70

FLI<20 FLI<60 FLI>60

Fasting Insulin

* *

Insu

lin

conc

entra

tion

(pm

ol/l)

0

10

20

30

40

50

60

FLI<20 FLI<60 FLI>60

ng/m

l

Gastaldelli A et al, Hepatology. 2009 49(5):1537-44

Q1 to Q5=quintiles of area under the curve (AUC) insulin (Q1=lowest quintile; Q5=highest quintile).

Proportion without major CHD event

Years 0

0 5

0.75

0.80

0.85

0.90

0.95

1.00

10 15 20 25

Log rank: Overall P=.001 Q5 vs Q1 P<.001

Q1

Q2

Q3 Q4

Q5

Kaplan-Meier Survival Curve

Pyörälä M et al. Circulation 1998;98:398–404.

Risk of Major CHD Event Associated With High Insulin Levels in Nondiabetic Men

NAFLD, Insulin resistance and CV diseases: Possible Links

NAFLD

Insulin Resistance

Compensatory Hyperinsulinemia

Heightened Sympathetic Neural Activity

Functional and structural

vascular involvement

Glucose Uptake

Exaggerated Salt and Water Retention

RAS activation

.

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 (AT1R)

The boxes enclosed with dashed lines are overlapping effects of Insulin and Ang II

The solid enclosed box is an effect of insulin only

Clinically overlapping effects of Insulin and angiotensin II

Townsend RR. Current Hypertension Reports 2003, 5:110-116

Effects of insulin on AT1 receptor mRNA expression in rat aortic SMC

Nickenig G et al, Basic Res Cardiol 1998

Gross MC et al, basic res cardiol 2002

SURFACE AREA STAINING FOR AT1 RECEPTOR AND DEGREE OF ATHEROSCLEROSIS (stary grade) IN HUMAN CORONARY ARTERIES

Effect of AT1 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;47:764-769

Hyperinsulinemia

AT1 receptor expression

Functional vascular damage

ATS & CV disease

Working hypothesis on the possible interactions between NAFLD, RAS activation, angio-II and CV diseases

Insulin resistance

NAFLD

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

Prevalence of excessive fibrosis in atenolol- and losartan-treated patients at baseline and after 36 week treatment

Ciulla MM. Hypertension. 2004; 110:552-557.

Therapy

57% 69%

Atenolol Losartan

61% 48%

Baseline

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.