Università Magna Græcia di Catanzaro Dipartimento di Medicina Sperimentale e Clinica Cattedra di Medicina Interna Scuola di Specializzazione in Geriatria U.O. Malattie Cardiovascolari Geriatriche Prof. Francesco Perticone Sindrome Infiammatoria Sistemica e Rischio CV

Association Between Airflow Obstruction, CRP and AMI Ukena C et al. Int J Cardiol 2010

Inflammatory Events in Complex Comorbidities Ukena C et al. Int J Cardiol 2010

Cardiopulmonary Continuum Concept of systemic inflammatory processes as underlying pathophysiological relationship between COPD and CAD Ukena C et al. Int J Cardiol 2010

Low-Dose Aspirin Reduces Thromboxane B2 but not CRP 140 100 60 20 140 100 60 20 28 Days 31 Days Serum CRP (% of Baseline) Serum Thromboxane (% of Baseline) * p<0.001 Low-dose aspirin reduces thromboxane B2 but not CRP In a prospective study of healthy volunteers, high-sensitivity CRP (hs-CRP) and serum platelet-cyclo-oxygenase-1–derived thromboxane B2 were studied in 57 men and women randomized to placebo or to aspirin 81 g/d, 325 g every third day, 81 g every third day, or 40 g every third day for 31 days. Compared with placebo, day-28 and -31 serum thromboxane B2 concentrations were reduced by 100%, 90%, 84%, and 78% in the respective aspirin treatment groups (p<0.001 vs. baseline in each active treatment group). On day 45, 14 days after discontinuation of treatment, serum thromboxane B2 concentration returned to baseline levels. In contrast, CRP levels did not change significantly from baseline in any treatment group. Body mass index (BMI) was the only independent predictor of day-31 CRP level. Reference: Feldman M, Jialal I, Devaraj S, Cryer B. Effects of low-dose aspirin on serum C-reactive protein and thromboxane B2 concentrations: a placebo-controlled study using a highly sensitive C-reactive protein assay. J Am Coll Cardiol 2001;37:2036-2041. * * Placebo (n=11) ASA 81 mg qd (n=13) Placebo (n=11) ASA 81 mg qd (n=13) Feldman M et al. J Am Coll Cardiol 2001;37:2036-2041 12

CARE: La Pravastatina Riduce il Rischio Rappresentato dall’Infiammazione P trend=0.005 3 P=0.007 2 Rischio relativo di un evento 1 Pravastatina Placebo Pravastatina Placebo Infiammazione Assente Infiammazione Presente ( PCR e SAA) Ridker et al: Circulation 1998;98:839–844

Serum L-ascorbic acid, % Controls PAD L-ascorbic Acid Depletion in Spiked Sera from Nonsmoking Men (10 control subjects, 15 PAD patients), Stratified for Serum CRP (5.0 mg/L) Correlation Between Serum L-ascorbic Acid and CRP Concentrations in PAD Patients Serum L-ascorbic acid, mmol/L r= -0.72 P< .001 Serum CRP, mg/L Tzoulaky I et al., Circulation 2005

Oxidative Stress and Atorvastatin Cangemi R et al, Eur Heart J 2008;29:54–62

Vascular Function According to Median of Hb Perticone F et al, Clin J Am Soc Nephrol, accepted

Before and After Smoking Hemodynamics and Flow Before and After Smoking 60 80 100 120 140 HR (b/m) and BP (mmHg) FBF 100 120 140 160 180 FBF (ml/min) SBP DBP HR Baseline 30 60 90 120 min J Lekakis et al, Am J Cardiol 1998;81:1225-28

J Lekakis et al, Am J Cardiol 1998 Flow-mediated Dilation of the Brachial Artery after Smoking, Sham Smoking and after Smoking a Second Cigarette 12 sham 10 1st cigarette 2nd cigarette 8 FMD (%) 6 4 2 30 60 90 120 Time, min J Lekakis et al, Am J Cardiol 1998

Relationship Between Smoking and Flow Mediated Dilation FMD % 10 5 P < .01 None 1 - 4 5 - 9 10 - 19 > 20 Celermajer et al, N Engl J Med 1996

Relationship Between Passive Smoking and Flow Mediated Dilation 20 P < .001 P = NS 15 FMD % 10 5 Controls Passive Active smokers smokers Celermajer et al, N Engl J Med 1996

NO production inactivation bioavailabilty O2 O-2 e- NADH/NA DPH Oxidase NO OONO- L-arginina NO- citrullina e-NOS bioavailabilty

Maximal vasodilatory response to ACh (%) probability of diabetes (%) Endothelial Dysfunction and C-Reactive Protein Are Risk Factors for Diabetes in Essential Hypertension Maximal vasodilatory response to ACh (%) probability of diabetes (%) 5.6-years estimated 1000 800 600 400 200 80 60 40 20 Exponential fitting r=0.85 P<0.001 Perticone F et al, Diabetes 2008 22

Sindrome Metabolica e Livelli di PCR 8 6 C-reactive Protein (mg/L) 4 2 1 2 3 4 5 Number of Components of the Metabolic Syndrome Ridker PM, et al. Circulation. 2003;107:391-397. 23

Coronary Heart Disease Mortality Unadjusted Kaplan-Meier Curves Coronary Heart Disease Mortality Cardiovascular Disease Mortality All Cause Mortality 20 20 20 15 15 15 RR (95% CI), 3.77 (1.74-8.17) RR (95% CI), 3.55 (1.96-6.43) RR (95% CI), 2.43 (1.64-3.61) Cumulative Hazard (%) 10 10 10 5 5 5 These are the curves for men with vs without the metabolic syndrome based on factor analysis (men in the highest quarter of the distribution of the metabolic syndrome factor were considered to have the metabolic syndrome). The unadjusted Kaplan-Meier hazard curve for the metabolic syndrome factor dichotomized according to the upper quartile are shown in the figure. The curves were constructed to show the relative risk of men with and without metabolic syndrome to die of any cause, CVD, or CHD after adjustment for factors such as age. Shown in the figure above, in Cox proportional hazards regression analyses after adjustment for age, year of examination, and the 3 other factors, men with loadings on the metabolic syndrome factor in the highest quarter had an increased mortality from CHD (RR, 3.61 [95% CI, 1.65-7.90]), CVD (RR, 3.18 [95% CI, 1.73-5.81]), and all causes (RR, 2.25 [95% CI, 1.51-3.35]). Mean follow up (range) for survivors was 11.6 (9.1-13.7) years. Cardiovascular disease and all-cause mortality are increased in men with the metabolic syndrome, even in the absence of baseline CVD and diabetes. Early identification, treatment, and prevention of the metabolic syndrome are important to recognize. Lakka H-M, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709-2716. 2 4 6 8 10 12 2 4 6 8 10 12 2 4 6 8 10 12 Follow-up, Y Follow-up, Y Follow-up, Y No. at Risk Metabolic Syndrome Yes No 866 288 852 279 834 234 292 100 866 288 852 279 834 234 292 100 866 288 852 279 834 234 292 100 Metabolic Syndrome: Yes No Lakka H-M, et al. JAMA. 2002;288:2709-2716.

Relationship between metabolic syndrome, lung dysfunction and CV disease

IL-6 TNF-α IL-1β 1rst 2nd 3rd 4th CRP quartiles PREVEND study, Kidney Int 63:654, 2003 Creatinine Cl (ml/min/1.73m2) 100 95 90 The 3 years risk for CV events in the women health study Ridker NEJM 2000; 342:836 8 6 4 2 4.4 un solido indicatore di rischio CV CRP

ADMA and Endothelial Vasodilation in Hypertension Achan V & Vallance P. ATVB 2003 FBF, % increase 400 800 0,4 0,6 0,8 1 r = 0.587 P < 0.0001 ADMA mmol/L Perticone F et al, J Am Coll Cardiol, 2005;46:518-23 ADMA -30 0 30 60 min SVR (change) 400 200 -200 MBP 5 -5 Perticone F et al, Int J Cardiol 2009 27

Sciacqua A et al, NMCD 2010

Fasting Insulin and Left Ventricular Mass LVMI, g/m2 70 120 170 220 10 20 30 Insulin, mU/mL r = 0.636 p< 0.0001 F Perticone et al, J Clin Endocrinol Metab 2001 G Sesti, F Perticone et al, J Hypertens 2007

Signaling Determining Mesenchimal-Cell Differentiation toward Osteoblasts and Signals Acting on Mature Osteoblasts to Enhance Bone Formation Signaling Pathways Used by Bone Morphometric Proteins in Osteoblasts

Deletion Polymorphism of ACE-Gene and Left Ventricular Hypertrophy Molecular signaling pathways linking ROS to cardiac hypertrophy and remodeling Deletion Polymorphism of ACE-Gene and Left Ventricular Hypertrophy Takimoto E , Kass DA, Hypertension 2007 Perticone F et al, J Am Coll Cardiol 1997;29:365-9

Scieffer B et al, Circulation, 2000;101:1372-78

Effect of Fructose on Various Organ Systems Johnson RJ et al, Endocrine Reviews 2009;30:96–116

Acido Urico, Funzione Endoteliale e Diabete 0.001 0.012 0.340 0.799 0.355 0.192 0.124 0.090 0.071 HR (plus uric acid 1 g/dL increase) ACh % of increase Perticone F et al, submitted

Endothelial Dysfunction and e-GFR Decline Perticone F et al, Circulation 2010

Effects of FFA on Various Organs Effects of LDL Particles on the Wessel Wall Rocha VZ and Libby P, Nat Rev Cardiol 2009;6:399-409

INFLAMMATION INSULIN RESISTANCE ENDOTHELIAL DYSFUNCTION HYPERTENSION DIABETES TARGET ORGAN DAMAGE AMI STROKE HEART FAILURE SUDDEN DEATH