Uricemia nei pazienti a rischio CV: fattore o marker di rischio? Claudio Borghi, FESC, FAHA Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna R.Magritte: La reproducion interdite
Urate production pathways Mandal A. et al. Annu Rev Physiol. 2015;77:323-45
J Hypertens, 2015 3
Norman Rockwell Triple self-portrait, (1960)
Serum Uric acid and HTN Bradford-Hill criteria for causation (Proc R Soc Med 1965; 58: 295-300) Strength of the association Consistency across studies Temporal sequence Biological gradient ( dose-response ) Plausibility and coherence Reversibility with intervention
Prognostic value of serum uric acid: CV and all-cause mortality. CV and all-cause mortality Odds ratio (OR) and 95% confidence interval (95% CI) of CV and news-onset HTN, all-cause mortality, associated to a 1 mg/dl increase of serum uric acid Bombelli M et al, J Hypertens 2014
Retrospective analysis on hospitalization and health care costs for high SUA in Italy SUA levels and Hx for kidney disease [Ref. 6 mg/dl] IRR (95% CIs) Total health care resource costs > 6 7 mg/dl 1.21 (1.09-1.35) > 7 8 mg/dl > 8 mg/dl 1.24 (1.08-1.41) 1.99 (1.77-2.24) 2,752 2,957 1.00 SUA levels and Hx for CVD [Ref. 6 mg/dl] IRR (95% CIs) > 6 7 mg/dl 1.10 (1.05-1.15) > 7 8 mg/dl 1.24 (1.18-1.32) Hospitalizations costs > 8 mg/dl 1.75 (1.65-1.85) 1.00 SUA levels and total mortality HR (95% CIs) [Ref. 6 mg/dl] 1,515 1,648 > 6 7 mg/dl > 7 8 mg/dl > 8 mg/dl 0.98 (0.92-1.04) 1.20 (1.11-1.29) 2.12 (1.98-2.27) 1.00 Degli Esposti L, Borghi C et al, in press
Serum Uric acid and HTN Bradford-Hill criteria for causation (Proc R Soc Med 1965; 58: 295-300) Strength of the association Consistency across studies Temporal sequence Biological gradient ( dose-response ) Plausibility and coherence Reversibility with intervention
9 prospective studies 165922 partecipants 6048 CV deaths Zhao et Al, Atherosclerosis 2013
Random effects analysis of multivariate risk of CVD associated with hyperuricemia Results of 29 studies with 958410 participants CHD morbidity CHD mortality Li M et al, Nature Open, 2016
Serum Uric acid and HTN Bradford-Hill criteria for causation (Proc R Soc Med 1965; 58: 295-300) Strength of the association Consistency across studies Temporal sequence Biological gradient ( dose-response ) Plausibility and coherence Reversibility with intervention
Hyperuricemia and Blood Pressure in rats Mazzali M et al. Hypertension 2001;38:1101-1106
Time to develop HTN in men with and without hyperuricemia in the MRFIT study Krishnan E et al, Hypertension 2007
Serum Uric acid and HTN Bradford-Hill criteria for causation (Proc R Soc Med 1965; 58: 295-300) Strength of the association Consistency across studies Temporal sequence Biological gradient Plausibility and coherence Reversibility with intervention
Quartiles of SUA and prevalence of CV risk factors and TOD in the cohort of the Brisighella Heart Study *p=0.005 Borghi C et al, J Hypertens 2013
Age and BP-adjusted HR for the associations between serum uric acid and cardiovascular disease: The Rotterdam Study Bos M J et al. Stroke. 2006;37:1503-1507
CV conditions associated with a gradient of SUA levels Hypertension Metabolic syndrome and (±) diabetes Incidence of CHD and stroke Incidence of renal failure Incidence of CHF CV morbidity and mortality
Serum Uric acid and HTN Bradford-Hill criteria for causation (Proc R Soc Med 1965; 58: 295-300) Strength of the association Consistency across studies Temporal sequence Biological gradient Plausibility and coherence Reversibility with intervention
Hyperuricemia and CV disease Beyond blood pressure A significant relationship between serum levels of UA and the following CV/renal disease has been reported: Acute Coronary Syndrome Chronic CHD and angina Atrial fibrillation (onset and relapse) Heart failure Renal failure
Serum Uric acid and HTN Bradford-Hill criteria for causation (Proc R Soc Med 1965; 58: 295-300) Strength of the association Consistency across studies Temporal sequence Biological gradient Plausibility and coherence Reversibility with intervention
Difference in the Change of Blood Pressure Between Allopurinol-Exposed (n=365) and Control Patients (n=6678) Beattie CJ et al. Hypertension. 2014 Nov;64(5):1102-7
Risk of CV events Risk of stroke MacIsaac RL et al, Hypertension 2016
Possible limitations Studies in unselected populations (treated/untreated for addtional RF s) Effects of Urate lowering in RCT s Genetics and Mendelian randomizations Renal SNP s (CV-/Gout+) XO SNP s (CV++)
Conceptual background for Mendelian randomization studies: Biomarkers can be associated with coronary artery disease but causality can be different. XO High LDL-C SUA (cardiovascular) Renal handling + Smoking SUA (gout) From: Jansen H et al. Eur Heart J 2014 (mod)