Impatto clinico dell’iperuricemia nella cardiopatia ischemica

e nello scompenso cardiaco

Massimo UguccioniAO San Camillo

Roma

Vasan R.S., Circulation 2006; 113: 2335-2362

Some Key Questions to Ask Before Using a New Biomarker in Practice

Biomarkers of Cardiovascular Disease: Molecular Basis

and Practical Considerations

Hyperuricaemia and metabolic syndrome in theNHANES survey (1988-1994)

Prevalence of metabolic syndrome

Uric acid level (mg/dl)

The prevalence of the metabolic syndrome increases substantially

with increasing levels of serum uric acid

Choi HK, Ford ES. Am J Med 2007;120:442-447.

Pre

vale

nce

(%)

Serum uric acid and risk of incident type 2 diabetes

Fix-effects model analysis for the overall RR (1.56, 95% CI = 1.39–1.76) of incident type 2 diabetes for the

highest compared with the lowest category of serum uric acid level. No evidence of heterogeneity across tudies

was found (I2 = 0.0%, P = 0.571). The square sizes are proportional to the weight of each study in the meta-

analysis; the horizontal lines represent 95% CIs; the diamond represents the overall RR with its 95% CI.

LV et al. PLoS One. 2013;8(2):e56864

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

9 prospective studiesin 165.922 patients with 6.048 deaths for CV causes

Zhao et al, Atherosclerosis 2013

Hyperuricemia is associated with increased CV mortality

Correlation between UA and outcomes in ACS patients

Int J Cardiol. 2017 Aug 1;240:25-29

Individual metanalysis from CAPRICORN, EPHESUS AND OPTIMAAL trials for unadjusted all-cause (A) and cardiovascular (CV) mortality (B) according to

quartiles of baseline serum uric acid (SUA)

Eur J Heart Fail. 2015 Nov;17(11):1144-51

NET RECLASSIFICATION INDEX 17,6%

ALL CAUSE MORTALITY CV MORTALITY

URIC ACID AND RISK OF INCIDENT HEART FAILURE: METANALYSISHuang et al. Eur J Heart Failure 2014

19% INCREASED RISK OF HF FOR EVERY 1 mg/dl SUA INCREASE

CATEGORICAL

DOSE EFFECT

CONTINUOS

URIC ACID AND PROGNOSIS IN PATIENTS WITH HEART FAILUE:METANALYSIS

Huang et al. Eur J Heart Failure 2014

CATEGORICAL, ALL CAUSE DEATH

CATEGORICAL, CV DEATH

CONTINUOS, ALL CAUSE DEATH

The interrelationship between hyperuricemia, XO, cell metabolism and insulin resistance(IR), tissue hypoxia, vascular dysfunction, cytokines, and oxygen free radicals in CHF

Feedback mechanisms cause increased XO activation and hence hyperuricemia. These complex interrelated mechanisms explain why UA levels are correlated with many different parameters and can serve as a metabolic marker with strong prognostic power. IR and tissue wasting (cell death) can cause accumulation of purine bodies and hence hyperuricemia. Increased activation of XO can be caused by tissue hypoxia, which itself is a consequence of vascular (and cardiac) dysfunction. Oxygen free radicals and inflammatory cytokines contribute to vascular dysfunction. Oxygen

free radicals promote production of inflammatory cytokines and are themselves produced by XO. Impaired kidney function and diuretic treatment can also contribute to hyperuricemia. PPP indicates pentose phosphate pathway; PPRP, phosphoribosylpyrophosphate.

Circulation. 2003 Apr 22;107(15):1991-7

J Am Coll Cardiol 2013;62:2284-2293

Overall LV ChangeHistogram of changes in (A) left ventricular (LV) mass and (B) LV mass index in the overall study population

MacIsaac RL et al, Hypertension 2016

Risk of CV events Risk of stroke

Savarese et al. Nutr Metab Cardiovasc Dis. 2013 Aug;23(8):707-14

Changes of serum uric acid and cardiovascular (CV) events:

a meta-regression analysis of 11 randomized trials - 21.392 patients

Change in Tau² p Tau

(t) (p)

All-cause death -0.88 0.418

CV death -0.78 0.468

Myocardial infarction -0.61 0.604

Cerebrovascular accidents -0.66 0.536

Heart failure -1.52 0.179

Conclusioni

• Elevati livelli di acido urico sono associati in maniera indipendente con una aumentata incidenza di fattori di rischio CV e di eventi CV

• Elevati livelli di acido urico sono associati con un aumento della incidenza di scompenso cardiaco ed una prognosi più sfavorevole

• Interventi terapeutici (ALLOPURINOLO) volti a ridurre i livelli sierici di acido urico hanno dati risultati non univoci sugli outcome clinici

• Trial clinici con gli inibitori selettivi delle XO (FEBUXOSTAT)

sono attualmente in corso

RCT with ULT:

Hard CV end-points

Trial Drug 1° objective Reference

BP and CV complications (CARES) Febuxostat vs.

Allopurinol

Serious CV events NCT01101035*

ongoing

New onset MS (FAST) Febuxostat vs.

Placebo

INS-res and

features MS

NCT01654276*

ongoing

Treatment of CHD (ALL-HEART) Allopurinol vs.

Standard care

MACE EudraCT 2013003559-39

ongoing

Cerebrovascular protection (XILO-

FIST)

Allopurinol

vs.Placebo

White matter

protection

NCT02122718*

Starting recruitment

Major CV disease (FREED) Febuxostat vs.

Placebo

MACE NCT01984749*

ongoing

*ClinicalTrial.gov