role of uricacid in cvd risk

1. DR. B. DURGA PAVAN MD;DM;AFESC
CONSULTANT INTERVENTIONAL CARDIOLOGIST
TRUST HOSPITAL
KAKINADA

2. OUTLINE
 BIOLOGIC FUNCTIONS
 ASYMPTOMATIC HYPERURECEMIA
 NONCRYSTAL DIPOSITION DISORDERS
 UA – CVD: EVIDENCE
 EVALUATION
 MANAGEMENT
 HYPERURICEMIC DRUGS AND CVD

5. Biologic functions of Uric acid
 OXIDANT - ANTIOXIDANT PARADOX

6. reduce the risk
of degenerative/inflammatory neurolo
gic disorders such as Alzheimer
disease

7. Asymptomatic hyperuricemia
 Serum urate concentration is elevated but in which
neither symptoms nor signs of monosodium urate
(MSU) crystal deposition disease(gout, or uric acid
renal disease)
 About 2/3rd or more of such individuals remain
asymptomatic, never developing gout flares,
tophaceous gout, acute or chronic hyperuricemic
nephropathy, or uric acid nephrolithiasis

8. Non-crystal deposition associations
with hyperuricemia
 Largely unrelated to crystal deposition
 hypertension,
 chronic kidney disease,
 cardiovascular disease,
 insulin resistance syndrome

9. Definition
 Persistent urate level of >8 mg/dL

10. CLASSIFICATION
 Excessive urate production
 Absolute or relative impairment of renal uric acid
clearance
 Combination of these mechanisms
 specific genetic
 comorbid disease-related
 environmental

11. Hyperuricemia - CAD
 PROINFLAMATORY
 MARKER
 EFFECT

18. Some of the cardiovascular benefits of
 Losartan - Losartan Intervention for Endpoint
Reduction in Hypertension (LIFE) study reported in
the Greek
 Atorvastatin - Atorvastatin and Coronary-
HeartDisease Evaluation (GREACE) study

20.  Increased incidence of CHD
 Increased mortality in those with and without
preexisting CHD
 It is unclear
 a causal effect
 simply a marker for other risk factors such as
hypertension, dyslipidemia, and diabetes

21. Hyperuricemia and HF

22. those with a serum UA above the threshold
value had a much poorer survival rate at four
years than those with lower levels (19 versus
79 percent).
Do not address the issue of whether
hyperuricemia is simply a marker for more
severe heart disease

24. Similar effects are seen in HF without hyperuricemia.
xanthine oxidase inhibition itself may be important

25. randomly assigned 253 patients with symptomatic HF, LV ejection fraction
(LVEF) ≤40 percent, and uric acid levels ≥9.5 mg/dL to receive allopurinol (target
dose, 600 mg daily) or placebo in a double-blind, multicenter trial.

26. Hyperuricemia and hypertension
Increased serum uric acid levelsIncreased serum uric acid levels
activation of renin-angiotensin system, vascular smooth muscle -
cellular proliferation and
sec arteriolosclerosis that
impairs pressure
natriuresis.

27. Hyperuricemia and hypertension
 More common in primary hypertension than in
secondary hypertension, at least in adolescents.
 one study an elevated uric acid level (>5.5 mg per
deciliter was observed in nearly 90% of adolescents
with essential hypertension
 whereas uric acid levels were significantly lower in
controls and teens with either white-coat or secondary
hypertension
 In some studies hyperuricemia is present in 40 to 60%
of subjects with untreated hypertension

28. Choi H K et al, The American Journal of Medicine (2007) 120, 442-44
Hyperuricemia anromed metabolic synd

29. EVALUATION
 Urate level in excess of 8 mg/Dl
 interval of at least a week.

30.  UA level between 7 - 8 mg/dL , needs repeat testing to
determine if it is >8 mg/dL in 6 - 12 months before
initiating a more detailed evaluation.
 < 7 mg/dl generally do not need further evaluation

31.  Marked hyperuricemia - > 10 mg/dL in a child or
>12 mg/dL in an adolescent
 Needs evaluation for underlying
 lymphoproliferative or myeloproliferative state, a
 congenital cardiac or pulmonary disorder,
 inherited enzyme defect - urate overproduction.

32.  History and physical examination,
 intercurrent medical conditions,
 diet or lifestyle choices,
 drug therapies,
 toxin exposure,
 known familial disorder that may result in
hyperuricemia.

33.  Laboratory testing
 CBP; ,
 renal function, electrolytes, calcium,
 liver chemistries
 urinalysis.

34. MANAGEMENT
 Lifestyle interventions
 reduction to ideal body weight
 avoidance of alcohol
 sugar-sweetened beverages,
 regular exercise
 Management of diseases accompanying hyperuricemia
 fenofibrate for hyperlipidemia and losartan or calcium
channel blockers for hypertension.
 avoided, when possible, include thiazide or loop diuretics,
angiotensin-converting enzyme (ACE) inhibitors, non-
losartan angiotensin II receptor blockers, and beta blockers

35. Pharmacologic urate-lowering
therapy
 Allopurinol: inhibits xanthine oxidase (XO) in the
vascular endothelium and can prevent the formation
of superoxide free radicals
 Reduce markers of oxidative stress and improve
endothelium-dependent vasodilation
 Independent of hypourisemic effect

36.  In rats with heart failure, chronic XO inhibition causes
reverse ventricular remodeling.
 In a study of 9 patients with allopurinol infused into
the left main coronary artery increased myocardial
efficiency.
 Some small studies s/o XO inhibition improves
endothelial dysfunction in chronic HF.

37. randomly assigned 253 patients with symptomatic HF, LV ejection fraction
(LVEF) ≤40 percent, and uric acid levels ≥9.5 mg/dL to receive allopurinol (target
dose, 600 mg daily) or placebo in a double-blind, multicenter trial.

38. Febuxostat – CVD

39.  The safety trial was conducted in over 6,000 patients
with gout treated with either febuxostat or allopurinol.
 The preliminary results show that overall, febuxostat
did not increase the risk of these combined events
compared to allopurinol.
 However, when the outcomes were evaluated
separately, febuxostat showed an increased risk of
heart-related deaths.
 The safety trial was not placebo controlled; thus, it
remains unclear whether allopurinol had beneficial
effects on mortality or whether febuxostat had
deleterious effects.

40.  These findings reinforce the preference for allopurinol
as the initial urate-lowering drug for most patients
with gout, especially those with high cardiovascular
risk.
 Until further information is available, treatment
decisions in patients already taking febuxostat should
be individualized and include discussion of safety
concerns raised by the FDA, the availability and risks
of alternative therapies, and the patient's
cardiovascular risk.

46. Take home
 Evidence regarding the relationship between high UA
and HTN and other CV RISK factors is extensive.
 Current data also suggest that hyperuricemia could
increase the risk of developing renal and CV disease.
 Pharmacological Rx not recommended for
asymptomatic hyperurisemia.
 Further studies are needed to assess the exact role of
uric acid reduction in the progression of cvd.

47. Thank you