JOURNAL

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Uric Acid and Cardiovascular
Disease: A Clinical Review
Oleh :
Achmad Istiyono Githa Laras Ayu
Ade Indra Setiawan Nur Syaidah
Ega Paembonan Sucitra Basri
Efi Sumarni

Pembimbing:
dr. Joel Herbet M.H. Manurung, Sp.JP, FIHA
SMF JANTUNG DAN PEMBULUH DARAH
RSUD JAYAPURA
FAKULTAS KEDOKTERAN
UNIVERSITAS CENDERAWASIH
TAHUN 2022
 Introduction
Uric acid represents the end-product of purine metabolism in apes and humans, which is mainly regulated by
xanthine oxi- doreductase (XOR), converting hypoxanthine to xanthine and xan- thine to uric acid. Intake of alcohol, red
meat, seafood, potato, and others can increase uric acid exogenously, although overall diet explains much less variance
in serum uric acid lev- els when compared with inherited genetic variants. Uric acid is also endogenously synthesized in
the liver, intestines, muscle, and vascular endothelium.
Pathological hyperuricemia caused by a purine/fructose-rich diet, genetic or environmental factors, as well as
overproduction from hepatic metabolism and cell turnover, and renal underexcretion or extra-renal underexcretion leads
to crystal precipitation in the joints, soft tissue, kidneys, and other organs
 Introduction
Beyond crystalline arthropathy and urolithiasis, accumulating evidence points toward an indicative marker or a
possible etiologic role of increased uric acid levels in the pathogenesis of cardiovascular risk factors and diseases such as
hypertension, atrial fibrillation (AF), chronic kidney disease (CKD), heart failure (HF), coronary artery disease (CAD),
and cardiovascular death.
In this review article, we provide a summary con- cerning the relation between uric acid and cardiovascular
disease from a clinical perspective.
 Inflammation, oxidative stress, and endothelial
dysfunction
Although uric acid has been recognized as an antioxidant by experimental studies, it is also known that uric acid induces
inflammation in vascular endothelial and smooth muscle cells, and intracellular oxidative stress, leading to endothelial
dysfunction.

During purine metabolism, oxygen species are generated by activity of xanthine oxidase (XO), promoting inflammatory
reaction and impairing endothelial function.

The endothelium functions as an endocrine organ secreting vasodilators (eg. nitric oxide and prostaglandin 12) and
vasoconstrictors (eg endothelin-1, thromboxane A, and angiotensin II) to regulate vascular tone, thrombo sis, inflammation,
and oxidation.

Endothelial dysfunction refers to a condition in which homeostasis is disturbed by an imbalance between endothelium
derived vasodilating and vasoconstricting factors. Despite numerous confounding factors, previous in vivo studies have
demonstrated that elevated uric acid level was sig nificantly associated with endothelial dysfunction assessed by different
endothelial function testing.
Inflammation, oxidative stress, and endothelial
dysfunction

Purine metabolism and putative mechanisms underlying cardiovascular disease

 Uric Acid and Cardiovascular Disease
Uric acid level is potentially associated with cardiovascular disease and prognosis, but the impact in general
populations is unclear. The large community based Framingham Heart Study showed that uric acid level at baseline did
not predict future cardiovascular events including coronary heart disease and death, after adjustment for confounding
clinical factors, while there are some studies indicating that serum uric acid levels were independently and significantly
associated with a risk of cardiovascular mortality.
 Uric Acid and Cardiovascular Disease
1. Hypertension
In the longitudinal cohort study in Japan, 433 young (age ≤50 years), non-obese, and normotensive men with no medication
at baseline were investigated. Systolic blood pressure (BP) was significantly increased from baseline to 5-year follow-up
(123±8 vs. 130±7 mmHg, p<0,05), and the increase in BP was associated with baseline BP and serum urin acid levels.

A meta-analysis of 25 observational studies with 97,824 participants showed the risk of incident hypertension increased by
13% for every 1 mg/dl increase in the uric acid level.

In the PIUMA study, 1720 patients with essential hypertension were followed-up for a mean duration of 4 years and were
divided into 4 groups according to the quartiles of serum uric acid (4.5, 5.2, and 6.2 mg/dl in men and 3.2, 3.9, and 4.6 mg/dl
in women) [17]. In this study, fatal cardiovascular events were observed in 0.41, 0.33, 0.38, and 1.23 per 100 person-years in
the 4 groups, suggesting that elevated uric acid level was a risk marker for subsequent cardiovascular outcomes in
hypertensive patients.
 Hypertension
In the single-center study, 60 prehypertensive, obese, adolescents were included and randomized to receive
allopurinol, probenecid, or matching placebo. At 2 months, 24-hour systolic BP was decreased by 9.2 and
8.9 mm Hg from baseline in the allopurinol and probenecid groups, while it was increased by 1.9 mm Hg
in the placebo group (p<0.001).

Interestingly, in a rat model, experimentally-induced hyperuricemia by the administration of oxonic acid, an inhibitor of uric-
ase, increased systolic BP. In this experimental model, elevated sys- tolic BP was significantly reduced by lowering uric acid
with an XO inhibitor, febuxostat.

Therefore, uric acid may be a part of causal factor in the development of hypertension, but therapeutic intervention of
lowering uric acid for BP control should be limited in clinical practice so far.
 Uric Acid and Cardiovascular Disease
2. Atrial fibrillation
Several studies have found an association between elevated serum uric acid and an increased risk of AF, although whether
uricacid plays a mechanistic role in the cause and maintenance of AF remains unclear.

Oxidative stress, inflammation, renin-angiotensin- aldosterone system activation, and endothelial dysfunction,
andsubsequent atrial remodeling may explain the pathogenic link be-tween uric acid and AF.

A meta-analysis in-cluding 6 cross-sectional studies and 3 cohort studies confirmedan increase in the risk of AF among those
with high serum uric (defined as >7 mg/dl or the highest level cut-off or quartile reported in the study) compared to those
with normal serumuric acid levels [relative risk 1.67, 95% confidence interval (CI) 1.23–2.27].
 2. Atrial fibrillation
Several studies have found an association between elevated serum uric acid and an
increased risk of AF, although whether uric acid plays a mechanistic role in the cause and
maintenance of AF remains unclear. Oxidative stress, inflammation, renin-angiotensin-
aldosterone system activation, and endothelial dysfunction, and subsequent atrial
remodeling may explain the pathogenic link between uric acid and AF.

Data on therapeutic challenge for AF are scarce, but in a canine model, allopurinol
suppressed AF promotion by preventing both electrical and structural remodeling.
 Uric Acid and Cardiovascular Disease
3. Chronic Kidney Disease
Even in normotensive healthy individuals with normal renal function, a prospective observational cohort (n = 900) found
the association between elevated serum uric acid and the likelihood of longitudinal kidney damage was confirmed after
adjusting for clinical factors.

In addition, as shown in meta-analyses, higher serum uric acid level is a prognostic marker of cardiovascular mortality in
patients with CKD.

Elevated serum uric acid may be related to renal involvement such as glomerulosclerosis and interstitial fibrosis by a
deposition of urate crystal, leading to impaired uric acid excretion and tubular secretion, and a reduced renal blood flow.
 Uric Acid and Cardiovascular Disease
3. Heart Failure
febuxostat may reduce the development of left ventricular
Jepang hypertrophy and the amount of cardiac collagen content, thus
Serum uric acid improving systolic function in mice
level 7,3 ± 2,4 mg/dl

wo small double-blind, placebo-control RCTs clearly

demonstrated that allopurinol improved endothelial
Hiperurisemia function in patients with chronic HF

Meta-analysis Framingham
offspring study
↑ 1 mg/dl Although uric acid levels were significantly reduced with
>6,3 mg/dl
allopurinol, no significant differences were observed
between the 2 groups in clinical status, HF scores, and 6-
minute walk distances.
 Uric Acid and Cardiovascular Disease
4. Coronary artery disease

Urine acid level (High) associated

Risk of MI & Stroke

Rotterdam study > 55 years
after the
adjustment for
other vascular
risk factors

Urine acid level -- 1 mg/dl (⇡)

A meta-analysis of
prospective cohort studies
the risk of CAD and all-cause mortality
increased by 20% and 9%, respectively
 Coronary artery disease
N = 1124 >6.7 mg/dl
Urine acid level
(elevated)

Japan Study Acute MI patient

higher mortality than their
counterparts
chronic coronary
syndrome
⇡ risk of target lesion revascularization
-- after contemporary drug-eluting stent implantation under intravascular ultrasound guidance

Coronary atherosclerosis
-- may be enhanced by the mechanisms mentioned
before
-- inflammation, oxidative stress, and endothelial
dysfunction
 Coronary artery disease
…previously reported
uric acid level (⇡ ) was correlated with greater coronary lipid plaques
--- assessed by integrated backscatter-intravascular ultrasound in vivo

indicatin
g
possible surrogate of
significant relation of XOR to coronary lipid plaques evaluated by near-
having vulnerable plaque
infrared spectroscopy in patients with chronic coronary syndrome
in patients with acute
coronary syndrome.

Of note, however….
no relations between XOR activity and systemic inflammation
or endothelial function was found
- other mechanisms in the development of coronary atherosclerosis with
- uric acid and XOR beyond endothelial dysfunction and inflammatory
reaction
 Coronary artery disease
epicardial obstructive CAD

In
addition
serum uric acid is reportedly associated
with inflammation and endothelial (e.g. vasospastic angina & coronary microvascular dysfunction)
function in patients with non-
obstructive CAD

XOR activity significantly deteriorated coronary vasospasm

assessed by intracoronary acetylcholine provocation test.
From a multifactorial perspective, uric acid and XOR may play
a role in the development of CAD. Therapeutic significance in
this population remains largely unknown.

Watanabe et al.
 Mendelian randomization and genetic
studies
More recently, a phenome-wide Mendelian randomization study with sensitivity analyses indicated a robust association of
serum uric acid with cardiovascular diseases such as hypertension, CKD, HF, and CAD, although the association was probably
due to the pleiotropic effects of genetic variants on uric acid and metabolic traits.

Mendelian randomization is helpful in this context but does not draw a conclusion, and serum uric acid levels are attributed to
many environmental factors such as nutrient intake, volume status, acid base balance, renal function, and the use of drugs,
beyond genetic factors. Serum uric acid level is at least use- ful for risk stratification, and urate-lowering therapy may improve
clinical outcomes irrespective of the causality.

Serum uric acid level is at least useful for risk stratification, and urate-lowering therapy may improve clinical outcomes irrespective of
the causality.
Uric acid lowering treatment on renal and
cardiovascular disease
.
Urate-lowering treatment can be divided into two main cate-gories, reducing uric acid

production with XO inhibitors (e.g. allopurinol, febuxostat, and topiroxostat) and increasing uric

acid excretion by using uricosurics (e.g. probenecid, benzbromarone, and dotinurad).

Uric acid lowering treatment on renal and
cardiovascular disease
However, recently reported double-blind, placebo-control RCTs such as the FEATHER ( n = 441), CKD-FIX
( n = 363), and PEAL ( n = 530) found no evidence of clinical benefits of serum uric acid reduction with allopurinol
or febuxostat on kidney outcomes among patients with CKD. Thus, a renoprotective effect of urate-lowering
therapy is unclear.
The FEATHER, FREED, and PRIZE studies found no signals of increased mortality with febuxo- stat in
Japanese patients as well as the FAST study, reinforcing the safety of the drug. Other than allopurinol and
febuxostat, the ther- apeutic impact of antihyperuricemic drugs on clinical outcomes is mostly unknown.
In summary, although XO inhibition by allopurinol and febuxostat may provide a benefit on surrogate endpoints such
as BP, endothelial function, proteinuria, and carotid intima-media thickness in a specific population as shown in small clinical
trials, the effiacy of uric acid-lowering treatment on clinical outcomes has not been established.
 Conclusions
Elevated serum uric acid level is associated with cardiovascu- lar diseases
such as hypertension, CKD, HF, and CAD, and is useful for risk stratification.
Despite numerous investigations including Mendelian randomization studies, the
causality is still controversial. The beneficial effect of uric acid-lowering treatment
has been suggested on surrogate endpoints, although the improvement in clinical
outcomes remains unknown. Future studies focusing on patients with elevated uric
acid levels and high cardiovascular risks are warranted.
Thank You 