Elevated serum uric acid levels are associated with diastolic dysfunction in patients with dilated cardiomyopathy

Cicoira, Mariantonietta; Zanolla, Luisa; Rossi, Andrea; Golia, Giorgio; Franceschini, Lorenzo; Brighetti, Giovanna; Zeni, Prisca; Zardini, Piero

doi:10.1067/mhj.2002.122122

Cited by 86 publications

(70 citation statements)

References 31 publications

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“…28 We included patients with relatively severe CHF patients compared with those in the former study and furthermore we measured the transcardiac gradient of UA, which increased with the severity of CHF. These differences in our study may support the possibility that XO is activated, especially in severe CHF, and contributes to cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Serum Level of Uric Acid, Partly Secreted From the Failing Heart, is a Prognostic Marker in Patients With Congestive Heart Failure

Sakai

Tsutamoto

Tsutsui

et al. 2006

Circ J

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Methods PatientsStudy 1 Fifty consecutive patients with mild to severe CHF (left ventricular ejection fraction (LVEF) <45%, New York Heart Association (NYHA) functional classes II-IV) underwent diagnostic cardiac catheterization. Patients taking allopurinol, with renal failure, malignancy or congenital malformations of the heart or vessels were excluded. Renal failure was defined as an estimated glomerular filtration rate (eGFR) <30 ml · min -1 · (1.73 m 2 ) -1 according to the MDRD equation. 20 Informed consent was given by all patients before participating in the study, and the protocol Background A recent study suggested that xanthine oxidase is activated in congestive heart failure (CHF). However, whether uric acid (UA) is secreted from the failing heart remains unknown, so it is currently unclear whether serum UA can provide prognostic information independent of brain natriuretic peptide (BNP). Methods and ResultsSerum UA was measured in the aortic root (AO) and the coronary sinus (CS) of 74 patients with CHF. The serum UA level was significantly higher in the CS than in the AO. The transcardiac gradient of UA (CS -AO) increased with the severity of CHF, inversely correlated with left ventricular ejection fraction (LVEF) and positively correlated with left ventricular end-diastolic volume index. The plasma levels of norepinephrine, BNP, UA, and LVEF were monitored prospectively in 150 CHF patients for a mean follow-up of 3 years. High plasma levels of UA (p<0.001) and BNP (p<0.001) were shown by multivariate stepwise analysis to be independent predictors of mortality. Conclusions High plasma UA level, partly secreted from the failing heart, is a prognostic predictor independent of BNP in patients with CHF. Monitoring a combination of BNP and UA may be useful for the management of patients with CHF. (Circ J 2006; 70: 1006 -1011

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Section: Discussionmentioning

confidence: 99%

Serum Level of Uric Acid, Partly Secreted From the Failing Heart, is a Prognostic Marker in Patients With Congestive Heart Failure

Sakai

Tsutamoto

Tsutsui

et al. 2006

Circ J

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“…Neurohumoral/mechanical stimulation with AIIϩP probably activated AMPD as reflected by increased adenine nucleotide catabolism and loss in phosphorylation potential. Intriguingly, AMP catabolites, particularly uric acid, are associated with worsened CHF prognosis and independent predictors of elevated diastolic pressure (Cicoira et al, 2002). Among the proposed mechanisms for this are increases in xanthine oxidase expression and activity that enhance purine catabolism and urate synthesis and serve as a source for oxidative stress (Doehner et al, 2002).…”

Section: Controlsmentioning

confidence: 99%

“…Increased Mg 2ϩ -ADP competes with ATP-myosin binding to favor strongly bound cross-bridges that increase stiffness and slow motor velocity. Cross-activity of MMP9 on AMP catabolism (Iwaki-Egawa et al, 2001) could contribute to the formation of oxypurines, such as uric acid, which itself is correlated with diastolic dysfunction in heart-failure patients (Cicoira et al, 2002). Accordingly, the present study examined the effect of a broad MMP inhibitor on cardiac function, the extracellular matrix, and HEP stores and enzymatic activities involved in AMP catabolism in a canine model of subacute heart failure (AIIϩP) exhibiting prominent diastolic dysfunction.…”

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confidence: 99%

Metalloproteinase Inhibitor Counters High-Energy Phosphate Depletion and AMP Deaminase Activity Enhancing Ventricular Diastolic Compliance in Subacute Heart Failure

Paolocci

Tavazzi

Biondi

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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Cardiac matrix metalloproteinases (MMPs) stimulated by the sympathomimetic action of angiotensin II (AII) exacerbate chamber diastolic stiffening in models of subacute heart failure. Here we tested the hypothesis that MMP inhibition prevents such stiffening by favorably modulating high-energy phosphate (HEP) stores more than by effects on matrix remodeling. Dogs were administered AII i.v. for 1 week with tachypacing superimposed in the last two days (AIIϩP; n ϭ 8). A second group (n ϭ 9) underwent the same AIIϩP protocol but was preceded by oral treatment with an MMP inhibitor PD166793 [(S)-2-(4-bromo-biphenyl-4-sulfonylamino-3-methyl butyric acid] 1 week before and during the AIIϩP period. Pressure-volume analysis was performed in conscious animals, and myocardial tissue was subjected to in vitro and in situ zymography, collagen content, and HEP analysis (high-performance liquid chromatography). As reported previously, AIIϩP activated MMP9 and MMP2 and specifically exacerbated diastolic stiffening (ϩ130% in chamber stiffness). PD166793 cotreatment prevented these changes, although myocardial collagen content, subtype, and cross-linking were unaltered. AIIϩP also reduced ATP, free energy of ATP hydrolysis (⌬G ATP ), and phosphocreatine while increasing free [ADP], AMP catabolites (nucleoside-total purines), and lactate. PD166793 reversed most of these changes, in part due to its inhibition of AMP deaminase. MMP activation may influence cardiac diastolic function by mechanisms beyond modulation of extracellular matrix. Interaction between MMP activation and HEP metabolism may play an important role in mediating diastolic dysfunction. Furthermore, these data highlight a potential major role for increased AMP deaminase activity in diastolic dysfunction.

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“…First, there is evidence that increased levels of uric acid strongly correlate with mortality rates in congestive heart failure ( Fig. 6) (Alderman, 2002;Cicoira et al, 2002;Doehner et al, 2002;Anker et al, 2003;Alderman and Aiyer, 2004), and XO inhibitors exert certain beneficial effects both in animals and humans with heart failure (see Table 3). Second, allopurinol and its active metabolite oxypurinol are well known and relatively safe drugs that have been used for decades to treat gout.…”

Section: Therapeutic Effects Of Xanthine Oxidase Inhibitorsmentioning

confidence: 99%

Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol

Pacher

Nivorozhkin

Szabó

2006

Pharmacological Reviews

1,062

837

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Elevated serum uric acid levels are associated with diastolic dysfunction in patients with dilated cardiomyopathy

Cited by 86 publications

References 31 publications

Serum Level of Uric Acid, Partly Secreted From the Failing Heart, is a Prognostic Marker in Patients With Congestive Heart Failure

Serum Level of Uric Acid, Partly Secreted From the Failing Heart, is a Prognostic Marker in Patients With Congestive Heart Failure

Metalloproteinase Inhibitor Counters High-Energy Phosphate Depletion and AMP Deaminase Activity Enhancing Ventricular Diastolic Compliance in Subacute Heart Failure

Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol

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