Evidence for a pathogenetic role of xanthine oxidase in the "stunned" myocardium

Charlat, M. I.; O’Neill, Padraig Gearoid; Egan, JM; Abernethy, D. R.; Michael, L. H.; Myers, Mary Lee; Roberts, Robert; Bolli, Roberto

doi:10.1152/ajpheart.1987.252.3.h566

Cited by 62 publications

(34 citation statements)

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“…20 In humans, studies report myocardial XO activity to be either high, 21 low, 22 or undetectable. 23,24 Although there is some considerable evidence that suggests that the enzyme XO may indeed be expressed in the human myocardium, [25][26][27] we believe that the effect may be local. No systemic effects from the myocardial activity of XO have been reported.…”

Section: Discussionmentioning

confidence: 89%

Uric Acid and Survival in Chronic Heart Failure

et al. 2003

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Background-Serum uric acid (UA) could be a valid prognostic marker and useful for metabolic, hemodynamic, and functional (MFH) staging in chronic heart failure (CHF). Methods and Results-For the derivation study, 112 patients with CHF (age 59Ϯ12 years, peak oxygen consumption [V O 2 ] 17Ϯ7 mL/kg per minute) were recruited. In separate studies, we validated the prognostic value of UA (nϭ182) and investigated the relationship between MFH score and the decision to list patients for heart transplantation (nϭ120). In the derivation study, the best mortality predicting UA cutoff (at 12 months) was 565 mol/L (9.50 mg/dL) (independently of age, peak V O 2 , left ventricular ejection fraction, diuretic dose, sodium, creatinine, and urea; PϽ0.0001). In the validation study, UA Ն565 mol/L predicted mortality (hazard ratio, 7.14; PϽ0.0001). In 16 patients (from both studies) with UA Ն565 mol/L, left ventricular ejection fraction Յ25% and peak V O 2 Յ14 mL/kg per min (MFH score 3), 12-month survival was lowest (31%) compared with patients with 2 (64%), 1 (77%), or no (98%, PϽ0.0001) risk factor. In an independent study, 51% of patients with MFH score 2 and 81% of patients with MFH score 3 were listed for transplantation. The positive predictive value of not being listed for heart transplantation with an MFH score of 0 or 1 was 100%. Conclusions-High serum UA levels are a strong, independent marker of impaired prognosis in patients with moderate to severe CHF. The relationship between serum UA and survival in CHF is graded. MFH staging of patients with CHF is feasible.

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Section: Discussionmentioning

confidence: 89%

Uric Acid and Survival in Chronic Heart Failure

et al. 2003

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“…The source of the oxygen radicals is unclear, although xanthine oxidase may be an important mediator of oxyradical production (21). Oxyradicals may interact with cellular proteins, lipids, calcium, and myofilaments to induce contractile depression.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1β

Pomerantz

Reznikov

Harken

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

280

188

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The proinflammatory cytokine IL-18 was investigated for its role in human myocardial function. An ischemia͞reperfusion (I͞R) model of suprafused human atrial myocardium was used to assess myocardial contractile force. Addition of IL-18 binding protein (IL-18BP), the constitutive inhibitor of IL-18 activity, to the perifusate during and after I͞R resulted in improved contractile function after I͞R from 35% of control to 76% with IL-18BP. IL-18BP treatment also preserved intracellular tissue creatine kinase levels (by 420%). Steady-state mRNA levels for IL-18 were elevated after I͞R, and the concentration of IL-18 in myocardial homogenates was increased (control, 5.8 pg͞mg vs. I͞R, 26 pg͞mg; P < 0.01). Active IL-18 requires cleavage of its precursor form by the IL-1␤-converting enzyme (caspase 1); inhibition of caspase 1 also attenuated the depression in contractile force after I͞R (from 35% of control to 75.8% in treated atrial muscle; P < 0.01). Because caspase 1 also cleaves the precursor IL-1␤, IL-1 receptor blockade was accomplished by using the IL-1 receptor antagonist. IL-1 receptor antagonist added to the perifusate also resulted in a reduction of ischemia-induced contractile dysfunction. These studies demonstrate that endogenous IL-18 and IL-1␤ play a significant role in I͞R-induced human myocardial injury and that inhibition of caspase 1 reduces the processing of endogenous precursors of IL-18 and IL-1␤ and thereby prevents ischemia-induced myocardial dysfunction.

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“…We found that the xanthine oxidase inhibitor, allopurinol, produced a marked improvement in the functional recovery of the stunned myocardium.136 Furthermore, allopurinol inhibited the increased cardiac production of urate observed in control dogs during ischemia and early reperfusion, indicating effective inhibition of xanthine oxidoreductase. 136 Attenuation of stunning has also been demonstrated with oxypurinol after 15137 and 90 minutes138 of ischemia and reperfusion. These data suggest that xanthine oxidase is one of the sources of the oxygen radicals that contribute to postischemic dysfunction in the dog.…”

Section: Decreased Sensitivity Of Myofilaments To Calciummentioning

confidence: 97%

Mechanism of myocardial "stunning".

1990

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Among the numerous mechanisms proposed for myocardial stunning, three appear to be more plausible: 1) generation of oxygen radicals, 2) calcium overload, and 3) excitation-contraction uncoupling. First, the evidence for a pathogenetic role of oxygen-derived free radicals in myocardial stunning is overwhelming. In the setting of a single 15-minute coronary occlusion, mitigation of stunning by antioxidants has been reproducibly observed by several independent laboratories. Similar protection has been recently demonstrated in the conscious animal, that is, in the most physiological experimental preparation available. Furthermore, generation of free radicals in the stunned myocardium has been directly demonstrated by spin trapping techniques, and attenuation of free radical generation has been repeatedly shown to result in attenuation of contractile dysfunction. Numerous observations suggest that oxyradicals also contribute to stunning in other settings: after global ischemia in vitro, after global ischemia during cardioplegic arrest in vivo, and after multiple brief episodes of regional ischemia in vivo. Compelling evidence indicates that the critical free radical damage occurs in the initial moments of reflow, so that myocardial stunning can be viewed as a sublethal form of oxyradical-mediated "reperfusion injury." Second, there is also considerable evidence that a transient calcium overload during early reperfusion contributes to postischemic dysfunction in vitro; however, the importance of this mechanism in vivo remains to be defined. Third, inadequate release of calcium by the sarcoplasmic reticulum, with consequent excitation-contraction uncoupling, may occur after multiple brief episodes of regional ischemia, but its role in other forms of postischemic dysfunction has not been explored. It is probable that multiple mechanisms contribute to the pathogenesis of myocardial stunning. The three hypotheses outlined above are not mutually exclusive and in fact may represent different steps of the same pathophysiological cascade. Thus, generation of oxyradicals may cause sarcoplasmic reticulum dysfunction, and both of these processes may lead to calcium overload, which in turn could exacerbate the damage initiated by oxygen species. The concepts discussed in this review should provide not only a conceptual framework for further investigation of the pathophysiology of reversible ischemia-reperfusion injury but also a rationale for developing clinically applicable interventions designed to prevent postischemic ventricular dysfunction.

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Evidence for a pathogenetic role of xanthine oxidase in the "stunned" myocardium

Cited by 62 publications

References 0 publications

Uric Acid and Survival in Chronic Heart Failure

Uric Acid and Survival in Chronic Heart Failure

Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1β

Mechanism of myocardial "stunning".

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