Giancarlo Marenzi

Circulating microRNAs are new and sensitive biomarkers of myocardial infarction

Aims Circulating microRNAs (miRNAs) may represent a novel class of biomarkers; therefore, we examined whether acute myocardial infarction (MI) modulates miRNAs plasma levels in humans and mice. Methods and results Healthy donors (n = 17) and patients (n = 33) with acute ST-segment elevation MI (STEMI) were evaluated. In one cohort (n = 25), the first plasma sample was obtained 517 ± 309 min after the onset of MI symptoms and after coronary reperfusion with percutaneous coronary intervention (PCI); miR-1, -133a, -133b, and -499-5p were ∼15- to 140-fold control, whereas miR-122 and -375 were ∼87–90% lower than control; 5 days later, miR-1, -133a, -133b, -499-5p, and -375 were back to baseline, whereas miR-122 remained lower than control through Day 30. In additional patients (n = 8; four treated with thrombolysis and four with PCI), miRNAs and troponin I (TnI) were quantified simultaneously starting 156 ± 72 min after the onset of symptoms and at different times thereafter. Peak miR-1, -133a, and -133b expression and TnI level occurred at a similar time, whereas miR-499-5p exhibited a slower time course. In mice, miRNAs plasma levels and TnI were measured 15 min after coronary ligation and at different times thereafter. The behaviour of miR-1, -133a, -133b, and -499-5p was similar to STEMI patients; further, reciprocal changes in the expression levels of these miRNAs were found in cardiac tissue 3–6 h after coronary ligation. In contrast, miR-122 and -375 exhibited minor changes and no significant modulation. In mice with acute hind-limb ischaemia, there was no increase in the plasma level of the above miRNAs. Conclusion Acute MI up-regulated miR-1, -133a, -133b, and -499-5p plasma levels, both in humans and mice, whereas miR-122 and -375 were lower than control only in STEMI patients. These miRNAs represent novel biomarkers of cardiac damage.

Sustained improvement in functional capacity after removal of body fluid with isolated ultrafiltration in chronic cardiac insufficiency: Failure of furosemide to provide the same result

OBJECTIVES This study was designed to investigate whether a subclinical accumulation of fluid in the lung interstitium associated with moderate congestive heart failure interferes with the patients functional capacity, and whether furosemide treatment can promote reabsorption of the excessive fluid. BACKGROUND In patients with moderate congestive heart failure, pulmonary overhydration may be detected by chest roentgenography even if therapy is optimized to keep the urinary output normal and to prevent weight gain and dependent edema formation. Removal of the overhydration may help define its significance. METHODS Patients, whose regimens of digoxin, oral furosemide, and angiotensin-converting enzyme (ACE) inhibitor therapy were kept constant, were randomly allocated to receive ultrafiltration (8 cases) or an intravenous bolus of supplemental furosemide (mean dose: 248 mg; 8 cases). The amount of body fluid removed with each method approximated 1600 mL. Functional performance was assessed with cardiopulmonary exercise tests. RESULTS Soon after fluid withdrawal by either method, the filling pressures of the two ventricles and body weight were reduced and plasma renin activity, norepinephrine, and aldosterone were augmented. After furosemide administration, hormone levels remained elevated for the next 4 days, and during this period, patients had positive water metabolism, recovery of the elevated ventricular filling pressures, and re-occurrence of lung congestion with no improvement in functional capacity. After ultrafiltration, levels of renin, norepinephrine, and aldosterone fell to below control values within the first 48 hours and water metabolism was equilibrated at a new set point (less fluid intake and diuresis without weight gain). The favorable circulatory and ventilatory adjustments consequent to the reabsorption of lung water improved the functional capacity of these patients. That may also have restored the lungs ability to clear norepinephrine, thus restraining its facilitation of renin release. The improvement continued 3 months after the procedure. CONCLUSIONS In patients with congestive heart failure the set point of fluid balance is altered in spite of oral furosemide therapy; supplemental intravenous furosemide does not shift the set point, at least not when combined with ACE inhibition. Excessive, although asymptomatic, lung water limits the functional capacity of the patient.

Contrast volume during primary percutaneous coronary intervention and subsequent contrast-induced nephropathy and mortality

Context Contrast-induced nephropathy (CIN) can complicate percutaneous coronary intervention (PCI). A better understanding of the relationship among contrast volume, patient characteristics, and CIN could help to reduce this complication. Contribution Of 561 patients who underwent primary PCI in the setting of ST-segment elevation myocardial infarction, 20% developed CIN, and those with CIN were more likely than those without CIN to die in hospital. Higher contrast volume and contrast ratio (volume administered/volume calculated) were associated with CIN and in-hospital death. Caution It is unclear whether the worse outcomes were due to the contrast or whether unmeasured aspects of disease severity led to both the need for more contrast and the worse outcomes. The Editors Primary percutaneous coronary intervention (PCI), defined as intervention in the culprit vessel within 12 hours after the onset of chest pain without previous thrombolytic or other clot-dissolving therapy, is the best available strategy for treatment of ST-segment elevation acute myocardial infarction (STEMI) (1). Patients having primary PCI, however, are at higher risk for contrast-induced nephropathy (CIN), although most of them do not have preprocedural renal dysfunction (2). Contrast-induced nephropathy is associated with a marked increase in in-hospital morbidity and mortality rates, which may partially thwart the survival benefit of primary PCI in patients who develop this serious renal complication (2, 3). Effective CIN prevention may further improve the clinical outcome of patients with STEMI who receive primary PCI. Potential preventive strategies include protecting the kidney from contrast- or ischemic-induced injury and limiting the amount of contrast administered. Studies of the antioxidant agent N-acetylcysteine (4) have yielded promising results for kidney protection. N-acetylcysteine has been shown to be effective in reducing CIN incidence and in improving clinical outcomes after emergency or primary PCI, particularly when administered as a high-dose intravenous bolus or with sodium bicarbonate (4, 5). Conversely, because few previous studies have reported the amount of contrast used, data on the effect of contrast volume limitation during primary PCI are lacking. Moreover, investigators disagree on the relation between the volume of contrast administered during interventional procedures and the risk for CIN. Some studies have reported no relationship, whereas others have suggested an independent correlation (614). ST-segment elevation myocardial infarction further complicates the issue. Patients with STEMI who are not undergoing primary PCI may also have acute worsening of renal function with the same prognostic implications as for CIN (15), which suggests that acute kidney injury may result from hemodynamic compromise rather than from CIN per se. In addition, primary PCI success, a major determinant of clinical outcome in patients with STEMI (1618), may require larger amounts of contrast. Thus, an optimal procedural result should be carefully weighed against risk for CIN. The association of contrast volume, as an absolute and a weight- and creatinine-adjusted value (19); CIN incidence; and clinical outcome in the setting of primary PCI remains unknown. As a result, evidence-based recommendations to guide best procedural strategies during primary PCI are still lacking. We sought to prospectively assess the possible association between contrast volume and CIN incidence and in-hospital clinical outcome in patients with STEMI who undergo primary PCI. Methods Study Population We conducted our prospective observational study at the Centro Cardiologico Monzino, University of Milan, between 1 January 2002 and 30 September 2007. We enrolled all consecutive patients with STEMI who were undergoing primary PCI. According to our institute protocol, we included patients who presented within 12 hours (18 hours for STEMI complicated by cardiogenic shock) of the onset of symptoms (characteristic pain lasting for at least 30 minutes, not responsive to nitrates, with electrocardiographic ST-segment elevation of at least 0.2 mV in 2 or more contiguous leads, or left bundle-branch block). We excluded patients receiving long-term peritoneal or hemodialysis treatment. We also excluded patients if they had cardiac surgery for emergency coronary revascularization or STEMI-related mechanical complications, died during PCI, or had been treated with an intravenous bolus of N-acetylcysteine before PCI. The Ethics Committee of the Centro Cardiologico Monzino approved the study, and all patients gave written, informed consent. PCI Procedure A 24-hour on-call interventional team performed primary PCI according to standard clinical practice by using standard guide catheters (6 French), guide wires, and balloon catheters via the femoral approach. Patients received a 5000-U bolus of heparin, followed by additional boluses during the procedure to maintain an activated clotting time longer than 300 seconds (between 200 and 250 seconds when abciximab was used). Coronary stenting was performed with standard technique. Contrast dose was left to the discretion of the interventional cardiologist. All patients received nonionic, low-osmolar contrast agents (iomeprol or iohexol). After contrast exposure, patients received isotonic (0.9%) saline intravenously at a rate of 1 mL/kg per hour for 12 hours. In patients with a left ventricular ejection fraction (LVEF) lower than 40% or overt heart failure, the hydration rate was reduced to 0.5 mL/kg per hour. Poststenting antithrombotic treatment consisted of aspirin and either clopidogrel or ticlopidine at standard dosages. Data Collection We measured serum creatinine concentration in all patients at hospital admission (before primary PCI), every day for the following 3 days, at discharge from the coronary care unit, and at hospital discharge. We estimated creatinine clearance by applying the CockcroftGault formula to the serum creatinine concentration (20). We defined preprocedural renal insufficiency as a creatinine clearance less than 1 mL/s (60 mL/min) (21). We calculated the maximum contrast dose (MCD) for each patient by using the formula proposed by Cigarroa and colleagues (19): MCD (mL) = (5body weight [kg]) divided by serum creatinine (mg/dL). From this contrast limit, we determined the contrast ratio by dividing the administered contrast amount by the calculated MCD. We left the use of -adrenergic blocking agents, angiotensin-converting enzyme inhibitors, platelet glycoprotein IIb/IIIa receptor inhibitors (abciximab), diuretics, intra-aortic balloon pump, or inotropic drug support to the discretion of the interventional and coronary care unit cardiologists, on the basis of the current standards of care recommended by published guidelines (22). During hospitalization, medications were changed as needed at the discretion of the cardiologist responsible for the patient. The primary end point of the study was the occurrence of CIN, defined as a greater than 25% increase in creatinine concentration from the baseline value in the 72 hours after primary PCI (23). In-hospital mortality rate and other major adverse clinical events were also evaluated as secondary end points. Statistical Analysis On the basis of our previous study (2), we calculated a sample size of 550 patients, assuming a 30% incidence of patients exceeding the MCD and a 10% incidence of CIN in patients with a contrast ratio less than 1. This sample size allowed 84% statistical power to assess a significantly higher ( error of 0.05) CIN incidence of 20% (odds ratio, 2) in the group with a contrast ratio greater than 1. We present continuous variables as means (SDs); we compared them by using the t test for independent samples or one-way analysis of variance, as appropriate. We compared categorical data by using the chi-square test or the Fisher exact test, as appropriate. The P values reported in Table 1 were not adjusted for multiple comparisons. Table 1. Patient and Procedure Characteristics We explored the relationship between contrast ratio and maximum percentage increase in creatinine concentration after primary PCI by using linear regression analysis. Both variables were log-transformed before analysis. We estimated predicted probabilities of CIN and mortality from the logistic models with the covariates set to the population average values. We assessed the association among contrast volume, contrast ratio, and clinical outcomes (CIN and in-hospital mortality) through logistic regression analysis. First, we included only contrast volume or contrast ratio (model 1). To adjust for potential confounders selected among recognized clinical predictors of the 2 outcomes (age, body weight, infarct location, LVEF, time to reperfusion, and baseline creatinine level), we developed 2 multivariable logistic regression models: model 2, which adjusted for the 2 major predictors (LVEF and creatinine level), and model 3, which adjusted for the 6 considered variables. Because contrast ratio is a calculated variable that includes both body weight and creatinine, we did not include those 2 variables in the models when we tested the association with contrast ratio. Thus, model 2 included LVEF and time to reperfusion, whereas model 3 included age, infarction location, LVEF, and time to reperfusion. Because of the relatively small number of events, we only considered mortality models with 2 or fewer covariates. To assess whether the effect of contrast volume on CIN differed in patients with renal insufficiency, we stratified our sample according to creatinine clearance (1 or <1 mL/s [60 or <60 mL/min]) and tested the appropriate interaction terms by using logistic regression, adjusting with model 2. All tests were 2-sided. We performed all calculations by using SAS, version 9.13 (SAS Institute, Cary, North Carolina). Role of the Funding Source The Centro Cardiologico Monz

Circulatory response to fluid overload removal by extracorporeal ultrafiltration in refractory congestive heart failure

OBJECTIVES The goal of this study was to investigate the hemodynamic and circulatory adjustments to extracorporeal ultrafiltration (UF) in refractory congestive heart failure (rCHF). BACKGROUND In rCHF, UF allows clinical improvement and restores diuretic efficacy. However, in the course of a UF session, patients are exposed to rapid variations of body fluid composition so that, as fluid is withdrawn from the intravascular compartment, hypotension or even shock could occur. METHODS In 24 patients with rCHF undergoing UF, we measured, after every liter of plasma water removed, hemodynamics, blood gas analysis (in both systemic and pulmonary arteries), plasma volume changes (PV) and plasma refilling rate (PRR). The PV and PRR were calculated by considering hematocrit and ultrafiltrate volume. RESULTS In all patients, UF was performed safely, without side effects or hemodynamic instability (ultrafiltrate = 4,880 +/- 896 ml). Mean right atrial, pulmonary artery and wedge pressures progressively reduced during the procedure. Cardiac output increased at the end of the procedure and, to a greater extent, 24 h later, in relation to the increase of stroke volume. Heart rate and systemic vascular resistance did not increase, and other peripheral biochemical parameters did not worsen during UF. Intravascular volume remained stable throughout the entire duration of the procedure, indicating that a proportional volume of fluid was refilled from the congested parenchyma. CONCLUSIONS In patients with rCHF, subtraction of plasma water by UF is associated with hemodynamic improvement. Fluid refilling from the overhydrated interstitium is the major compensatory mechanism for intravascular fluid removal, and hypotension does not occur when plasma refilling rate is adequate to prevent hypovolemia.

Improvement of Alveolar–Capillary Membrane Diffusing Capacity With Enalapril in Chronic Heart Failure and Counteracting Effect of Aspirin

BACKGROUND KII ACE, the enzyme that converts angiotensin I and inactivates bradykinin, is highly concentrated in the lungs; its blockade reduces exposure to angiotensin II and enhances exposure to prostaglandins generated by local kinin hyperconcentration. Our hypothesis is that ACE inhibitors improve pulmonary function in chronic heart failure (CHF) by readjusting lung vessel tone and permeability or alveolar-capillary membrane diffusion. METHODS AND RESULTS In 16 CHF patients and 16 normal volunteers or mild untreated hypertensives, pulmonary function and exercise tests with respiratory gas analysis were assessed on placebo, enalapril (10 mg BID), enalapril plus aspirin (325 mg/d), or aspirin, in random order and double blind, for 15 days each. In CHF, enalapril increased pulmonary carbon monoxide diffusion (DLCO), oxygen consumption (VO2), and exercise tolerance and reduced the ratio of dead space to tidal volume (VD/VT) and the ventilatory equivalent for carbon dioxide production (VE/VCO2). On enalapril, VO2 (r = .80, P < .0001) and VD/VT (r = -.69, P = .003) changes from placebo correlated with those in DLCO. These effects were inhibited by aspirin and were absent in control subjects. In 8 additional patients, hydralazine-isosorbide dinitrate, as an alternative treatment for reducing pulmonary capillary wedge pressure (PCWP) and increasing exercise capacity, were more effective than enalapril for the PCWP but did not affect DLCO and VE/VCO2; amelioration in VO2 and VD/VT was unrelated to DLCO and was not modified by aspirin. CONCLUSIONS ACE inhibition improved pulmonary diffusion in CHF. Hydralazine-isosorbide dinitrate failed to provide this result. Counteraction by aspirin, a prostaglandin inhibitor, bespeaks prostaglandin participation while on enalapril that might readjust capillary permeability or alveolar-capillary membrane diffusion.

Prevention of contrast nephropathy by furosemide with matched hydration: The MYTHOS (induced diuresis with matched hydration compared to standard hydration for contrast induced nephropathy prevention) trial

OBJECTIVES This study investigated the effect of furosemide-forced diuresis and intravenous saline infusion matched with urine output, using a novel dedicated device designed for contrast-induced nephropathy (CIN) prevention. BACKGROUND CIN is a frequent cause of acute kidney injury associated with increased morbidity and mortality. METHODS A total of 170 consecutive patients with chronic kidney disease (CKD) undergoing coronary procedures were randomized to either furosemide with matched hydration (FMH group, n = 87) or to standard intravenous isotonic saline hydration (control group; n = 83). The FMH group received an initial 250-ml intravenous bolus of normal saline over 30 min followed by an intravenous bolus (0.5 mg/kg) of furosemide. Hydration infusion rate was automatically adjusted to precisely replace the patients urine output. When a urine output rate >300 ml/h was obtained, patients underwent the coronary procedure. Matched fluid replacement was maintained during the procedure and for 4 h post-treatment. The definition of CIN was a ≥25% or ≥0.5 mg/dl rise in serum creatinine over baseline. RESULTS In the FMH group, no device- or therapy-related complications were observed. Four (4.6%) patients in the FMH group developed CIN versus 15 (18%) controls (p = 0.005). A lower incidence of cumulative in-hospital clinical complications was also observed in FMH-treated patients than in controls (8% vs. 18%; p = 0.052). CONCLUSIONS In patients with CKD undergoing coronary procedures, furosemide-induced high urine output with matched hydration significantly reduces the risk of CIN and may be associated with improved in-hospital outcome. (Induced Diuresis With Matched Hydration Compared to Standard Hydration for Contrast Induced Nephropathy Prevention [MYTHOS]; NCT00702728).

Interrelation of humoral factors, hemodynamics, and fluid and salt metabolism in congestive heart failure: Effects of extracorporeal ultrafiltration

PURPOSE We investigated the mechanisms involved in the regulation of salt and water metabolism in patients with congestive heart failure (CHF). Extracorporeal ultrafiltration was utilized as a nonpharmacologic method for withdrawal of body fluid. PATIENTS, METHODS, AND RESULTS In 32 consecutive patients with CHF (New York Heart Association functional class II to IV) and different degrees of water retention, 24-hour diuresis and natriuresis were inversely best correlated with the combination of circulating renin, aldosterone, norepinephrine, and renal perfusion pressure (RPP, mean aortic pressure minus mean right atrial pressure). Fluid withdrawal (600 to 5,000 mL) at a rate of 500 mL/h, until right atrial pressure decreased to 50% of baseline, caused variable humoral, circulatory, and diuretic effects that were mainly related to the extent of fluid retention. In fact, in 10 patients (Group 1) with overhydration refractory to drug therapy and with urinary output less than 1,000 mL/24 h (mean, 370 mL), soon after the procedure, plasma renin (-39%), aldosterone (-50%), and norepinephrine (-47%) were reduced and RPP was increased (+16%), and in the subsequent 24 hours, diuresis was increased by 493%; in 9 patients (Group 2) whose baseline urinary output exceeded 1,000 mL/24 h (mean, 1,785 mL), renin increased by 40%, norepinephrine, aldosterone, and RPP each decreased by 12%, and diuresis remained unchanged; in 13 patients (Group 3) with a daily urinary excretion as in Group 2 and without overhydration, RPP decreased (-7%), renin (+196%), aldosterone (+170%), and norepinephrine (+52%) increased, and diuresis decreased by 45%. There was an overall correlation (p < 0.0001) between the combination of changes in these circulatory and hormonal variables and changes in diuresis and natriuresis with ultrafiltration. CONCLUSIONS It appears that in CHF, (1) retention of sodium and water results from an interaction of hormonal and hemodynamic (primarily RPP) alterations that may exert a reciprocal positive feedback; (2) depending on the presence and severity of fluid retention, the response to withdrawal of body fluid may vary from neurohumoral activation and restriction of diuresis to neurohumoral depression and extreme potentiation of salt and water excretion; (3) refractory CHF requires the interruption of the humoral-hemodynamic vicious circle, and ultrafiltration is able to accomplish that.

Circulating CD4+CD25hiCD127lo Regulatory T-Cell Levels Do Not Reflect the Extent or Severity of Carotid and Coronary Atherosclerosis

Objective—Regulatory T (Treg) cells play a protective role in experimental atherosclerosis. In the present study, we investigated whether the levels of circulating Treg cells relate to the degree of atherosclerosis in carotid and coronary arteries. Methods and Results—We studied 2 distinct populations: (1) 113 subjects, selected from a free-living population (carotid study), in which we measured the intima-media thickness of the common carotid artery, as a surrogate marker of initial atherosclerosis; and (2) 75 controls and 125 patients with coronary artery disease (coronary study): 36 with chronic stable angina, 50 with non-ST-elevation acute coronary syndrome, 39 with ST-elevation acute myocardial infarction. Treg-cell levels were evaluated by flow cytometry (Treg cells identified as CD3+CD4+CD25highCD127low) and by mRNA expression of forkhead box P3 or of Treg-associated cytokine interleukin 10. In the carotid study, no correlation was observed between Treg-cell levels and intima-media thickness. No differences in Treg-cell levels were observed comparing rapid versus slow intima-media thickness progressors from a subgroup of patients (n=65), in which prospective data on 6-year intima-media thickness progression were available. In the coronary group, Treg-cell levels were not altered in chronic stable angina patients. In contrast, nonunivocal variations were observed in patients suffering an acute coronary syndrome (with a Treg-cell increase in ST-elevation acute myocardial infarction and a Treg-cell decrease in non-ST-elevation acute coronary syndrome patients). Conclusion—The results suggest that determination of circulating Treg-cell levels based on flow cytometry or mRNA assessment is not a useful indicator of the extent or severity of atherosclerosis.

Apparent paradox of neurohumoral axis inhibition after body fluid volume depletion in patients with chronic congestive heart failure and water retention.

BACKGROUND--Hypovolaemia stimulates the sympathoadrenal and renin systems and water retention. It has been proposed that in congestive heart failure reduction of cardiac output and any associated decrease in blood pressure cause underfilling of the arterial compartment, which promotes and perpetuates neurohumoral activation and the retention of fluid. This study examined whether an intravascular volume deficit accounts for patterns that largely exceed the limits of a homoeostatic response, which are sometimes seen in advanced congestive heart failure. METHODS AND RESULTS--In 22 patients with congestive heart failure and water retention the body fluid mass was reduced by ultrafiltration and the neurohumoral reaction was monitored. A Diafilter, which was part of an external venous circuit was regulated to produce 500 ml/hour of ultrafiltrate (mean (SD) 3122 (1199) ml) until right atrial pressure was reduced to 50% of baseline. Haemodynamic variables, plasma renin activity, noradrenaline, and aldosterone were measured before and within 48 hours of ultrafiltration. After ultrafiltration, which produced a 20% reduction of plasma volume and a moderate decrease in cardiac output and blood pressure (consistent with a diminished degree of filling of the arterial compartment), there was an obvious decrease in noradrenaline, plasma renin activity, and aldosterone. In the next 48 hours plasma volume, cardiac output, and blood pressure recovered; the neurohumoral axis was depressed; and there was a striking enhancement of water and sodium excretion with resolution of the peripheral oedema and organ congestion. The neurohumoral changes and haemodynamic changes were not related. There were significant correlations between the neurohumoral changes and increase in urinary output and sodium excretion. CONCLUSIONS--In advanced congestive heart failure arterial underfilling was not the main mechanism for activating the neurohumoral axis and retaining fluid. Because a decrease in circulating hormones was associated with reabsorption of extravascular fluid it is likely that hypoperfusion and/or congestion of organs, such as the kidney and lung, reduce the clearance of circulating noradrenaline and help to keep plasma concentrations of renin and aldosterone raised. A positive feedback loop between fluid retention and plasma hormone concentrations may be responsible for progression of congestive heart failure.

High-dose N-acetylcysteine for the Prevention of Contrast-induced Nephropathy

BACKGROUND Whether N-acetylcysteine is beneficial for the prevention of contrast-induced nephropathy is uncertain. METHODS We conducted a meta-analysis to evaluate the efficacy of high-dose N-acetylcysteine for the prevention of contrast-induced nephropathy. Our prespecified inclusion criteria were as follows: adult subjects; English language literature; administration of high-dose N-acetylcysteine a priori defined as a daily dose greater than 1200 mg or a single periprocedural dose (within 4 hours of contrast exposure) greater than 600 mg; prospective trials of individuals randomized to N-acetylcysteine, administered orally or intravenously, versus a control group; and trials that included the end point of the incidence of contrast-induced nephropathy. Trials that compared N-acetylcysteine with another active treatment were excluded. RESULTS Sixteen comparisons of patients randomized to high-dose N-acetylcysteine versus controls met our prespecified inclusion criteria with a total sample size of 1677 subjects (842 assigned to high-dose N-acetylcysteine and 835 assigned to the control arm). The average population age was 68 years, 38.7% were diabetic, and the majority was male (67.8% of reported instances). The weighted mean baseline creatinine of the overall population was 1.58 mg/dL. No significant heterogeneity was detected (P = .09; I(2) = 34%). The overall effect size assuming a common odds ratio revealed an odds ratio of 0.46 (95% confidence interval [CI], 0.33-0.63) for the occurrence of contrast-induced nephropathy with the use of high-dose N-acetylcysteine. The results of the more conservative random effects approach were similar (odds ratio = 0.52; 95% CI, 0.34-0.78). There was no evidence of publication bias (P = .34). CONCLUSION Our results suggest that high-dose N-acetylcysteine decreases the incidence of contrast-induced nephropathy.