Carlo Sponzilli

Activation of complement and kinin systems after thrombolytic therapy in patients with acute myocardial infarction. A comparison between streptokinase and recombinant tissue-type plasminogen activator

BackgroundWe have previously shown that treatment with streptokinase induces abrupt complement activation and transient neutropenia in patients with acute myocardial infarction (AMI). The purpose of this study was to compare the effects of two different thrombolytic agents—streptokinase (SK) and recombinant tissue-type plasminogen activator (rTPA)—on activation of the complement and kinin systems in plasma of patients with AMI. Methods and ResultsForty-one patients with AMI who were eligible for thrombolytic therapy were studied. Twenty-three patients were treated with streptokinase (1.5 million IU IV over 60 minutes) and 18 were treated with rTPA (8 with bolus of 10 mg IV, followed by 50 mg infused over 60 minutes and then 40 mg infused over 120 minutes; 10 patients were administered rTPA and heparin according to the accelerated infusion protocol indicated by the GUSTO study). C4a and C3a were measured by radioimmunoassay, soluble terminal complement components (SC5b-9) and anti-SK IgG antibodies were measured by ELISA. Cleaved high molecular weight kininogen (HK) was quantitated in plasma by SDS-PAGE and immunoblotting analysis. C4a levels were significantly and similarly increased in both groups, whereas the levels of C3a and SC5b-9 after rTPA infusion were only slightly elevated and were significantly lower than after SK. No differences were observed between patients treated with slow or accelerated rTPA regimens. The titer of antibodies to SK was highly correlated with the levels of C3a and SC5b- 9, whereas a lesser correlation was observed with C4a. Treatment with rTPA did not induce the transient neutropenia observed after SK infusion. The cleavage products of HK were significantly greater after SK than after rTPA infusion. ConclusionsOur results show that both thrombolytic agents activate the classic complement pathway and that plasmin could be the common trigger for this phenomenon. A significant activation of the complement common pathway (from C3 to terminal components) was observed only with SK infusion and is attributable to the rapid formation of immunocomplexes between SK and anti-SK antibodies present in plasma as a consequence of previous streptococcal infections. The minimal activation of C5 component of the common pathway explains the absence of leukopenia in patients treated with rTPA. Cleavage of HK, larger after SK than after rTPA infusion, represents a condition enhancing the generation of bradykinin by kallikrein. The recent experimental data that indicate a damaging effect of complement activation on the infarcted zone and the contrasting favorable effect consequent to bradykinin formation raise some questions about the clinical importance of the different biological consequences of SK versus rTPA.

Prevention of Contrast‐induced Nephropathy: A Single Center Randomized Study

Contrast‐induced nephropathy (CIN) is the third cause of acute deterioration of renal function in hospitalized patients.

Dobutamine stress echocardiography for the identification of multivessel coronary artery disease after uncomplicated myocardial infarction: the importance of test end-point

Our aim was to verify whether the sensitivity of pharmachological stress echocardiography for multivessel disease after acute myocardial infarction may be improved by a more aggressive protocol, i.e. not considering the appearance of the first wall motion abnormality as the absolute end-point if it occurs in the infarcted area without clinical or instrumental markers of extensive ischemia or left ventricular dysfunction. One-hundred twenty-one consecutive patients (age 32-71 years) prospectively underwent dobutamine-atropine stress echo (dobutamine infusion up to 40 micrograms/kg/min with additional atropine 1 mg) 11.8 +/- 4.8 days after uncomplicated myocardial infarction and coronary angiography within 6 weeks. Criteria for stopping the test were: significant ST depression or elevation, typical chest pain, major arrhythmias and left ventricular dysfunction. The test was considered as positive if a deterioration of basal wall motion pattern was observed: it was defined homozonally positive (the deterioration occurred in the myocardial area fed by the culprit vessel) or heterozonally positive (the deterioration occurred in a different vascular area). A coronary stenosis > 70% of vessel lumen was defined as critical. Thirty-four patients showed a negative test result. Among the 87 patients with positive test, 65 had no further wall motion deterioration from the first-induced wall motion abnormality (WMA) to peak test (Group A), whereas nine patients showed further homozonal (Group B) and 13 further heterozonal (Group C) asynergies. Sensitivity, specificity and accuracy of dobutamine stress echocardiography for multivessel disease were, respectively, 63%, 96% and 82% using the first-induced wall motion abnormality as test end-point, whilst they were 84% (P < 0.01), 93% and 89% according to the aggressive approach previously described. Dobutamine stress time of patients with multivessel disease was higher in Groups B and C (13.1 +/- 3.6 min) than in Group A (9.8 +/- 3.7 min, P < 0.01) and, finally, the mean obstruction of non-culprit vessel was higher in Group A (62.2%) than in Group C (47.4%, P < 0.05). No major complications were found. We conclude that the sensitivity of dobutamine stress echocardiography for multivessel disease following recent myocardial infarction is critically dependent on the test end-point. It may be improved by a more aggressive approach capable to identify less severe heterozonal coronary lesions.

A comparison between two different definitions of contrast-induced acute kidney injury in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

BACKGROUND Contrast-induced acute kidney injury (CI-AKI) is associated with significantly increased mortality after primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI). The prognostic value of CI-AKI depends on the definitions used to define it. We compare the predictive accuracy of long-term mortality of two definitions of CI-AKI on consecutive patients undergoing pPCI for STEMI. METHODS Incidence, risk factors and long-term prognosis of CI-AKI were assessed according to two different definitions: the first as an increase in serum creatinine ≥ 25% or ≥ 0.5 mg/dl from baseline within 72 h after pPCI (contrast-induced nephropathy (CIN) criteria), the second one according to Acute Kidney Injury Network (AKIN) classification system. RESULTS A total of 402 patients were enrolled. The median follow-up period was 12 ± 4 months. Long-term mortality rate was 9.5%. Independent predictors of long-term mortality were: older age, basal renal impairment, left ventricular ejection fraction <40%, in-hospital major bleedings and CI-AKI. A significant correlation was found between mortality and CI-AKI as assessed by both CIN (HR 4.84, 95% CI: 2.56-9.16, p=0.000) and AKIN (HR 9.70, 95% CI: 5.12-18.37, p=0.000) definitions. The area under the receiver operating curve was significantly larger for predicting mortality with AKIN classification than with CIN criteria (0.7984 versus 0.7759; p=0.0331). CONCLUSIONS In patients with STEMI treated by pPCI, CI-AKI is a frequent complication irrespective of the criteria used for its definition. AKIN, however, seems to provide a better accuracy in predicting long-term mortality than CIN criteria.

Clinical and angiographic correlates of dobutamine-induced wall motion patterns after myocardial infarction

The ability of different dobutamine-induced wall motion patterns to define the anatomic status of the infarct-related artery (IRA) was evaluated in 159 patients who underwent dobutamine stress echocardiography (DSE) and coronary angiography 10 +/- 2 and 18 +/- 3 days, respectively, after hospital admission. The DSE result was classified as: (1) biphasic: improvement with a low dose followed by deterioration with a high dose; (2) worsening: direct deterioration at low or high doses; (3) sustained improvement: improvement with a low dose that was maintained at high dose; and (4) no change: no change during the entire protocol. A diameter narrowing >70% (50% for the left main stem) of major coronary arteries indicated a severe lesion. Angiograms were classified according to the jeopardy score and collateral circulation graded according to Rentrops classification. DSE was positive in 92 patients (22 had biphasic results and 70 had worsening results) and negative in 67 patients (14 had sustained improvement and 53 had no changes). Biphasic response was associated with more frequent anterior infarction (p <0.05) and higher resting (p <0.001) and peak (p <0.01) wall motion score indexes. The IRA was totally occluded in 4 of the 92 patients (4%) with positive (worsening pattern) and 12 of the 67 patients (18%) with negative (no change pattern) tests. The biphasic pattern was associated with the highest jeopardy score and was significantly (p <0.05) more specific (100%) compared with worsening (78%) in identifying a severe stenosis of the IRA. The combination of ischemic patterns provided a significantly superior sensitivity (p <0.0001). Logistic regression analysis identified the biphasic pattern as the only significant predictor. Conversely, the prediction of total occlusion of the IRA was poor. Sustained improvement was the most specific (100%) predictor of absence of severe stenosis of the IRA, whereas the combination with no change pattern provided a significantly superior sensitivity (p <0.0001). Thus, DSE effectively predicts the residual stenosis of the IRA. In particular, the biphasic response has an excellent specificity and positive predictive value and is the only significant predictor among clinical and echocardiographic variables.

Intracoronary Epinephrine for Contrast-Medium-Induced Microvascular Obstruction in a Chronically Hemodialyzed Patient

istered intravenously. The fi rst injection of the non-ionic, iso-osmolar CM iodixanol revealed an apparently normal fl ow in the whole left coronary, but at the following angiogram a distal stagnation of previously injected CM was detected ( fi g. 1 ). Coronary Dear Sir, Due to their burden of coronary artery disease, end-stage renal disease (ESRD) patients often need cardiac catheterization procedures. Coronary angiography performed in ESRD patients is associated with a high incidence of complications, mostly radiographic contrast medium (CM)-induced nephropathy [1] . Nevertheless, no data exist about CM-related coronary vasomotor or thrombogenic effects in this population. Epinephrine improves coronary fl ow in patients with no-refl ow after coronary percutaneous intervention [2] , but, to our knowledge, its use in the treatment of coronary fl ow impairment of other etiologies has never been described. Here, we report the use of intracoronary epinephrine in an ESRD patient who experienced a case of sudden impairment in myocardial perfusion during a coronary angiography. A 68-year-old Caucasian male underwent coronary angiography for dilated cardiomyopathy. He presented with hypertension and ESRD treated by hemodialysis. Home therapy consisted of carvedilol 6.25 mg daily, calcitriol 0.25 g daily, calcium carbonate 0.5 g daily, polystyrene sulfonate 30 g daily and erythropoietin 2,000 U every 2 weeks. Blood analysis showed potassium 5.3 mmol/l, sodium 147 mmol/l, creatinine 6 mg/dl, urea 97 mg/dl and hemoglobin 11.5 mg/dl. Basal electrocardiogram revealed a sinus rhythm and a left bundle branch block. Before cardiac catheterization, 1,000 U of heparin were adminReceived: September 29, 2004 Accepted: October 4, 2004 Published online: April 12, 2005

APpropriAteness of percutaneous Coronary interventions in patients with ischaemic HEart disease in Italy: The APACHE pilot study

Objectives To first explore in Italy appropriateness of indication, adherence to guideline recommendations and mode of selection for coronary revascularisation. Design Retrospective, pilot study. Setting 22 percutaneous coronary intervention (PCI)-performing hospitals (20 patients per site), 13 (59%) with on-site cardiac surgery. Participants 440 patients who received PCI for stable coronary artery disease (CAD) or non-ST elevation acute coronary syndrome were independently selected in a 4:1 ratio with half diabetics. Primary and secondary outcome measures Proportion of patients who received appropriate PCI using validated appropriate use scores (ie, AUS≥7). Also, in patients with stable CAD, we examined adherence to the following European Society of Cardiology recommendations: (A) per cent of patients with complex coronary anatomy treated after heart team discussion; (B) per cent of fractional flow reserve-guided PCI for borderline stenoses in patients without documented ischaemia; (C) per cent of patients receiving guideline-directed medical therapy at the time of PCI as well as use of provocative test of ischaemia according to pretest probability (PTP) of CAD. Results Of the 401 mappable PCIs (91%), 38.7% (95% CI 33.9 to 43.6) were classified as appropriate, 47.6% (95% CI 42.7 to 52.6) as uncertain and 13.7% (95% CI 10.5% to 17.5%) as inappropriate. Median PTP in patients with stable CAD without known coronary anatomy was 69% (78% intermediate PTP, 22% high PTP). Ischaemia testing use was similar (p=0.71) in patients with intermediate (n=140, 63%) and with high PTP (n=40, 66%). In patients with stable CAD (n=352) guideline adherence to the three recommendations explored was: (A) 11%; (B) 25%; (C) 23%. AUS was higher in patients evaluated by the heart team as compared with patients who were not (7 (6.8) vs 5 (4.7); p=0.001). Conclusions Use of heart team approaches and adherence to guideline recommendations on coronary revascularisation in a real-world setting is limited. This pilot study documents the feasibility of measuring appropriateness and guideline adherence in clinical practice and identifies substantial opportunities for quality improvement. Trial registration number NCT02748603.

Acute myocardial infarction as first manifestation of left atrial myxoma in a young woman: role of echocardiography.

We report the case of a young woman with an acute myocardial infarction secondary to coronary embolization from a left atrial myxoma, as unusual presentation of a cardiac tumor.We also describe the role of transthoracic echocardiograpy in the multidisciplinary approach to diagnosis and treatment of this life-threatening condition.

COMPARISON OF CRUSADE AND ACUITY-HORIZONS BLEEDING RISK SCORES IN PATIENTS WITH ACUTE CORONARY SYNDROMES

BACKGROUND Compare the discriminative performance of two validated bleeding risk models for in-hospital bleeding events in a non-selected cohort of acute coronary syndrome (ACS) patients. METHODS CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) and ACUITY-HORIZONS (Acute Catheterization and Urgent Intervention Triage strategY-Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) scores were calculated in 501 consecutive patients (median age 68 years (IQR 57-77), 31% female) admitted for ACS to the coronary care unit (CCU) of San Paolo Hospital in Milan (Italy). In-hospital haemorrhagic events and mortality were recorded and calibration and discrimination of the two risk models were evaluated using the Hosmer-Lemeshow test and the C-statistic, respectively. RESULTS Overall bleeding events were observed in 32 patients and major bleedings in 11 (with an incidence of 6.4% and 2.2%, respectively). In-hospital mortality was 2.6%. Regarding major bleedings both risk scores demonstrated an adequate calibration (H-L test p>0.20) and a moderate discrimination with no significant difference in predictive accuracy between the two models (C-statistic 0.69 for CRUSADE and 0.73 for ACUITY-HORIZONS). We also tested the performance of the two risk models in predicting in-hospital mortality, showing an adequate calibration and a very good discrimination (C-statistic 0.88 and 0.89 for the CRUSADE and ACUITY-HORIZONS scores, respectively), with no significant difference in predictive accuracy. CONCLUSIONS In our ACS population the CRUSADE and the ACUITY-HORIZONS risk scores showed a fairly good and comparable predictive accuracy regarding in-hospital bleeding events and they appeared to be very good predictors of in-hospital mortality.

Management of diabetic patients hospitalized for acute coronary syndromes: a prospective multicenter registry

Background Patients with diabetes mellitus and acute coronary syndrome (ACS) present an increased risk of adverse cardiovascular events. An Italian Consensus Document indicated ‘three specific must’ to obtain in this subgroup of patients: optimal oral antiplatelet therapy, early invasive approach and a tailored strategy of revascularization for unstable angina/non-ST-elevation-myocardial infarction (UA/NSTEMI); furthermore, glycemia at admission should be managed with dedicated protocols. Aim To investigate if previous recommendations are followed, the present multicenter prospective observational registry was carried out in Lombardia during a 9-week period between March and May 2015. Methods and results A total of 559 consecutive ACS patients (mean age 68.7 ± 11.3 years, 35% ≥75 years, 50% STEMI), with ‘known DM’ (56%) or ‘hyperglycemia’, this last defined as blood glucose value ≥ 126 mg/dl at admission, were included in the registry at 29 hospitals with an on-site 24/7 catheterization laboratory. Patients with known diabetes mellitus received clopidogrel in 51% of the cases, whereas most patients with hyperglycemia (72%) received a new P2Y12 inhibitor: according to clinical presentation in case STEMI prasugrel/ticagrelor were more prescribed than clopidogrel (70 vs. 30%, P < 0.001); on the contrary, no significant difference was found in case of UA/NSTEMI (48 vs. 52%, P = 0.57). Overall, 96% of the patients underwent coronary angiography and 85% received a myocardial revascularization (with percutaneous coronary intervention in 92% of cases) that was however performed in fewer patients with known diabetes mellitus compared with hyperglycemia (79 vs. 90%, P = 0.001). Among UA/NSTEMI, 85% of patients received an initial invasive approach, less than 72 h in 80% of the cases (51% <24 h); no difference was reported comparing known diabetes mellitus to hyperglycemia. Despite similar SYNTAX score, patients with known diabetes mellitus had a higher rate of Heart Team discussion (29 vs. 12%, P = 0.03) and received a surgical revascularization in numerically more cases. Most investigators (85%) followed a local protocol for glycemia management at admission, but insulin was used in fewer than half of the cases; diabetes consulting was performed in 25% of the patients and mainly in case of known diabetes mellitus. Conclusion Based on data of the present real world prospective registry, patients with ACS and known diabetes mellitus are treated with an early invasive approach in case of UA/NSTEMI and with a tailored revascularization strategy, but with clopidogrel in more cases; glycemia management is taken into account at admission.