Faculty Bibliography

CONTEXT: Cardiogenic shock complicating acute myocardial infarction (MI) remains a common and lethal disorder despite aggressive use of early revascularization. Systemic inflammation, including expression of inducible nitric oxide synthase (NOS) and generation of excess nitric oxide, is believed to contribute to the pathogenesis and inappropriate vasodilatation of persistent cardiogenic shock. Preliminary, single-center studies suggested a beneficial effect of NOS inhibition on hemodynamics, renal function, and survival in patients with cardiogenic shock. OBJECTIVE: To examine the effects of an isoform-nonselective NOS inhibitor in patients with MI and refractory cardiogenic shock despite establishment of an open infarct artery. DESIGN, SETTING, AND PATIENTS: International, multicenter, randomized, double-blind, placebo-controlled trial (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock [TRIUMPH]) with planned enrollment of 658 patients at 130 centers. Participants were enrolled between January 2005 and August 2006 when the study was terminated early. INTERVENTION: Tilarginine (L-N(G)-monomethylarginine [L-NMMA]), 1-mg/kg bolus and 1-mg/kg per hour 5-hour infusion, vs matching placebo. MAIN OUTCOME MEASURES: The primary outcome was 30-day all-cause mortality among patients who received study medication. Secondary outcomes included shock resolution and duration, New York Heart Association (NYHA) functional class at 30 days, and 6-month mortality. RESULTS: Enrollment was terminated at 398 patients based on a prespecified futility analysis. Six-month follow-up was completed in February 2007. There was no difference in 30-day all-cause mortality between patients who received tilarginine (97/201 [48%]) vs placebo (76/180 [42%]) (risk ratio, 1.14; 95% confidence interval, 0.92-1.41; P = .24). Resolution of shock (133/201 [66%] tilarginine vs 110/180 [61%] placebo; P = .31) and duration of shock (median, 156 [interquartile range, 78-759] hours tilarginine vs 190 [100-759] placebo; P = .16) were similar. At 30 days a similar percentage of patients had heart failure (48% tilarginine vs 51% placebo; P = .51) with a similar percentage of those patients in NYHA class I/II (73% tilarginine vs 75% placebo; P = .27). After 6 months mortality rates were similar in the 2 groups (58% tilarginine vs 59% placebo; hazard ratio, 1.04; 95% confidence interval, 0.79-1.36; P = .80). CONCLUSIONS: Tilarginine, 1-mg/kg bolus and 5-hour infusion, did not reduce mortality rates in patients with refractory cardiogenic shock complicating MI despite an open infarct artery. Early mortality rates in this patient group are high. Further research is needed to develop effective therapies for patients with cardiogenic shock following acute MI. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00112281

BACKGROUND: Women with acute myocardial infarction are more likely than men to experience reinfarction, bleeding, or death. This difference has been hypothesized to be due to older age, treatment delay, and comorbidities in women. Use of diagnostic and therapeutic modalities may also differ. There is controversy regarding whether female sex is an independent risk factor for death and/or bleeding. METHODS: The GUSTO (Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes) V Investigators studied standard-dose reteplase vs standard-dose abciximab plus half-dose reteplase in patients with myocardial infarction. RESULTS: Women were older and more often had diabetes mellitus and hypertension. Angiography and percutaneous coronary intervention were less frequent in women. Death (9.8% vs 4.4% at 30 days; odds ratio [OR], 2.00; 95% confidence interval, 1.59-2.53; P < .001) and bleeding (6.4% vs 2.5%; OR, 1.31; 95% confidence interval, 1.18-1.45; P < .01) were more common in women. There was no association between treatment assignment and death in either sex; bleeding was more common in both sexes receiving combination therapy. Female sex was independently associated with mortality. After Killip class greater than 1 (OR, 4.7), female sex (OR, 2.0) was the strongest correlate of death. Female sex was independently associated with bleeding for both treatments. CONCLUSIONS: Female sex is independently associated with death and bleeding complications among fibrinolytic-treated patients with myocardial infarction. There remains a sex differential in the use of angiography and, therefore, percutaneous coronary intervention after fibrinolysis. Further research will determine what mediates excess risk in women

BACKGROUND: Paradoxical septal motion (PSM) is the systolic movement of the interventricular septum toward the right ventricle despite normal thickening. The PSM is a frequent echocardiographic finding after cardiac surgery. Although it is universally recognized, there has been no large-scale study to correlate PSM with the type of surgical procedure. The cause of PSM is unknown; prevailing theories include: (1) operation on the heart alters the degree to which it is restrained by the pericardium and the chest wall and (2) transient ischemia alters septal motion. HYPOTHESIS: The PSM is related to type of surgery and surgical approach. METHODS: Between 1996 and 2002, 3,292 patients underwent a first cardiac operation and had a postoperative echocardiogram; 313 were excluded due to other explanations for PSM (severe tricuspid regurgitation [TR] cardiac pacing), leaving a study group of 2,979 patients. Univariate and multivariate analyses were performed to determine which surgical characteristics were correlated with postoperative PSM. Septal thickening was assessed in a subset. RESULTS: On multivariate analysis, aortic (p = 0.02) and mitral valve surgery (p < 0.001) and longer cardiopulmonary bypass time (p < 0.001) were independently associated with PSM. Coronary artery bypass grafting (CABG) was less likely to cause PSM than non-CABG surgery (p = 0.003) and off-pump coronary artery bypass (OPCAB) caused less PSM than did on-pump CABG. CONCLUSIONS: 1. Valve surgery is more likely to cause PSM than CABG. 2. Among patients with CABG, OPCAB causes less PSM. 3. Cardiopulmonary bypass time is associated with the development of PSM. 4. The cause of PSM is likely to be multifactorial

BACKGROUND: Left ventricular diastolic abnormalities are associated with adverse outcome in myocardial infarction. Intra-aortic balloon pump (IABP) support is associated with improved diastolic filling. In the SHOCK trial and registry, average left ventricular ejection fraction (LVEF) was approximately 30%, higher than expected based on the classic paradigm. We hypothesized that restrictive physiology plays a role in cardiogenic shock (CS). METHODS: Echocardiograms obtained during the SHOCK trial within 24 hours of randomization were centrally interpreted. Patients with quantifiable mitral E-wave deceleration time were included (n = 64). The restrictive filling pattern was defined as deceleration time < 140 milliseconds. RESULTS: The restrictive pattern was seen in 60.9% of patients studied. Patients with this pattern had lower LVEF (31.1% vs 39.0%, P = .02) and higher wall motion score index (2.1 vs 1.8, P = .05). Patients with restriction were more likely to have IABP support during echocardiography (73.7% vs 43.5%, P = .03). There was no difference with and without restriction in demographic and hemodynamic variables or in mitral regurgitation degree or extent of coronary disease. The restrictive pattern had positive predictive value of 80% for pulmonary capillary wedge pressure > or = 20 mm Hg. Thirty-day survival was 53.9% with restriction versus 68.0% without restriction, P = .31. There was no difference in New York Heart Association class at 1 year between groups. CONCLUSIONS: The restrictive filling pattern is common in patients with CS, which may suggest that diastolic dysfunction contributes to CS pathogenesis. Patients with the restrictive pattern had lower LVEF despite IABP support. An association between the restrictive pattern and mortality was not demonstrated; power was limited by sample size

BACKGROUND: It is unclear whether stable, high-risk patients with persistent total occlusion of the infarct-related coronary artery identified after the currently accepted period for myocardial salvage has passed should undergo percutaneous coronary intervention (PCI) in addition to receiving optimal medical therapy to reduce the risk of subsequent events. METHODS: We conducted a randomized study involving 2166 stable patients who had total occlusion of the infarct-related artery 3 to 28 days after myocardial infarction and who met a high-risk criterion (an ejection fraction of <50% or proximal occlusion). Of these patients, 1082 were assigned to routine PCI and stenting with optimal medical therapy, and 1084 were assigned to optimal medical therapy alone. The primary end point was a composite of death, myocardial reinfarction, or New York Heart Association (NYHA) class IV heart failure. RESULTS: The 4-year cumulative primary event rate was 17.2% in the PCI group and 15.6% in the medical therapy group (hazard ratio for death, reinfarction, or heart failure in the PCI group as compared with the medical therapy group, 1.16; 95% confidence interval [CI], 0.92 to 1.45; P=0.20). Rates of myocardial reinfarction (fatal and nonfatal) were 7.0% and 5.3% in the two groups, respectively (hazard ratio, 1.36; 95% CI, 0.92 to 2.00; P=0.13). Rates of nonfatal reinfarction were 6.9% and 5.0%, respectively (hazard ratio, 1.44; 95% CI, 0.96 to 2.16; P=0.08); only six reinfarctions (0.6%) were related to assigned PCI procedures. Rates of NYHA class IV heart failure (4.4% vs. 4.5%) and death (9.1% vs. 9.4%) were similar. There was no interaction between treatment effect and any subgroup variable (age, sex, race or ethnic group, infarct-related artery, ejection fraction, diabetes, Killip class, and the time from myocardial infarction to randomization). CONCLUSIONS: PCI did not reduce the occurrence of death, reinfarction, or heart failure, and there was a trend toward excess reinfarction during 4 years of follow-up in stable patients with occlusion of the infarct-related artery 3 to 28 days after myocardial infarction. (ClinicalTrials.gov number, NCT00004562 [ClinicalTrials.gov].)