Fatty acids and TxA(2) generation, in the absence of platelet-COX-1 activity.

BACKGROUND AND AIMS: Omega-3 fatty acids suppress Thromboxane A(2) (TxA(2)) generation via mechanisms independent to that of aspirin therapy. We sought to evaluate whether baseline omega-3 fatty acid levels influence arachidonic acid proven platelet-cyclooxygenase-1 (COX-1) independent TxA(2) generation (TxA(2) generation despite adequate aspirin use). METHODS AND RESULTS: Subjects with acute myocardial infarction, stable CVD or at high risk for CVD, on adequate aspirin therapy were included in this study. Adequate aspirin action was defined as complete inhibition of platelet-COX-1 activity as assessed by <10% change in light transmission aggregometry to ≥1 mmol/L arachidonic acid. TxA(2) production was measured via liquid chromatography-tandem mass spectrometry for the stable TxA(2) metabolite 11-dehydro-thromboxane B2 (UTxB2) in urine. The relationship between baseline fatty acids, demographics and UTxB(2) were evaluated. Baseline omega-3 fatty acid levels were not associated with UTxB(2) concentration. However, smoking was associated with UTxB(2) in this study. CONCLUSION: Baseline omega-3 fatty acid levels do not influence TxA(2) generation in patients with or at high risk for CVD receiving adequate aspirin therapy. The association of smoking and TxA(2) generation, in the absence of platelet COX-1 activity, among aspirin treated patients warrants further study.

Relative importance of patient, procedural and anatomic risk factors for early vein graft thrombosis after coronary artery bypass graft surgery.

AIM: The aim of the present study was to investigate the relative importance of a wide array of patient demographic, procedural, anatomic and perioperative variables as potential risk factors for early saphenous vein graft (SVG) thrombosis after coronary artery bypass graft (CABG) surgery. METHODS: The patency of 611 SVGs in 291 patients operated on at four different hospitals enrolled in the Reduction in Graft Occlusion Rates (RIGOR) study was assessed six months after CABG surgery by multidetector computed tomography coronary angiography or clinically-indicated coronary angiography. The odds of graft occlusion versus patency were analyzed using multilevel multivariate logistic regression with clustering on patient. RESULTS: SVG failure within six months of CABG surgery was predominantly an all-or-none phenomenon with 126 (20.1%) SVGs totally occluded, 485 (77.3%) widely patent and only 16 (2.5%) containing high-grade stenoses. Target vessel diameter ≤ 1.5 mm (adjusted OR 2.37, P=0.003) and female gender (adjusted OR 2.46, P=0.01) were strongly associated with early SVG occlusion. In a subgroup analysis of 354 SVGs in which intraoperative graft blood flow was measured, lower mean flow was also significantly associated with SVG occlusion when analyzed as a continuous variable (adjusted OR 0.984, P=0.006) though not when analyzed dichotomously, <40 mL/min versus ≥ 40 mL/min (adjusted OR 1.86, P=0.08). CONCLUSION: Small target vessel diameter, female gender and low mean graft blood flow are significant risk factors for SVG thrombosis within six months of CABG surgery in patients on postoperative aspirin therapy. This information may be useful in guiding revascularization strategies in selected patients.

Effect of anti-platelet factor-4/heparin antibody induction on early saphenous vein graft occlusion after coronary artery bypass surgery.

BACKGROUND: Antibodies to complexes of heparin and platelet factor 4 (PF4) are capable of causing heparin-induced thrombocytopenia (HIT). Recent evidence suggests that anti-PF4/heparin antibodies may be prothrombogenic even in the absence of thrombocytopenia and clinically-recognized HIT. OBJECTIVES: To determine if induction of anti-PF4/heparin antibodies is an independent risk factor for early saphenous vein graft (SVG) occlusion or adverse clinical outcome after coronary artery bypass graft (CABG) surgery. PATIENTS/METHODS: Anti-PF4/heparin antibody titers were measured in 368 patients prior to and then 4 days, 6 weeks and 6 months after CABG surgery. Serotonin release assay (SRA) and antibody isotype analysis were also performed on 6-week samples. SVG patency was determined in 297 patients 6 months after surgery by multidetector computed tomography coronary angiography. RESULTS: Six weeks after surgery, 52% of patients were anti-PF4/heparin seropositive and 9% were SRA positive. Six months after surgery, neither the percentage of occluded SVG (19% vs. 20%, P = NS), the percentage of patients with an occluded SVG (33% vs. 33%, P = NS) nor the incidence of adverse clinical events (21% vs. 24%, P = NS) differed between seropositive and seronegative groups. Neither IgG isotype nor SRA positivity was additionally predictive of SVG occlusion or adverse clinical outcome. CONCLUSION: Induction of anti-PF4/heparin antibodies, even those capable of heparin-dependent platelet activation, is not independently associated with early SVG occlusion or adverse clinical outcomes after CABG surgery.

Usefulness of magnesium sulfate in stabilizing cardiac repolarization in heart failure secondary to ischemic cardiomyopathy.

Experimental heart failure is associated with cardiac magnesium loss, causing increased beat-to-beat variability in the action potential. Unstable repolarization contributes to sudden death, but no therapy has been shown to reduce repolarization variability safely. We sought to test whether a prolonged infusion of magnesium sulfate (MgSO(4); 40 mmol/24 hours) would normalize QT interval variability in patients with compensated heart failure. Fifteen patients (New York Heart Association class II to III; mean age 63 years) were enrolled in a placebo-controlled, double-blind study. Surface electrocardiograms were recorded and digitized at entry and at 48 and 168 hours (drug washout). Repolarization stability was assessed using an automated method measuring each QT interval in a 5-minute epoch. The QT variability index was derived as the ratio of normalized QT-to-normalized heart rate variability. Seven of 15 patients received MgSO(4). Mean heart rate and QT did not change in either group. The QT variability index was stable in the placebo group (-0.69 +/- 0.15 at entry, -0.71 +/- 0.22 at 48 hours, -0.70 +/- 0.18 at 168 hours), but decreased significantly in the treated group at 48 hours (-0.95 +/- 0.19 to -1.36 +/- 0.13, p <0.05 repeated-measures analysis of variance), returning to baseline at 168 hours (-0.84 +/- 0.18). Regression analyses showed that administration of MgSO(4) resulted in a stronger correlation between the QT and RR interval (p <0.01). Thus, MgSO(4) stabilizes cardiac repolarization in patients with compensated heart failure due to ischemic heart disease. Magnesium therapy may be useful in altering the proarrhythmic substrate in heart failure.

Medical therapy versus coronary angioplasty in stable coronary artery disease: a critical review of the literature.

The recent publication of the Atorvastatin Versus Revascularization Treatment (AVERT) trial has renewed debate on the optimal management strategy for relatively stable patients with coronary artery disease. Currently, coronary angiography and percutaneous coronary intervention are often performed in stable patients with good exercise tolerance who have not been treated with proven medications such as aspirin, statins and beta-adrenergic blocking agents in conjunction with comprehensive lifestyle modification. We review the results of prior trials comparing medical therapy with angioplasty and assess their strengths and limitations and then make conclusions about the aggregate data. Next, we describe the ongoing Clinical Outcome Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, which will be the largest of the studies comparing optimal medical therapy and percutaneous revascularization. This study will employ intensive medical management in all patients with coronary disease, and the incremental benefit of state of the art revascularization techniques in terms of clinical event reduction, quality of life issues and cost-effectiveness will be addressed. For now, aggressive medical therapy and revascularization should be viewed as complementary rather than opposing strategies. All patients with coronary heart disease should receive proven medical and lifestyle prescriptions to favorably alter the atherosclerotic process. Percutaneous revascularization without comprehensive risk factor modification is a suboptimal therapeutic strategy.

Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years.

BACKGROUND: The benefit of intravenous thrombolytic therapy in elderly patients with myocardial infarction is uncertain. There are no randomized trials of thrombolytic efficacy or observational studies of clinical effectiveness that focus specifically on the elderly. METHODS AND RESULTS: To determine whether thrombolytic therapy for elderly patients is associated with a survival advantage in a large observational database, we conducted a retrospective cohort study of 7864 Medicare fee-for-service patients aged 65 to 86 years with the primary discharge diagnosis of acute myocardial infarction who were admitted with clinical and ECG indications for thrombolytic therapy and no absolute contraindications. The study included all US acute care nongovernment hospitals without on-site angioplasty capability. Using proportional-hazards methods, we found that in a comprehensive multivariate model, there was a significant interaction (P<0.001) between age and the effect of thrombolytic therapy on 30-day mortality rates. For patients 65 to 75 years old, thrombolytic therapy was associated with a survival benefit, consistent with randomized trials. Among patients aged 76 to 86 years, thrombolytic therapy was associated with a survival disadvantage, with a 30-day mortality hazard ratio of 1.38 (95% CI 1. 12 to 1.71, P=0.003). For these patients, there was no benefit from thrombolytic therapy in any clinical subgroup. CONCLUSIONS: In nationwide clinical practice, thrombolytic therapy for patients >75 years old is unlikely to confer survival benefit and may have a significant survival disadvantage. Reperfusion research that is focused on elderly patients is urgently needed.

Hemodynamic effects of unloading the old heart.

A reduction in upright exercise capacity with aging in healthy individuals is accompanied by acute left ventricular (LV) dilatation and impaired LV ejection. To determine whether acute vasodilator administration would improve LV ejection during exercise, sodium nitroprusside (NP) was administered to 16 healthy subjects, ages 64-84 yr, who had been screened for the absence of coronary heart disease by prior exercise thallium scintigraphy. Infusion of NP (0. 3-1.0 microgram. kg(-1). min(-1)), titrated to reduce the resting mean arterial pressure 10% (and eliminate the late augmentation of carotid arterial pressure), increased LV ejection fraction (EF) compared with placebo during upright, maximal graded cycle exercise at all work rates and permitted an equivalent stroke volume and stroke work from a smaller end-diastolic volume. The maximum increase in exercise EF in older subjects during NP infusion was equal to that in healthy, younger (22-39 yr) control subjects. The maximum cycle work rate and cardiac index were unchanged compared with placebo. Thus combined preload and afterload reduction with NP in older individuals improves overall LV ejection phase function: exercise LV stroke work is reduced, EF is increased, and stroke volume is maintained in the setting of a reduced ventricular size. These findings suggest that at least some of the age-associated decline in cardiac function during maximal aerobic exercise may be secondary to adverse loading conditions.

Transmyocardial laser revascularisation compared with continued medical therapy for treatment of refractory angina pectoris: a prospective randomised trial. ATLANTIC Investigators. Angina Treatments-Lasers and Normal Therapies in Comparison.

BACKGROUND: Transmyocardial revascularisation (TMR) is an operative treatment for refractory angina pectoris when bypass surgery or percutaneous transluminal angioplasty is not indicated. We did a prospective randomised trial to compare TMR with continued medication. METHODS: We recruited 182 patients from 16 US centres with Canadian Cardiovascular Society Angina (CCSA) score III (38%) or IV (62%), reversible ischaemia, and incomplete response to other therapies. Patients were randomly assigned TMR and continued medication (n=92) or continued medication alone (n=90). Baseline assessments were angina class, exercise tolerance, Seattle angina questionnaire for quality of life, and dipyridamole thallium stress test. We reassessed patients at 3 months, 6 months, and 12 months, with independent masked angina assessment at 12 months. FINDINGS: At 12 months, total exercise tolerance increased by a median of 65 s in the TMR group compared with a 46 s decrease in the medication-only group (p<0.0001, median difference 111 s). Independent CCSA score was II or lower in 47.8% in the TMR group compared with 14.3% in the medication-only group (p<0.001). Each Seattle angina questionnaire index increased in the TMR group significantly more than in the medication-only group (p<0.001). INTERPRETATION: TMR lowered angina scores, increased exercise tolerance time, and improved patients' perceptions of quality of life. This operative treatment provided clinical benefits in patients with no other therapeutic options.

Reduced left ventricular dimension and normalized atrial natriuretic hormone level after repair of aortic coarctation in an adult.

Although unusual in the older patient, coarctation of the aorta can be an occult cause of cardiomyopathy. This report describes a 53-year-old man with new-onset heart failure symptoms, global left ventricular (LV) dysfunction, and underlying aortic coarctation. Surgical correction resulted in reduced LV size, resolution of symptoms, and normalization of atrial natriuretic hormone levels.

Cardiovascular consequences of the aging process.

There are many challenges in the study of the normal age-associated changes that occur in the cardiovascular system, the most important of which is the fact that cardiovascular disease is so common in the elderly. In animal models and healthy humans, three age-associated changes with increasing age include (1) impaired left ventricular diastolic filling, (2) reduction in the adrenergic responsiveness to catecholamines, and (3) an increase in arterial stiffness. These changes likely are influenced by the increasingly sedentary lifestyle in the elderly. These age-associated changes also influence the manifestations of cardiovascular disease in the elderly and the response to therapy.

Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction.

BACKGROUND: The extent of microvascular obstruction during acute coronary occlusion may determine the eventual magnitude of myocardial damage and thus, patient prognosis after infarction. By contrast-enhanced MRI, regions of profound microvascular obstruction at the infarct core are hypoenhanced and correspond to greater myocardial damage acutely. We investigated whether profound microvascular obstruction after infarction predicts 2-year cardiovascular morbidity and mortality. METHODS AND RESULTS: Forty-four patients underwent MRI 10 +/- 6 days after infarction. Microvascular obstruction was defined as hypoenhancement seen 1 to 2 minutes after contrast injection. Infarct size was assessed as percent left ventricular mass hyperenhanced 5 to 10 minutes after contrast. Patients were followed clinically for 16 +/- 5 months. Seventeen patients returned 6 months after infarction for repeat MRI. Patients with microvascular obstruction (n = 11) had more cardiovascular events than those without (45% versus 9%; P=.016). In fact, microvascular status predicted occurrence of cardiovascular complications (chi2 = 6.46, P<.01). The risk of adverse events increased with infarct extent (30%, 43%, and 71% for small [n = 10], midsized [n = 14], and large [n = 14] infarcts, P<.05). Even after infarct size was controlled for, the presence of microvascular obstruction remained a prognostic marker of postinfarction complications (chi2 = 5.17, P<.05). Among those returning for follow-up imaging, the presence of microvascular obstruction was associated with fibrous scar formation (chi2 = 10.0, P<.01) and left ventricular remodeling (P<.05). CONCLUSIONS: After infarction, MRI-determined microvascular obstruction predicts more frequent cardiovascular complications. In addition, infarct size determined by MRI also relates directly to long-term prognosis in patients with acute myocardial infarction. Moreover, microvascular status remains a strong prognostic marker even after control for infarct size.

Unstable angina: integrating new treatments.

Although aspirin plus heparin remains the gold standard, clinicians will soon be able to select, from an array of antithrombotic strategies, the agents that best match the patient's hemodynamic status. Revascularization is not routinely indicated; it should be reserved for high-risk patients in whom medical therapy has failed, who have had a myocardial infarction, or who have other compromising factors.

Perioperative ST-segment depression is rare and may not indicate myocardial ischemia in moderate-risk patients undergoing noncardiac surgery.

OBJECTIVE: To identify a group of older asymptomatic patients in whom ST-segment changes are common and determine their correlation with occult coronary artery disease. DESIGN: Prospective, cohort study. SETTING: University hospital, single-center. PARTICIPANTS: Patients older than 45 years with at least one risk factor for coronary artery disease but without documented disease undergoing noncardiac, nonvascular surgery. INTERVENTIONS: Intraoperative and early postoperative continuous electrocardiographic monitoring, exercise treadmill testing, 24-month telephone follow-up. MEASUREMENTS AND MAIN RESULTS: A total of 190 patients were studied with a continuous ST-segment monitor, seven of whom demonstrated significant ST-segment changes during the intraoperative or early postoperative period. Three of the seven patients were evaluated by exercise treadmill testing, all of whom had a negative test. Follow-up was complete in 84% of the cohort without ST-segment changes and in all patients with ST-segment changes. One patient with perioperative ST-segment changes died of prostate cancer. None of the other patients showed any symptoms of coronary artery disease on follow-up. CONCLUSIONS: ST-segment changes are rare during the intraoperative and immediate postoperative period in asymptomatic patients at moderate risk for coronary artery disease. The low incidence of a positive stress test and lack of cardiovascular symptoms on follow-up in patients with perioperative ST-segment changes suggest that caution should be exercised before diagnosing myocardial ischemia and coronary artery disease.

Influence of gender, race, and education on patient preferences and receipt of cardiac catheterizations among coronary care unit patients.

The extent to which a preference for less aggressive care explains the lower rate of invasive cardiac services for women and African-Americans is unknown. A prospective observational study of 272 patients admitted to the coronary care unit was conducted at a tertiary referral teaching hospital and a community teaching hospital. In stepwise multivariate analysis, having less than a college education, poor cardiac function, not having undergone a previous cardiac catheterization, being a patient in a nonreferral community hospital, and current smoking were positively associated with a patient's stating that he or she would disagree with a physician's recommendation for a cardiac catheterization. The step-wise multivariate model with cardiac catheterization as the dependent variable indicated that being a patient in a referral medical center, patient willingness to accept a physician's recommendation for a cardiac catheterization, severe heart disease, and having attended high school were predictive. Women did not differ from men in their preference for or receipt of cardiac catheterization. Patients in the coronary care unit with lower levels of education were less likely to undergo cardiac catheterization. This association was only partly explained by less educated patients' being less willing to accept a physician's recommendation to undergo cardiac catheterization.

Refining the treatment of women with unstable angina--a randomized, double-blind, comparative safety and efficacy evaluation of Integrelin versus aspirin in the management of unstable angina.

BACKGROUND: Although women typically develop coronary artery disease several years after men, once they have symptomatic disease their thromboembolic complications are worse than in men. The mechanism mediating this gender difference in outcome after thromboembolic events is unknown. We previously studied platelet functions in siblings from patients with premature coronary artery disease. We observed that platelets from women are responsive than their male counterparts. In particular, platelets from women stimulated ex vivo with various agonists bind more fibrinogen molecules than platelets from men. HYPOTHESIS: We hypothesized that in patients with acute coronary events, the control of platelet activity might require stronger antagonists in women than in men. METHODS: To test this hypothesis, we investigated retrospectively the results of a trial on Integrelin in unstable angina. RESULTS: We report that platelet aggregation and Holter-detected ischemic episodes are significantly reduced in women with unstable angina treated with the specific GPIIb-IIIa inhibitor, Integrelin, compared with the standard platelet inhibitor aspirin. In contrast, both platelet aggregation and Holter-detected ischemic events are well controlled in men with unstable angina treated with standard therapy including aspirin. CONCLUSION: Integrelin does provide protection in men, but, in contrast with women, not beyond what can be achieved with aspirin. Our data are consistent with the concept that the platelets from women require stronger and more specific inhibitors to limit their activity, and that platelets may play a more important role in women with acute coronary syndromes than in men. Most important, specific GPIIb-IIIa inhibitors may represent a therapeutic option which provides as much suppression of ischemic events in women as they do in men with coronary artery disease.