Jeffrey Lefkovits

Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure.

OBJECTIVES The aim of this study was to characterize cardiac sympathetic nervous function in patients with severe heart failure and to investigate the influence of the cause of heart failure, hemodynamic variables and central nervous system catecholamine release on cardiac sympathetic tone. BACKGROUND Although heart failure is generally accompanied by sympathoexcitation, the integrity of cardiac sympathetic nerve function in heart failure remains controversial, particularly in relation to nerve firing activity and to the capacity of sympathetic nerves to recapture norepinephrine. Additionally, the location of the afferent and central neural pathways implicated in heart failure-induced sympathoexcitation remains unclear. METHODS Radiotracer techniques were applied in 41 patients with severe heart failure and 15 healthy control subjects to study the biochemical aspects of whole body and cardiac sympathetic activity. Hemodynamic indexes of cardiac performance were measured in the heart failure group, and their association with sympathetic activity was studied. Jugular venous catechol spillover was measured to study the central noradrenergic control of sympathetic outflow. RESULTS Sympathoexcitation was evident in the heart failure group, reflected by a 62% increase (p < 0.001) in total body and a 277% increase (p < 0.001) in cardiac norepinephrine spillover rates. These changes were accompanied by significant increases in the cardiac spillover of the norepinephrine precursor dihydroxyphenylalanine, the sympathetic cotransmitter neuropeptide Y and the extraneuronal metabolite 3-methoxy-4-hydroxyphenylglycol. The level of cardiac sympathetic activity was significantly correlated (r = 0.59, p < 0.001) with the mean pulmonary artery pressure. An increase in the spillover of dihydroxyphenylalanine and 3-methoxy-4-hydroxyphenylglycol from the brain was present, suggesting activation of central noradrenergic neurons. CONCLUSIONS Cardiac sympathetic activation is present in severe heart failure, bearing a close relation with pulmonary artery pressures, independent of heart failure etiology. Activation of noradrenergic neurons in the brain is also present and may be the underlying central nervous mechanism of the sympathoexcitation observed in heart failure.

Effects of platelet glycoprotein IIb/IIIa receptor blockade by a chimeric monoclonal antibody (Abciximab) on acute and six-month outcomes after percutaneous transluminal coronary angioplasty for acute myocardial infarction

Percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction is an attractive alternative to thrombolysis, but is still limited by recurrent ischemia and restenosis. We determined whether adjunctive platelet glycoprotein IIb/IIIa receptor blockade improved outcomes in patients undergoing direct and rescue PTCA in the Evaluation of c7E3 for Prevention of Ischemic Complications (EPIC) trial. Of the 2,099 patients undergoing percutaneous intervention who randomly received chimeric 7E3 Fab (c7E3) as a bolus, a bolus and 12-hour infusion, or placebo, 42 underwent direct PTCA for acute myocardial infarction and 22 patients had rescue PTCA after failed thrombolysis. The primary composite end point comprised death, reinfarction, repeat intervention, or bypass surgery. Outcomes were assessed at 30 days and 6 months. Baseline characteristics were similar in direct and rescue PTCA patients. Pooling the 2 groups, c7E3 bolus and infusion reduced the primary composite end point by 83% (26.1% placebo vs 4.5% c7E3 bolus and infusion, p = 0.06). No reinfarctions or repeat urgent interventions occurred in c7E3 bolus and infusion patients at 30 days, although there was a trend toward more deaths in c7E3-treated patients. Major bleeding was increased with c7E3 (24% vs 13%, p = 0.28). At 6 months, ischemic events were reduced from 47.8% with placebo to 4.5% with c7E3 bolus and infusion (p = 0.002), particularly reinfarction (p = 0.05) and repeat revascularization (p = 0.002). We conclude that adjunctive c7E3 therapy during direct and rescue PTCA decreased acute ischemic events and clinical restenosis in the EPIC trial. These data provide initial evidence of benefit for glycoprotein IIb/IIIa receptor blockade during PTCA for acute myocardial infarction.

Predictors and Sequelae of Distal Embolization During Saphenous Vein Graft Intervention From the CAVEAT-II Trial

BACKGROUND The purpose of this study was to identify the predictors and sequelae of distal embolization from a multicenter, randomized trial of saphenous vein graft intervention. The CAVEAT-II trial demonstrated that saphenous vein graft directional coronary atherectomy (DCA) was associated with greater angiographic success and less need for repeat intervention compared with percutaneous transluminal coronary angioplasty (PTCA) but at the cost of more acute complications--notably distal embolization. METHODS AND RESULTS In CAVEAT-II, 305 patients were randomly assigned to DCA (149 patients) or PTCA (156 patients) for lesions with > 60% diameter stenosis in vein grafts > or = 3 mm in diameter. Distal embolization occurred in 20 patients (13.4%) assigned to DCA and 8 patients (5.1%) assigned to PTCA (P = .011). Independent predictors of distal embolization were use of DCA (71% in distal embolization patients versus 47% in patients without distal embolization, P = .011) and presence of thrombus (39% in distal embolization patients versus 14% in patients without distal embolization, P < .00). In-hospital adverse events were more frequent after distal embolization; 71% versus 20%, odds ratio plus (95% confidence intervals) 9.87 (4.65, 20.94). At 12-month follow-up, adverse event rates were also higher in patients with distal embolization (odds ratio, 3.05 [1.95, 4.76]). CONCLUSIONS In this first prospective multicenter trial of saphenous vein graft intervention, distal embolization was more common after DCA than PTCA and in lesions containing thrombus. It also was associated with worse in-hospital and 12-month outcomes. The risk and sequelae of distal embolization should be considered when choosing a treatment strategy for vein graft disease.

Acute coronary syndrome care across Australia and New Zealand: the SNAPSHOT ACS study.

Objectives: To characterise management of suspected acute coronary syndrome (ACS) in Australia and New Zealand, and to assess the application of recommended therapies according to published guidelines.

Increased Central Nervous System Monoamine Neurotransmitter Turnover and Its Association With Sympathetic Nervous Activity in Treated Heart Failure Patients

BACKGROUND Congestive heart failure is a debilitating disease characterized by impaired cardiac function with accompanying activation of a variety of neural and hormonal counter-regulatory systems. Abnormal activity of the sympathetic nervous system and renin-angiotensin-aldosterone axis and a predisposition to the generation of fatal ventricular arrhythmias are often associated with the development of the disease. Although the underlying cause of sudden death in these patients remains to be unequivocally elucidated, abnormally increased cardiac sympathetic nervous activity may be involved. METHODS AND RESULTS Twenty-two patients with severe congestive heart failure (New York Heart Association functional class III or IV with left ventricular ejection fraction of 18 +/- 1%) and 29 healthy male volunteers participated in this study. By combining direct sampling of internal jugular venous blood via a percutaneously placed catheter with a norepinephrine and epinephrine isotope dilution method for examining neuronal transmitter release, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters and investigate their association with the increased efferent sympathetic outflow that is variably present in treated patients with this condition. Mean cardiac norepinephrine spillover was 145% higher in treated heart failure patients than in healthy subjects (P < .05), with norepinephrine release from the heart in 6 of 22 patients being more than the highest control value. Raised internal jugular venous spillover of epinephrine (26 +/- 12 versus 2 +/- 4 pmol/min, P < .05) and of norepinephrine and its metabolites (2740 +/- 480 versus 875 +/- 338 pmol/min, P < .05), indicative of increased central nervous system turnover of both catecholamines, occurred in cardiac failure and was quantitatively linked to the degree of activation of the cardiac sympathetic nervous outflow, as was the jugular overflow of the principal serotonin metabolite, 5-hydroxyindoleacetic acid. CONCLUSIONS An association between the degree of activation of central monoaminergic neurons and the level of sympathetic nervous tone in the heart was identified in treated patients with heart failure. Epinephrine neurons in the brain may contribute to the sympathoexcitation that is seen in this condition, with the activation of sympathoexcitatory noradrenergic neurons, most likely those of the forebrain, playing an accessory role.

Platelet glycoprotein IIb/IIIa receptor inhibitors in ischemic heart disease.

The key role of platelets in the pathogenesis of ischemic heart disease has led to the development of new classes of agents to control platelet function. The platelet glycoprotein IIb/IIIa receptor mediates the final common pathway to platelet aggregation. Drugs that block the glycoprotein IIb/IIIa receptor potently inhibit platelet aggregation. Monoclonal antibodies, cyclic peptides, and peptide-derivative glycoprotein IIb/IIIa inhibitors have been developed. The monoclonal antibody Fab fragment, chimeric 7E3, has been shown to significantly reduce ischemic complications and clinical restenosis after high-risk angioplasty in the large-scale Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial. A number of glycoprotein IIb/IIIa inhibitors have been tested in patients with unstable angina with similarly positive results, and initial trials in patients with acute myocardial infarction are also encouraging. Further evaluation of these agents in large scale trials is currently underway and should help determine the place and appropriate use of these agents in the clinical arena.

Impact of early percutaneous coronary intervention on short- and long-term outcomes in patients with cardiogenic shock after acute myocardial infarction

This study assesses the impact of early percutaneous coronary intervention in patients presenting with cardiogenic shock after acute myocardial infarction. Predictors of in-hospital death include the need for intubation, cardiopulmonary resuscitation, and angiographic failure; long-term outcomes at 2 years in hospital survivors are favorable.

Clopidogrel, Prasugrel or Ticagrelor in Patients with Acute Coronary Syndromes undergoing Percutaneous Coronary Intervention.

Guidelines recommend prasugrel or ticagrelor instead of clopidogrel in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary interventions (PCI).

TRENDS IN DOOR-TO-BALLOON TIME AND OUTCOMES FOLLOWING PRIMARY PCI FOR STEMI

Background: US guidelines recommend a door-to-balloon time (DTBT) of ≤90 minutes for patients presenting with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). System improvements to reduce DTBT were implemented across the period of this study and included regular peer-based review of results, reductions in system delay through electronic transmission of ECGs from the field and the bypassing of emergency departments.

Comparison of event and procedure rates following percutaneous transluminal coronary angioplasty in patients with and without previous coronary artery bypass graft surgery (the ROSETTA Registry)

To compare 6-month post-percutaneous transluminal coronary angioplasty (PTCA) outcomes and cardiac procedure use among patients with and without prior coronary artery bypass graft (CABG) surgery, we examined 791 patients who were enrolled in the Routine versus Selective Exercise Treadmill Testing after Angioplasty (ROSETTA) Registry. The ROSETTA Registry is a prospective, multicenter registry that examines the use of functional testing after successful PTCA. Most patients were men (76%, mean age 61 ± 11 years) who underwent single-vessel PTCA (85%) with stent implantation (58%). Baseline and procedural characteristics differed between patients with a prior CABG (n = 131) and patients with no prior CABG (n = 660), including Canadian Cardiovascular Society angina class III to IV (60% vs 49%, respectively, p = 0.03) and stenosis involving the proximal left anterior descending coronary artery (10% vs 22%, p = 0.004). Event rates among patients with prior CABG were higher than among patients with no prior CABG, including unstable angina (19% vs 11%, p = 0.02), myocardial infarction (2% vs 1%, p = 0.2), death (4% vs 2%, p = 0.08), and composite clinical events (22% vs 12%, p = 0.003). Furthermore, patients with prior CABG had higher rates of follow-up cardiac procedures, including angiography (24% vs 14%, p = 0.008) and PTCA (13% vs 7%, p = 0.04), but not repeat CABG (2% vs 3%, p = 0.8). A multivariate analysis that included baseline clinical and procedural characteristics demonstrated that prior CABG was a significant independent predictor of clinical events and cardiac procedure use (odds ratio 2.3, 95% confidence interval 1.5 to 3.5, p = 0.0001). Within the prior CABG group, patients with a PTCA of a bypass graft had a higher composite clinical event rate than patients with a PTCA of a native vessel (32% vs 17%, p = 0.05). In contrast, patients with a PTCA of a native vessel had event rates similar to those of patients with no prior CABG (17% vs 12%, p = 0.2). Thus, post-CABG patients have an increased risk of developing a cardiac event or needing a follow-up cardiac procedure during the 6 months after PTCA.