Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

PHARMACOKINETICS AND REGIONAL ELECTROPHYSIOLOGICAL EFFECTS OF INTRACORONARY AMIODARONE ADMINISTRATION

Background The reason for the delay in onset of the electrophysiological effects and antiarrhythmic efficacy of amiodarone is not clear. The relation between the development of the electrophysiological effects of amiodarone and its myocardial concentration is unknown. We therefore examined the time course of development of electrophysiological effects during intracoronary infusion of amiodarone and related these changes to myocardial concentrations. Methods and Results Amiodarone (0.139 mg/min) or normal saline was infused for 10 hours into the proximal left anterior descending coronary artery of 24 open-chest dogs. Nineteen animals received intracoronary amiodarone and 5 received normal saline (control group). Ten of the 19 that received amiodarone underwent electrophysiological study (amio-EPS group). Sixteen of the 19, including 7 from the amino-EPS group, underwent pharmacological study (PS group). In the amio-EPS group during pacing at a cycle length of 300 ms, changes in conduction velocities in drug-exposed myocardium referenced to nonexposed myocardium at 1 hour of infusion were -3.7% in the longitudinal direction (P=NS) and -7.2% in the transverse direction (P<.05); at 3 hours, -12.9% (P<.05) and -9.1% (P<.05); and at 9 hours, -32.9% (P<.02) and -31.7% (P<.01). These changes were dependent on amiodarone concentration (R(2)=.83). There was also an obvious rate-dependent effect that was more pronounced for transverse conduction velocities. This effect was also dependent on amiodarone concentration. In the PS group, amiodarone levels in the drug-exposed myocardium increased from a mean of 5.95 mug/g at 15 minutes of infusion to 188.88 mug/g at the 10th hour. This increase was time dependent (R(2)=.91). In the nonexposed myocardium, amiodarone levels were always low and increased minimally over time from a mean of 2.68 to 14.45 mug/g. This increase was also time dependent (R(2)=.97). Conclusions Selective intracoronary amiodarone infusion resulted in selective drug accumulation and concomitant time-dependent reduction of myocardial conduction velocity. There was a significant correlation between the extent of reduction of conduction velocity and myocardial amiodarone concentration but not coronary arterial or systemic concentration. Repolarization was not significantly altered

COUNTERPULSATION - HISTORICAL BACKGROUND, TECHNICAL IMPROVEMENTS, HEMODYNAMIC AND METABOLIC EFFECTS

The intraaortic balloon counterpulsation is performed today on the same principles that were described in its first experimental use in 1962. Experimental studies have shown significant increase of the mean aortic diastolic pressure, the diastolic pressure-time index, endocardial viability ratio, cardiac output, ejection fraction, coronary cerebral and renal blood flow, lactate utilization and myocardial oxygen supply and significant decrease of the systolic aortic pressure, left-ventricular end-diastolic pressure, left-ventricular work, tension time index, myocardial oxygen consumption and lactate production. In similar studies, intraaortic balloon pump (IABP) decreases the size of myocardial infarction. New IABP driving systems, small size sheaths and balloon catheters for percutaneous insertion made the use of the IABP easier and safer. The paraaortic counterpulsation device is suitable for chronic mechanical assistance. It is more effective than the IABP and shows excellent biocompatibility in chronic experiments. Its clinical application in 3 patients showed excellent biocompatibility and promising hemodynamic effects. In conclusion, the salutary hemodynamic effects of the IABP have been shown in several experimental studies. The technical improvements and the development and use of new devices suggest that we still need to learn more about the usefulness of the counterpulsation technique

Resuscitation from adrenaline resistant electro-mechanical dissociation facilitated by levosimendan in a young man with idiopathic dilated cardiomyopathy

A 32-year-old man with severe congestive heart failure due to idiopathic cardionnyopathy developed ventricutar tachycardia followed by etectromechanical dissociation. High doses of conventional inotropic medications failed to restore haemodynamics. The additional infusion of levosimendan in conjunction with external chest compressions for 2.5h restored haemodynamics, followed by complete recovery, including normal neurological function. The anti-stunning properties of levosimendan probably attenuated post-ischaemic myocardial dysfunction and helped to restore normal cardiac output. (c) 2005 Elsevier Ireland Ltd. All rights reserved