Elevation of plasma milrinone concentrations in stage D heart failure associated with renal dysfunction.

PURPOSE: To determine steady state milrinone concentrations in patients with stage D heart failure (HF) with and without renal dysfunction METHODS: We retrospectively identified patients with stage D HF at a single medical center on continuous milrinonein fusion at the time of plasma collection for entry into a research registry database. Milrinone was prescribed and titrated to improve hemodynamic and clinical status by a cardiologist. Plasma samples were obtained at steady state milrinone concentrations. Patients were stratified by creatinine clearance (CrCl) into 4 groups: group 1 (CrCl >60 mL/min), group 2 (CrCl 60-30 mL/min), group 3 (CrCl <30 mL/min), and group 4 (intermittent hemodialysis). Retrospective chart review was performed to quantify the post milrinone hemodynamic changes by cardiac catheterization and electrophysiologic changes by implantable cardiac defibrillator (ICD) interrogation. RESULTS: A total of 29 patients were identified: group 1 (n=14), group 2 (n=10), group 3(n=3), and group 4 (n = 2). The mean infusion rate (0.391+0.08 mg/kg/min) did not differ between groups (P=0.14). The mean milrinone concentration was 451+243 ng/mL in group 1, 591+293 ng/mL in group 2, 1575+962 ng/mL in group 3, and 6252+4409 ng/mL in group 4 (P<0.05 compared to groups 1). There was no difference in post milrinone hemodynamic improvements between the groups (P=0.41). The ICD interrogation revealed limited comparisons, but 6 of the 8 post milrinone ventricular tachycardia episodes requiring defibrillation occurred in group 4 patients. CONCLUSION: Patients with stage D HF having severe renal dysfunction have elevated milrinone concentrations. Future studies of milrinone concentrations are warranted to investigate the potential risk of life-threatening arrhythmias and potential dosing regimens in renal dysfunction.

Impact of implanted recalled sprint Fidelis lead on patient mortality.

OBJECTIVES: This study sought to compare all-cause mortality in patients with Fidelis leads (Medtronic, Minneapolis, Minnesota) to those with a nonadvisory lead. BACKGROUND: Although Fidelis leads are prone to fracture, and rare deaths due to lead failure have been reported, it is unclear whether the presence of a Fidelis lead is associated with increased mortality. This study compares all-cause mortality in a large cohort of patients with Fidelis and Quattro implantable cardioverter-defibrillator (ICD) leads. METHODS: All patients with Fidelis (Medtronic models 6931, 6948, and 6949) and Quattro (Medtronic model 6947) leads followed at 3 tertiary care centers were identified from the medical records (implant dates: November 19, 2001, to December 23, 2008). Clinical and device-specific data were collected into a common database. Deaths were identified from medical records and the Social Security Death Index. Survival was estimated using the Kaplan-Meier method. RESULTS: A total of 2,671 patients (1,030 Fidelis and 1,641 Quattro) were identified. There were 398 deaths: 147 in the Fidelis group (mean follow-up: 34.4 months) and 251 in the Quattro group (mean follow-up: 39.9 months). No deaths were associated with 85 Fidelis and 23 Quattro failures. At 4 years, survival was diminished in patients with Fidelis compared with Quattro leads (80.7% vs. 83.9%, p = 0.025). After adjustment for factors associated with mortality, survival was similar between groups. One hundred percent pacing was not associated with mortality. Elective removal of nonfailed leads was performed in 5.1% of Fidelis and 0.9% of Quattro patients. CONCLUSIONS: In a conservatively managed cohort, in whom observation was predominantly utilized, adjusted survival is similar between patients with Fidelis and Quattro ICD leads.

Longevity of Sprint Fidelis implantable cardioverter-defibrillator leads and risk factors for failure: implications for patient management.

BACKGROUND: Sprint Fidelis (Fidelis) implantable cardioverter-defibrillator leads are prone to fractures that have caused adverse events, primarily inappropriate shocks, and a few reported deaths. More than 100 000 patients have Fidelis leads. No independent multicenter long-term performance information exists for this lead, and single-center studies suggest that certain patients are at increased risk for Fidelis failure. Our aim was to assess the longevity of Fidelis leads and to evaluate clinical variables and adverse events associated with Fidelis failure. The results were compared with like data for Quattro Secure (Quattro) implantable cardioverter-defibrillator leads implanted at our centers. METHODS AND RESULTS: This 3-center study included adults ≥18 years of age who received Fidelis or Quattro leads for the prevention of sudden cardiac death. From November 2001 to January 2009,1023 Fidelis and 1668 Quattro leads were implanted and followed up. The failure rate for Fidelis leads was 2.81%/y compared with 0.43%/y for Quattro leads (P<0.0001). No deaths or injuries occurred as a result of lead failure, but 42% of fractures caused inappropriate shocks. The survival of Fidelis leads at 4 years was 87.0% (95% confidence interval, 83.6 to 90.1) compared with 98.7% (95% confidence interval, 97.9 to 99.4) for Quattro leads (P<0.0001). Multivariate predictors of Fidelis failure were younger age (hazard ratio, 0.98; 95% confidence interval, 0.96 to 0.99), female gender (hazard ratio, 0.61; 95% confidence interval, 0.40 to 1.00), and cardiac disease (P=0.041). CONCLUSIONS: Compared with Quattro leads, the survival of Fidelis leads continues to decline, and Fidelis failure is notably higher in younger patients, women, individuals with hypertrophic cardiomyopathy, and patients with arrhythmogenic right ventricular dysplasia or channelopathies. These findings have significant implications for the management of patients who have Fidelis leads, and they demonstrate the importance of weighing clinical variables in assessments of implantable cardioverter-defibrillator lead performance.

High throughput screening via mass spectrometry: a case study using acetylcholinesterase.

Mass spectrometry-based screening can be applied to a wide range of targets, including those intractable targets that use substrates such as lipids, fatty acids, phospholipids, steroids, prostaglandins, and other compounds not generally amenable to conventional screening techniques. The major limitation to this approach is throughput, making HTS via mass spectrometry impractical. We present a mass spectrometry-based technique and hardware for lead discovery applications. Mass spectrometry enables the design of label-free assays using biologically native substrates for a wide range of enzymatic targets. This system can be used for the direct quantification of analytes in complex reaction mixtures with typical throughputs of 4-5 s per sample. A mass spectrometry-based assay was developed to identify inhibitors of acetylcholinesterase, an enzyme with clinical importance in Alzheimer's disease. The system was used to screen a small chemical library. Several potent inhibitors were identified, and the IC(50) values of the inhibitors were determined.