Tammy M. Joska

Emotional and Physical Precipitants of Ventricular Arrhythmia

Background—Observational studies have suggested that psychological stress increases the incidence of sudden cardiac death. Whether emotional or physical stressors can trigger spontaneous ventricular arrhythmias in patients at risk has not been systematically evaluated. Methods and Results—Patients with implantable cardioverter-defibrillators (ICDs) were given diaries to record levels of defined mood states and physical activity, using a 5-point intensity scale, during 2 periods preceding spontaneously occurring ICD shocks (0 to 15 minutes and 15 minutes to 2 hours) and during control periods 1 week later. ICD-stored electrograms confirmed the rhythm at the time of shock. A total of 107 confirmed ventricular arrhythmias requiring shock were reported by 42 patients (33 men; mean age, 65 years; 78% had coronary artery disease) between August 1996 and September 1999. In the 15 minutes preceding shock, an anger level ≥3 preceded 15% of events compared with 3% of control periods (P <0.04; odds ratio, 1.83; 95% confidence intervals, 1.04 to 3.16) Other mood states (anxiety, worry, sadness, happiness, challenge, feeling in control, or interest) did not differ. Patients were more physically active preceding shock than in control periods. Anger and physical activity were independently associated with the preshock period. Conclusions—Anger and physical activity can trigger ventricular arrhythmias in patients with ICDs. Future investigations of therapies aimed at blocking a response to these stressors may decrease ventricular arrhythmias and shocks in these patients.

Psychological traits and emotion-triggering of ICD shock-terminated arrhythmias.

Objective: We have previously reported on the triggering of arrhythmia and hence, implanted cardioverter-defibrillators (ICD) shock by strong emotion. The purpose of the present study was to examine whether concordant psychological traits distinguish patients who experience emotion-triggered ICD shock. Methods: Two hundred forty ICD patients completed the Speilberger Trait Anxiety and Anger Inventories and Anger Expression Scale, and the abridged Cook-Medley Hostility Scale approximately 2 months after ICD implantation. Patients were also given a structured diary to record mood states retrospectively for the period 0 to 15 minutes preceding ICD shock and for a period corresponding to the same time of day 1 week later. Patients who reported emotion-triggered ICD shock were compared on concordant psychological measures to patients who did not. Results: Patients who reported at least moderate anger in the 0 to 15 minutes before ICD shock scored significantly higher on Speilberger Trait Anger (24.18 ± 3.97 vs. 17.04 ± 2.17, p < .0001), and Cook-Medley Aggressive Responding (5.76 ± 0.75 vs. 3.96 ± 1.30, p < .0001) and Hostile Affect (3.59 ± 0.80 vs. 2.04 ± 1.02, p < .0001), and lower on Speilberger Anger Control (7.94 ± 1.43 vs. 10.64 ± 1.19, p < .001) than those who did not. In multivariate analysis, only Trait Anger remained a significant predictor of anger-triggered shock (&khgr;2 = 7.10, p < .008). Patients who reported at least moderate anxiety in the 0 to 15 minutes before ICD shock scored significantly higher on Speilberger Anxiety (22.43 ± 1.65 vs. 19.96 ± 1.71, p < .0001) than those who did not. Conclusion: Stable psychological factors are associated with risk for ICD-shock triggered by concordant strong emotion. ICD = implantable cardioverter-defibrillator; VT = ventricular tachycardia; VF = ventricular fibrillation; CAD = coronary artery disease; CHD = coronary heart disease.

Synthetic and Crystallographic Studies of a New Inhibitor Series Targeting Bacillus anthracis Dihydrofolate Reductase

Bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. Serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. Bacillus anthracis is known to be insensitive to the clinically used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. Herein, we describe a novel lead series of B. anthracis dihydrofolate reductase inhibitors characterized by an extended trimethoprim-like scaffold. The best lead compound adds only 22 Da to the molecular weight and is 82-fold more potent than trimethoprim. An X-ray crystal structure of this lead compound bound to B. anthracis dihydrofolate reductase in the presence of NADPH was determined to 2.25 A resolution. The structure reveals several features that can be exploited for further development of this lead series.

Structure-Activity Relationships of Bacillus cereus and Bacillus anthracis Dihydrofolate Reductase: toward the Identification of New Potent Drug Leads

ABSTRACT New and improved therapeutics are needed for Bacillus anthracis, the etiological agent of anthrax. To date, antimicrobial agents have not been developed against the well-validated target dihydrofolate reductase (DHFR). In order to address whether DHFR inhibitors could have potential use as clinical agents against Bacillus, 27 compounds were screened against this enzyme from Bacillus cereus, which is identical to the enzyme from B. anthracis at the active site. Several 2,4-diamino-5-deazapteridine compounds exhibit submicromolar 50% inhibitory concentrations (IC50s). Four of the inhibitors displaying potency in vitro were tested in vivo and showed a marked growth inhibition of B. cereus; the most potent of these has MIC50 and minimum bactericidal concentrations at which 50% are killed of 1.6 μg/ml and 0.09 μg/ml, respectively. In order to illustrate structure-activity relationships for the classes of inhibitors tested, each of the 27 inhibitors was docked into homology models of the B. cereus and B. anthracis DHFR proteins, allowing the development of a rationale for the inhibition profiles. A combination of favorable interactions with the diaminopyrimidine and substituted phenyl rings explains the low IC50 values of potent inhibitors; steric interactions explain higher IC50 values. These experiments show that DHFR is a reasonable antimicrobial target for Bacillus anthracis and that there is a class of inhibitors that possess sufficient potency and antibacterial activity to suggest further development.