Preoperative Amiodarone and Primary Graft Dysfunction in Heart Transplantation.

BACKGROUND: Preoperative amiodarone effects on postorthotopic heart transplant (OHT) outcomes remain controversial. OBJECTIVE: The purpose of this study was to determine the effect of cumulative pre-OHT amiodarone exposure on severe primary graft dysfunction (PGD). METHODS: We retrospectively reviewed adult OHT recipients between August 2012 and June 2018. Primary outcome was severe PGD in patients receiving amiodarone at 3, 6, and 12 months prior to OHT compared with those not receiving amiodarone. Secondary outcomes included intensive care unit (ICU) and hospital length of stay, duration of mechanical ventilation, early graft failure (EGF), mortality at 3, 6, and 12 months post-OHT, and 30-day incidence of postoperative tachyarrhythmias, bradycardia, permanent pacemaker implantation, and rejection. RESULTS: Incidence of severe PGD was 12.5% in those who received amiodarone compared to 6.8% in those who did not (14 vs 6, P = 0.18). Cumulative preoperative amiodarone significantly increased the odds of severe PGD at 3 months (odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.001-1.06; P = 0.044) and 6 months (OR: 1.02, 95% CI: 1.003-1.044; P = 0.024) in a multivariate logistic regression. Patients on amiodarone had significantly higher rates of postoperative bradycardia (13.4% vs 4.5%, P = 0.03). CONCLUSION AND RELEVANCE: A trend toward increased PGD was present in patients receiving preoperative amiodarone. This finding combined with the regression showing significantly increased odds of PGD with increasing 3 and 6 month cumulative amiodarone dose is clinically concerning. Escalation of care with pacemaker implantation was required more frequently in patients on pre-OHT amiodarone.

Clinically important interaction between statin drugs and Clostridium difficile toxin?

Clostridium difficile associated disease (CDAD), a common type of antibiotic associated diarrhea, is increasing in frequency and affecting patients outside of traditional populations. At one time CDAD exclusively occurred in hospitalized patients or frail elderly patients receiving antibiotic therapy. It is now occurring more commonly in younger patients who are relatively healthy and may not be receiving antibiotics. Co-factors that might explain this increase incidence and changing demographic are of great public health interest. Recent investigations have identified gastric acid suppression, particularly via proton pump inhibitors, as a risk factor for the development of CDAD by mechanisms which are not entirely clear. C. difficile toxin comes as two major forms that are closely related, toxin A and toxin B and both are able to produce CDAD. These toxins have a glucosyltransferase domain that glucosylates actived Rho, a small GTP binding protein involved in multiple cellular signaling pathways. Glucosylation inactivates Rho and modifies cell cycle, cytoskeletal and inflammatory pathways. The lipid lowering drugs called statins also inhibit Rho but at an earlier step in the Rho pathway. Statins inhibit the isoprenylation of Rho and therefore inhibits membrane anchoring a key step in Rho signaling. We propose that statins potentiate C. difficile toxin effects on colonic epithelium which leads to an increased risk of CDAD. We present preliminary data from a retrospective cohort which demonstrated an increased rate of CDAD in patients receiving statins compared to non-statin controls. The weight of the evidence leads to our hypothesis that statins interact with C difficile toxin A and B causing an increase in the rate and severity of CDAD.