Faculty Bibliography

Purpose: Heart transplantation (HTx) from hepatitis C virus (HCV) positive donors to HCV negative recipients may reduce waitlist time and increase access to viable organs. Direct acting antivirals (DAAs) are highly successful at curing HCV infection, but the effect of DAAs on the pharmacokinetics of calcineurin inhibitors is largely unknown. We describe the effect on tacrolimus dosage requirements in recipients of HCV viremic donors. Method(s): We retrospectively reviewed HCV negative HTx patients who received a HCV positive organ. All patients received an 8 week course of glecaprevir-pibrentasvir (GP) for HCV treatment and were on standard triple immunosuppression therapy. Patients receiving concomitant medications that affect tacrolimus metabolism were excluded. All tacrolimus dosages and trough levels were collected from the time of initiation post-HTx until 1 month after completion of GP treatment. Tacrolimus dose normalized concentrations using the concentration:dose ration (ng/mL:mg/kg) were compared before, during, and after GP treatment. Result(s): Seven HTx recipients were included in the analysis. Tacrolimus dose normalized concentrations were 124.8, 163.4, and 196.7 (ng/mL)/(mg/kg/d) before, during and after GP treatment, respectively (Figure 1). Tacrolimus dosage requirements did not differ during GP treatment as compared to before or after GP treatment. The percentage of tacrolimus trough levels within goal range and the incidence of supratherapeutic tacrolimus levels, was 51% vs. 41% and 4% vs. 0% during GP treatment as compared to after GP treatment. Conclusion(s): We did not find a difference in tacrolimus dosage requirements while receiving GP treatment as compared to before or after GP treatment; however, this study was limited by a small sample size. No empiric dosage adjustments can be recommended when initiating or discontinuing GP treatment at this time. Further data will be needed to strengthen these findings.

BACKGROUND: The critical threshold and clinical significance of transient ischemic dilation (TID) for regadenoson, single-isotope (99m)Tc SPECT myocardial perfusion imaging (MPI) are not defined. METHODS: From 100 patients with low likelihood of CAD, we derived the abnormal TID threshold (mean + 2 SD). We validated the threshold in a cohort of 547 patients who received one-day, rest/regadenoson-stress, (99m)Tc-tetrofosmin SPECT-MPI followed by coronary angiography within 6 months. Patients were classified into three CAD severity strata: no significant CAD, mild to moderate CAD, and severe and extensive CAD. RESULTS: The abnormal TID threshold was determined to be 1.31. Though mean TID ratios were different between the three CAD severity groups and the derivation cohort (P < .001), there was no difference in the mean TID ratios between the categories of CAD severity or in the prevalence of severe CAD between TID+ and TID- groups (P = .74). By ROC analysis, TID had a poor discriminatory capacity in identifying severe and extensive CAD [AUC of 0.55 (95% CI 0.47-0.62, P = .25)]. Stepwise multivariate logistic analysis demonstrated that adding TID to clinical and perfusion data did not provide incremental diagnostic value (P = .87). CONCLUSIONS: The clinical utility of TID with regadenoson-stress MPI in this era of declining CAD burden is questionable.

Continuous-flow ventricular assist devices (CVADs) are associated with a significant complication profile that includes thrombosis of the ascending aorta and aortic valve, thromboembolism, and stroke. Despite an increasing number of reports of thromboembolic complications related to CVADs, there is little in the literature to guide their management. This report describes successful management strategies used during two cases of thrombosis of the ascending aorta during biventricular CentriMag (Levitronix LLC, Waltham, MA) support, including using pre-existing cannulas to initiate cardiopulmonary bypass.

Sinus bradycardia may be more significant in older patients than in a younger group because it could signal important or advanced conduction system and/or cardiac disease potentially modifiable with pacemaker implantation. We evaluated the clinical need for subsequent pacemaker implantation and mortality rate in outpatients >60 years of age with relatively asymptomatic bradycardia (heart rate <55 beats/min without a subsequent pacemaker implantation within 2 weeks) or not (heart rate 60 to 70 beats/min). The 2 groups were matched against pacemaker implantation and death records but without data on indication or cause. Kaplan-Meier survival curves and univariate and multivariable models examined pacemaker implantation and all-cause mortality. The cohort consisted of 470 patients with and 2,090 without asymptomatic bradycardia. Mean follow-up period was 7.2 +/- 2.9 years during which 137 patients (5.4%) underwent pacemaker implantation and 748 (29.2%) died. Incidence of pacemaker placement was higher in the bradycardia cohort (9% vs 5%, p <0.001). The higher incidence of pacemaker implantation did not appear in the first 4 years. Univariate analysis showed no increase in mortality in the bradycardia group (hazard ratio 0.87, 95% confidence interval 0.72 to 1.04, p = 0.130), whereas multivariable analysis showed protection (hazard ratio 0.78, 95% confidence interval 0.65 to 0.94, p = 0.010). In conclusion, older patients with asymptomatic bradycardia have a very low rate of pacemaker implantation, annualized to <1% per year. Their higher rate of pacemaker implantation compared to outpatients without bradycardia shows a latency period of approximately 4 years. It has no adverse impact on all-cause mortality and may even be protective.

BACKGROUND: Published work suggests that some types of endothelial cells undergo apoptosis in response to ligation of the receptor Fas (CD95, APO1) but other types are resistant. Because heterogeneity among endothelial cells from different tissues, has been demonstrated, the purpose of this study was to determine, if Fas ligation and/or activation by human Fas ligand induces apoptosis and caspase activities, in cultured human coronary artery endothelial cells, and the differences between TNF-a and FAS induced apoptosis in these cells. RESULTS: Cultured human coronary artery endothelial cells (HCAEC) were exposed to the monoclonal Fas-activating antibody CH-11, to purified recombinant human Fas ligand, to the Fas-neutralizing antibody ZB4, or to purified recombinant human TNF-alpha. Apoptosis was detected by assessment of chromatin condensation and nuclear fragmentation and by assay of the enzymatic activities of Caspase 1 and Caspase 3 with membrane-permeable substrates applied to intact cells. Fas protein was detected by immunoblotting of HCAEC lysates. Apoptosis was induced in HCAEC by purified Fas ligand or by the monoclonal activating antibody CH-11 at concentrations of 25 or 200 ng/ml, but not by nonspecific isotype-matched immunoglobulins. The apoptotic index elicited by either Fas activator was equal to that induced by TNF-a (3.0-3.6-fold versus control, p < 0.01). The Fas-neutralizing antibody ZB4 abrogated HCAEC apoptosis induced by CH-11, but had no inhibitory effect on apoptosis in response to TNF-a. Fas ligation significantly increased the activities of both Caspase 1 and Caspase 3 at 20 hours of stimulation (1.7- and 2.0-fold versus control, both p < 0.05); in contrast, purified TNF-a increased the activity of Caspase 3 but not Caspase 1 (2.1-fold, p < 0.05). Western blotting of HCAEC lysates with antibody CH-11 identified a single immunoreactive protein of 90 kDa. CONCLUSIONS: Cultured human coronary artery endothelial cells express functional Fas capable of inducing apoptosis in response to either purified Fas ligand or receptor-activating monoclonal antibodies, at levels equal to those inducible by purified TNF-alpha. Immunologic studies and differential kinetics of caspase activation suggest that Fas and TNF-alpha induce apoptosis in HCAEC by signaling pathways that are distinct but equal in potency.