Madhav Swaminathan

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Background: Tricuspid regurgitation (TR) is common immediately after orthotopic heart transplantation (OHT), though the expected outcomes of TR over time remain undefined. In this study, we examined the natural trajectory of TR in the first 120 days post‐transplantation. We observed the clinical phenotypes of trajectories of TR after OHT, and assessed trajectory correlation with 1‐year mortality and degree of right ventricular (RV) dysfunction.Methods: All patients who underwent OHT at a single institution from January 2009 to July 2019 were included, unless death occurred during the index hospitalization. TR and RV dysfunction on follow‐up transthoracic echocardiograms were tracked on 4‐point scales and latent‐class mixed modeling (LCMM) identified classes of TR trajectories. Fisher's exact test was used to compare 1‐year mortalities between classes.Results: Based on LCMM, four distinct classes of TR trajectories emerged, characterized as sustained (n = 40), variable (n = 172), stable (n = 175), and recovered (n = 189) TR. Significant differences in mortality rates were found amongst classes at 10.0%, 8.1%, 4.0%, and 2.6%, respectively (p = 0.025). The degree of RV dysfunction mirrored TR severity in all subsets except the sustained TR group.Conclusions: The trajectory of TR in the first 120 days post‐OHT is associated with 1‐year mortality. In many subsets, there is a close association with TR grade and RV function improvement. However, in the sustained TR group, RV function improved without subsequent improvement in TR severity. These findings could identify patients with higher mortality risk for whom more frequent follow‐up or intervention is warranted.

Background: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI. Methods: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments. Results: A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P =0.02; odds ratio, 0.58 (95% CI, 0.37–0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment. Conclusions: The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897). Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02610283.

Mesenchymal stem cells (MSCs) have natural immunoregulatory functions that have been explored for medicinal use as a cell therapy with limited success. A phase Ib study was conducted to evaluate the safety and immunoregulatory mechanism of action of MSCs using a novel ex vivo product (SBI-101) to preserve cell activity in patients with severe acute kidney injury. Pharmacological data demonstrated MSC-secreted factor activity that was associated with anti-inflammatory signatures in the molecular and cellular profiling of patient blood. Systems biology analysis captured multicompartment effects consistent with immune reprogramming and kidney tissue repair. Although the study was not powered for clinical efficacy, these results are supportive of the therapeutic hypothesis, namely, that treatment with SBI-101 elicits an immunotherapeutic response that triggers an accelerated phenotypic switch from tissue injury to tissue repair. Ex vivo administration of MSCs, with increased power of testing, is a potential new biological delivery paradigm that assures sustained MSC activity and immunomodulation.