Risk Factors for 1-Year Mortality After Heart Transplant in Obese Patients Bridged With an LVAD.

BACKGROUND: Heart transplantation is relatively contraindicated in morbidly obese patients because of increased morbidity and mortality. This study identified risk factors for post-heart transplantation mortality in obese patients with a left ventricular assist device (LVAD). METHODS: The United Network for Organ Sharing database was used to identify patients with a body mass index ≥35 kg/m2 who had a durable LVAD at the time of isolated heart transplantation between 2010 and 2021. The primary outcome was post-heart transplantation 1-year mortality. Multivariable Cox regression modeling was used to identify significant risk factors for 1-year mortality. Receiver-operating characteristic analyses were performed to identify optimal thresholds for continuous variables associated with the primary outcome. Patients were stratified by the number of risk factors, and Kaplan-Meier analysis was used to compare survival. RESULTS: A total of 1222 obese patients were bridged to heart transplantation with a durable LVAD. Six risk factors were identified as significantly associated with 1-year post-heart transplantation mortality: recipient age >62.5 years, body mass index >36.6 kg/m2, bilirubin level >0.95 mg/dL, cold ischemic time >3.7 hours, recipient-donor sex mismatch, and pretransplantation mechanical ventilation. The distribution of cumulative risk factors was as follows: 8.6% with 0, 30.6% with 1, 37.0% with 2, and 23.8% patients with ≥3 risk factors. The 1-year survival rate decreased significantly from 96.0% in those patients with 0 risk factors to 77.6% in those with 3 or more risk factors. CONCLUSIONS: These data provide a useful guide for risk stratification and patient selection in obese LVAD candidates being considered for heart transplantation.

Outcomes of Combined Heart-Kidney Transplantation in Older Recipients.

Objectives: The upper limit of recipient age for combined heart-kidney transplantation (HKT) remains controversial. This study evaluated the outcomes of HKT in patients aged ≥65 years. Methods: The United Network of Organ Sharing (UNOS) was used to identify patients undergoing HKT from 2005 to 2021. Patients were stratified by age at transplantation: <65 and ≥ 65 years. The primary outcome was one-year mortality. Secondary outcomes included 90-day and 5-year mortality, postoperative new-onset dialysis, postoperative stroke, acute rejection prior to discharge, and rejection within one-year of HKT. Survival was compared using Kaplan-Meier analysis, and risk adjustment for mortality was performed using Cox proportional hazards modeling. Results: HKT in recipients aged ≥65 significantly increased from 5.6% of all recipients in 2005 to 23.7% in 2021 (p=0.002). Of 2,022 HKT patients in the study period, 372 (18.40%) were aged ≥65. Older recipients were more likely to be male and white, and fewer required dialysis prior to HKT. There were no differences between cohorts in unadjusted 90-day, 1-year, or 5-year survival in Kaplan-Meier analysis. These findings persisted after risk-adjustment, with an adjusted hazard for one-year mortality for age ≥65 of 0.91 (95% CI (0.63-1.29), p=0.572). As a continuous variable, increasing age was not associated with one-year mortality (HR 1.01 (95% CI (1.00-1.02), p=0.236) per year). Patients aged ≥65 more frequently required new-onset dialysis prior to discharge (11.56% vs. 7.82%, p=0.051). Stroke and rejection rates were comparable. Conclusion: Combined HKT is increasing in older recipients, and advanced age ≥65 should not preclude HKT.

Mechanotransduction-on-chip: vessel-chip model of endothelial YAP mechanobiology reveals matrix stiffness impedes shear response.

Endothelial mechanobiology is a key consideration in the progression of vascular dysfunction, including atherosclerosis. However mechanistic connections between the clinically associated physical stimuli, vessel stiffness and shear stress, and how they interact to modulate plaque progression remain incompletely characterized. Vessel-chip systems are excellent candidates for modeling vascular mechanobiology as they may be engineered from the ground up, guided by the mechanical parameters present in human arteries and veins, to recapitulate key features of the vasculature. Here, we report extensive validation of a vessel-chip model of endothelial yes-associated protein (YAP) mechanobiology, a protein sensitive to both matrix stiffness and shearing forces and, importantly, implicated in atherosclerotic progression. Our model captures the established endothelial mechanoresponse, with endothelial alignment, elongation, reduction of adhesion molecules, and YAP cytoplasmic retention under high laminar shear. Conversely, we observed disturbed morphology, inflammation, and nuclear partitioning under low, high, and high oscillatory shear. Examining targets of YAP transcriptional co-activation, connective tissue growth factor (CTGF) is strongly downregulated by high laminar shear, whereas it is strongly upregulated by low shear or oscillatory flow. Ankyrin repeat domain 1 (ANKRD1) is only upregulated by high oscillatory shear. Verteporfin inhibition of YAP reduced the expression of CTGF but did not affect ANKRD1. Lastly, substrate stiffness modulated the endothelial shear mechanoresponse. Under high shear, softer substrates showed the lowest nuclear localization of YAP whereas stiffer substrates increased nuclear localization. Low shear strongly increased nuclear localization of YAP across stiffnesses. Together, we have validated a model of endothelial mechanobiology and describe a clinically relevant biological connection between matrix stiffness, shear stress, and endothelial activation via YAP mechanobiology.