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Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer survival but are associated with treatment-limiting hypertension, often attributed to endothelial cell (EC) dysfunction. Using phosphoproteomic profiling of VEGFRi-treated ECs, drugs were screened for mitigators of VEGFRi-induced EC dysfunction and validated in primary aortic ECs, mice, and canine cancer patients. VEGFRi treatment significantly raised systolic blood pressure (SBP) and increased markers of endothelial and renal dysfunction in mice and canine cancer patients. a-Adrenergic-antagonists were identified as drugs that most oppose the VEGFRi proteomic signature. Doxazosin, one such a-antagonist, prevented EC dysfunction in murine, canine, and human aortic ECs. In mice with sorafenib-induced-hypertension, doxazosin mitigated EC dysfunction but not hypertension or glomerular endotheliosis, while lisinopril mitigated hypertension and glomerular endotheliosis without impacting EC function. Hence, reversing EC dysfunction was insufficient to mitigate VEGFRi-induced-hypertension in this mouse model. Canine cancer patients with VEGFRi-induced-hypertension were randomized to doxazosin or lisinopril and both agents significantly decreased SBP. The canine clinical trial supports safety and efficacy of doxazosin and lisinopril as antihypertensives for VEGFRi-induced-hypertension and the potential of trials in canines with spontaneous cancer to accelerate translation. The overall findings demonstrate the utility of phosphoproteomics to identify EC-protective agents to mitigate cardio-oncology side effects. [ABSTRACT FROM AUTHOR]

Background and Objectives: Despite the significant impact of heart failure on both members of the care dyad, few interventions focus on optimizing the health of the dyad. The current study examined the feasibility and acceptability of the novel Taking Care of Us (TCU) program with mid-late-life couples living with heart failure and explored preliminary efficacy., Research Design and Methods: This NIH Stage I study used a 2-arm randomized controlled trial with pretest-post-test design and an additional 5-month follow-up to compare TCU with an educational counseling attention-control condition. 37 couples were randomized to TCU (18 couples) or an educational control group (19 couples). Both programs were delivered virtually over 2 months., Results: Adults with heart failure were primarily male (mean age = 66.32, standard deviation [ SD ] = 13.72); partners were primarily female (mean age = 63.00, SD  = 12.73). Feasibility findings were mixed with over half of the eligible couples randomized, but only 67% of TCU couples completed the post-test. Acceptability of the TCU program was strong for both adults with heart failure and their partners. Recommendations for change focused on shortening session length, offering fewer sessions, and providing alternative modes of delivery. Exploratory between-group analyses found medium effect sizes for physical and mental health and dyadic management for both members of the couple, with many effects remaining 3 months later., Discussion and Implications: Findings suggest the TCU program is acceptable to couples with heart failure and shows promise for optimizing outcomes. Recommendations and strategies for improving retention and a more diverse sample are discussed., Clinical Trial Registration: NCT04737759., Competing Interests: None., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Gerontological Society of America.)

Elevated pulmonary vascular resistance (PVR) is a risk factor for mortality after heart transplantation (HT), but whether this association differs for patients with and without left ventricular assist device (LVAD) support before HT is unknown. We analyzed adult first-time HT recipients from the United Network for Organ Sharing (UNOS) registry transplanted between 2010 and 2021. We quantified the association between PVR and the outcomes of 30 day graft failure and 1 year mortality using multivariable logistic regression, stratified by LVAD support status at the time of HT. Pulmonary vascular resistance was modeled using restricted cubic splines to identify clinically relevant risk thresholds. We also examined the association with 10 year survival using multivariable Cox proportional hazards regression. For PVR values less than approximately 2 WU, higher PVR was independently associated with a higher risk of early graft failure (odds ratio [OR] = 1.58, 95% CI: 1.06-2.36) and a higher risk of 1 year mortality (OR = 1.32, 95% CI: 1.10-1.59) among LVAD patients only (interaction p = 0.023 and 0.03, respectively). However, for patients surviving at least 1 year, PVR was not associated with long-term mortality among either subgroup. Whether more aggressive reduction of PVR among HT candidates supported with LVADs can mitigate these risks requires further study., Competing Interests: Disclosure: G.G. is the site PI for a clinical trial sponsored by Windtree Therapeutics and has received travel support from Abiomed. A.R.V. is the site PI for clinical trials sponsored by Corvia and CareDx. M.S.K. has served as a steering committee member for Medtronic. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)