Estrogen Receptor-β Agonists Modulate T-Lymphocyte Activation and Ameliorate Left Ventricular Remodeling During Chronic Heart Failure.

Rosenzweig R, Kumar V, Gupta S, Bermeo-Blanco O, ... Gumina RJ, Bansal SS
Background
CD4⁺ T cells temporally transition from protective to pathological during ischemic heart failure (HF; 8 weeks postmyocardial infarction). Cellular mechanisms mediating this shift are unknown.
Methods
RNA-sequencing of cardiac CD4⁺ T cells and flow cytometric analysis of immune cells was conducted.
Results
RNA-sequencing of CD4⁺ T cells from the failing hearts of male mice indicated activation of ER (estrogen receptor)-α signaling. Flow cytometric analysis showed that ERα in CD4⁺ T cells decreases significantly at 3-day postmyocardial infarction but increases during HF. To antagonize ERα, we tested a novel ERβ agonist (OSU-ERb-012) to inhibit T cells and blunt left ventricular remodeling. Proliferation assays showed that OSU-ERb-012 dose-dependently inhibited proliferation and proinflammatory cytokine expression in anti-CD3/CD28 stimulated splenic T cells isolated from both the sexes. For in vivo efficacy, 10- to 12-week-old male and ovariectomized female mice were randomized at 4 weeks postmyocardial infarction and treated with either vehicle or drug (60 mg/kg per day; oral). While vehicle-treated HF mice displayed progressive left ventricular dilatation with significantly increased end-systolic and end-diastolic volumes from 4 to 8 weeks postmyocardial infarction, treatment with OSU-ERb-012 significantly blunted these changes and stopped left ventricular remodeling in both the sexes. Reduction in tibia-normalized heart and left ventricular weights, cardiomyocyte hypertrophy and interstitial fibrosis further supported these results. Additionally, OSU-ERb-012 treatment selectively inhibited cardiac, splenic, and circulating CD4⁺ T cells without affecting other myeloid and lymphoid cells in the HF mice.
Conclusions
Our studies indicate that ERβ agonists and OSU-ERb-012, in particular, could be used as selective immunomodulatory drugs to inhibit CD4⁺ T cells during chronic HF.



Circ Heart Fail: 22 Jun 2022:CIRCHEARTFAILURE121008997; epub ahead of print

Donor Utilization in the Recent Era: Effect of Sex, Drugs, and Increased Risk.

Baran DA, Long A, Lansinger J, Copeland JG, Copeland H
Background
Heart transplantation volumes have increased in recent years, yet less than a third of donors are typically accepted for transplantation. Whether donor sex, donor drug use, or perception of increased risk affects utilization for transplantation is unclear.
Methods
The United Network for Organ Sharing database was queried for donors from January 1, 2007, to December 31, 2017. Donor toxicology was collected when available. Multivariate analysis was conducted to examine correlations with donor utilization.
Results
Between January 1, 2007, and December 31, 2017, there were 87 816 heart donors aged ≥15 years. The mean age was 42.7±15.8 years, and 24 831 donors (28.3%) were utilized for heart transplantation. Subsequent analyses focused on donors between 15 and 39 years old. The strongest associations with donor acceptance were for male donor sex, blood type, hepatitis C antibody, donor age, left ventricular hypertrophy, and history of donor drug use. After removing hepatitis C, Public Health Service Increased Risk was identified as a strong negative predictor. Most positive drug toxicology results were associated with donor nonuse except for donors between 15 and 19 years of age. Exceptions included alcohol, marijuana, and cocaine. Opiates were associated with less utilization at all donor ages. The Public Health Service Increased Risk status was associated with significantly less utilization in all age groups except 15- to 19-year-old donors.
Conclusions
While male donors were preferentially utilized, donors with drug use or those deemed Public Health Service Increased Risk were significantly less utilized for heart transplantation. Further consideration of such donors would be appropriate particularly as the demand for transplantation continues to increase.



Circ Heart Fail: 21 Jun 2022:101161CIRCHEARTFAILURE122009547; epub ahead of print