Estrogen-Based Gender-Affirming Hormone Therapy and Subclinical Cardiovascular Disease in Transgender Women with HIV.

Purpose: Transgender women (TW) are disproportionately affected by HIV infection and cardiovascular disease (CVD). This study evaluated whether estrogen-based gender-affirming hormone therapy (GAHT) in TW with HIV (TWH-GAHT) is associated with indices of subclinical CVD. Methods: Of the 40 HIV-seropositive persons enrolled, 20-60 years of age, on antiretroviral treatment with undetectable viral load, assessments were performed on 15 TWH; of these persons, 11 were GAHT treated. These TWH-GAHT were matched with HIV+ cisgender men and women based on age, ethnicity/race, body mass index, and antihypertensive medication use. Sex hormones, and cardiometabolic (waist circumference, blood pressure, insulin resistance, lipid profile, and C-reactive protein), vascular (flow-mediated dilation [FMD] and arterial stiffness), and proinflammatory measures were obtained. Results: TWH-GAHT displayed elevated estradiol and suppressed testosterone levels relative to normative ranges. Analyses indicated the TWH-GAHT displayed lower low-density lipoprotein compared with cisgender groups (p < 0.05). Although no difference was seen on FMD, the central augmentation index of aortic stiffness was higher in cisgender HIV+ women than cisgender HIV+ men (p < 0.05). No other group difference on subclinical CVD markers was observed. For TWH, partial correlations indicated associations of certain sex hormones with selected cardiometabolic outcomes and the inflammatory cytokine, interleukin-8. Conclusion: When well matched to HIV+ cisgender men and women, subclinical CVD pathophysiology did not appear elevated in TWH-GAHT, although tendencies emerged suggesting that some subclinical CVD indices may be higher, but others lower than cisgender groups. Longitudinal studies of TWH are needed to more precisely evaluate the moderating effect of GAHT on cardiometabolic pathophysiology.

Allogeneic Cell Combination Therapy Ameliorates Chronic Kidney Disease-Induced Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Left ventricular hypertrophy and heart failure with preserved ejection fraction (HFpEF) are primary manifestations of the cardiorenal syndrome in patients with chronic kidney disease (CKD). Therapies that improve morbidity and mortality in HFpEF are lacking. Cell-based therapies promote cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that cell-based therapy ameliorates CKD-induced HFpEF. METHODS AND RESULTS: Yorkshire pigs (n = 26) underwent 5/6 embolization-mediated nephrectomy. CKD was confirmed by increased creatinine and decreased glomerular filtration rate (GFR). Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks. HFpEF was evident at 4 weeks by increased LV mass, relative wall thickening, end-diastolic pressure, and end-diastolic pressure-volume relationship, with no change in ejection fraction (EF). Four weeks post-embolization, allogeneic (allo) bone marrow-derived mesenchymal stem cells (MSC; 1 × 107 cells), allo-kidney-derived stem cells (KSC; 1 × 107 cells), allo-cell combination therapy (ACCT; MSC + KSC; 1:1 ratio; total = 1 × 107 cells), or placebo (Plasma-Lyte) was delivered via intra-renal artery. Eight weeks post-treatment, there was a significant increase in MAP in the placebo group (21.89 ± 6.05 mmHg) compared to the ACCT group. GFR significantly improved in the ACCT group. EF, relative wall thickness, and LV mass did not differ between groups at 12 weeks. EDPVR improved in the ACCT group, indicating decreased ventricular stiffness. CONCLUSIONS: Intra-renal artery allogeneic cell therapy was safe in a CKD swine model manifesting the characteristics of HFpEF. The beneficial effect on renal function and ventricular compliance in the ACCT group supports further research of cell therapy for cardiorenal syndrome.

Mesenchymal Stem Cell Secretion of SDF-1α Modulates Endothelial Function in Dilated Cardiomyopathy.

BACKGROUND: Endothelial dysfunction contributes to the pathophysiology of dilated cardiomyopathy (DCM). Allogeneic but not autologous mesenchymal stem cells (MSCs) improve endothelial function in DCM patients. We hypothesized that these effects are modulated by release of stromal derived factor-1α (SDF-1α). METHODS: Plasma TNFα and endothelial progenitor cell-colony forming units (EPC-CFUs) were assessed at baseline and 3-months post-injection in a subset of POSEIDON-DCM patients that received autologous (n = 11) or allogeneic (n = 10) MSCs. SDF-1α secretion by MSCs, endothelial cell (EC) TNFα mRNA expression, and levels of reactive oxygen species (ROS) in response to SDF-1α were measured in vitro. RESULTS: As previously shown, DCM patients (n = 21) had reduced EPC-CFUs at baseline (3 ± 3), which were restored to normal by allogeneic MSCs 3-months post-treatment (Δ10 ± 4). DCM patients had elevated baseline plasma TNFα (n = 15, 22 ± 9.4 pg/mL). Allogeneic MSCs (n = 8) decreased, and autologous MSCs (n = 7) increased, plasma TNFα (-7.1 ± 3.1 vs. 22.2 ± 17.1 pg/mL, respectively; P = 0.0005). In culture, autologous MSCs (n = 11) secreted higher levels of SDF-1α than allogeneic MSCs (n = 6) [76.0 (63.7, 100.9) vs. 22.8 (7.2, 43.5) pg/mL, P = 0.0002]. SDF-1α and plasma TNFα negatively correlated with EPC-CFUs in both treatment groups (R = -0.7, P = 0.0004). ECs treated with 20 ng SDF-1α expressed lower levels of TNFα mRNA than cells treated with 100 ng (0.7 ± 0.2 vs. 2.1 ± 0.3, P = 0.0008). SDF-1α at low but not high concentration inhibited the generation of ROS. CONCLUSION: MSC secretion of SDF-1α inversely correlates with EPC-CFU production in DCM patients and therefore may be a modulator of MSC therapeutic effect in this clinical setting. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01392625, identifier NCT01392625.

Randomized Comparison of Allogeneic Versus Autologous Mesenchymal Stem Cells for Nonischemic Dilated Cardiomyopathy: POSEIDON-DCM Trial.

BACKGROUND: Although human mesenchymal stem cells (hMSCs) have been tested in ischemic cardiomyopathy, few studies exist in chronic nonischemic dilated cardiomyopathy (NIDCM). OBJECTIVES: The authors conducted a randomized comparison of safety and efficacy of autologous (auto) versus allogeneic (allo) bone marrow-derived hMSCs in NIDCM. METHODS: Thirty-seven patients were randomized to either allo- or auto-hMSCs in a 1:1 ratio. Patients were recruited between December 2011 and July 2015 at the University of Miami Hospital. Patients received hMSCs (100 million) by transendocardial stem cell injection in 10 left ventricular sites. Treated patients were evaluated at baseline, 30 days, and 3-, 6-, and 12-months for safety (serious adverse events [SAE]), and efficacy endpoints: ejection fraction, Minnesota Living with Heart Failure Questionnaire, 6-min walk test, major adverse cardiac events, and immune biomarkers. RESULTS: There were no 30-day treatment-emergent SAEs. Twelve-month SAE incidence was 28.2% with allo-hMSCs versus 63.5% with auto-hMSCs (p = 0.1004 for the comparison). One allo-hMSC patient developed an elevated (>80) donor-specific calculated panel reactive antibody level. The ejection fraction increased in allo-hMSC patients by 8.0 percentage points (p = 0.004) compared with 5.4 with auto-hMSCs (p = 0.116; allo vs. auto p = 0.4887). The 6-min walk test increased with allo-hMSCs by 37.0 m (p = 0.04), but not auto-hMSCs at 7.3 m (p = 0.71; auto vs. allo p = 0.0168). MLHFQ score decreased in allo-hMSC (p = 0.0022) and auto-hMSC patients (p = 0.463; auto vs. allo p = 0.172). The major adverse cardiac event rate was lower, too, in the allo group (p = 0.0186 vs. auto). Tumor necrosis factor-α decreased (p = 0.0001 for each), to a greater extent with allo-hMSCs versus auto-hMSCs at 6 months (p = 0.05). CONCLUSIONS: These findings demonstrated safety and clinically meaningful efficacy of allo-hMSC versus auto-hMSC in NIDCM patients. Pivotal trials of allo-hMSCs are warranted based on these results. (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy [PoseidonDCM]; NCT01392625).