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. 2021 May 26:8:664277.
doi: 10.3389/fcvm.2021.664277. eCollection 2021.

Sex-Based Differences in Autologous Cell Therapy Trials in Patients With Acute Myocardial Infarction: Subanalysis of the ACCRUE Database

Paul M Haller  1 , Mariann Gyöngyösi  1 , Lourdes Chacon-Alberty  2 , Camila Hochman-Mendez  2 , Luiz C Sampaio  3 , Doris A Taylor  2
Affiliations

Sex-Based Differences in Autologous Cell Therapy Trials in Patients With Acute Myocardial Infarction: Subanalysis of the ACCRUE Database

Paul M Haller et al. Front Cardiovasc Med. .

Abstract

Background: Sex-based differences are under-studied in cardiovascular trials as women are commonly underrepresented in dual sex studies, even though major sex-based differences in epidemiology, pathophysiology, and outcomes of cardiovascular disease have been reported. We examined sex-based differences in patient characteristics, outcome, and BM-CD34+ frequency of the ACCRUE (Meta-Analysis of Cell-based CaRdiac studies) database involving patients with acute myocardial infarction (AMI) randomized to autologous cell-based or control treatment. Methods: We compared baseline characteristics and 1-year follow-up clinical data: composite major adverse cardiac and cerebrovascular events (primary endpoint), and changes in left ventricular ejection fraction (LVEF), end-diastolic (EDV), and end-systolic volumes (ESV) (secondary efficacy endpoint) in women and men (N = 1,252; 81.4% men). Secondary safety endpoints included freedom from hard clinical endpoints. Results: In cell-treated groups, women but not men had a lower frequency of stroke, AMI, and mortality than controls. The frequency of BM-CD34+ cells was significantly correlated with baseline EDV and ESV and negatively correlated with baseline LVEF in both sexes; a left shift in regression curve in women indicated a smaller EDV and ESV was associated with higher BM-CD34+ cells in women. Conclusions: Sex differences were found in baseline cardiovascular risk factors and cardiac function and in outcome responses to cell therapy.

Keywords: acute myocardial infarction; cardiovascular diseases; cell based therapy; cell therapy; clinical trials; sex characteristics; sex differences.

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Conflict of interest statement

DT is self-employed as a business consultant with RegenMedix Consulting LLC. At the time the work was performed DT was employed by Texas Heart Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Kaplan-Meier curves for clinical outcomes of women and men in cardiac regenerative studies after acute myocardial infarction. (A) Major adverse cardiac and cerebrovascular event(s) (MACCE), including all-cause death. (B) Combined hard clinical endpoint (all-cause death, stroke, and acute myocardial infarction). (C) All-cause death. (D) Target vessel revascularization.
Figure 2
Figure 2
Association between baseline ejection fraction (EF) and changes in EF in women and men. Significant but very weak negative correlation between baseline EF and changes in EF both in women and men, with no difference between the sexes.
Figure 3
Figure 3
(A) Correlation of baseline left ventricular ejection fraction with CD34+ cells. Left ventricular ejection fraction (EF) values correlated negatively with the percentage of CD34+ cells. The higher the EF is, the lower the number of BM-origin CD34+ cells (in percentage) in both sexes. The results were similar in men and women. Men: r = 0.282; y (lnCD34posPercent) = 2.81–0.025xEF (men); p < 0.001. Women: r = 0.32; y (lnCD34posPercent) = 3.547–0.029xEF (women); p = 0.001. (B) End-diastolic volume (EDV) values showed a significant exponential correlation with the percentage of CD34+ cells, suggesting an intrinsic repair mechanism in both sexes. The left shift of the curve in women indicates that a smaller EDV value was associated with a higher percentage of CD34+ cells in women. Men: r = 0.26; y (lnCD34posPercent) = 0.351+0.006xEDV (men); p < 0.001. Women: r = 0.362; y (lnCD34posPercent) = 0.243+0.011xEDV (women); p = 0.002. (C) Correlation of baseline end-systolic volume with CD34+ cells. End-systolic volume (ESV) showed an exponential correlation with the number of BM-origin CD34+ cells (in percentage). The left shift of the curve in women indicates that a smaller ESV results in a higher percentage of CD34+ cells in women as compared to men. Men: r = 0.316; y (lnCD34posercent) = 0.406+0.009xESV (men); p < 0.001. Women: r = 0.407; y (lnCD34posPercent) = 0.334+0.015xESV (women); p < 0.001. (D) Correlation of patient age with CD34+ cells. Age was negatively, weakly correlated with CD34+ cells in women, with a non-significant correlation in men. The lower the age of women, the higher the number of BM-origin CD34+ cells [in percentage]. Men: r = 0.094; y (lnCD34posPercent) = 1.60–0.01xAge (men); p = 0.054. Women: r = 0.285; y (lnCD34posPercent) = 4.52–0.027xAge (women); p = 0.013.
Figure 4
Figure 4
Kaplan-Meier curves for CD34+ cells stratified by quartiles and clinical outcomes. (A) Major adverse cardiac and cerebrovascular event(s) (MACCE). (B) Death. (C) Composite endpoint (mortality, stroke, acute myocardial infarction). (D) Target-vessel revascularization.
Figure 5
Figure 5
Correlation of CD34+ cells left ventricular functional data. (A) Delta EDV. (B) Delta ESV. (C) Delta EF. The regression line is shown for logarithmic transformed values of bone marrow CD34+ cells.
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