A pilot clinical trial of cell therapy in heart failure with preserved ejection fraction

Abstract

Aims: We investigated the effects of CD34+ cell therapy in patients with heart failure with preserved ejection fraction (HFpEF).

Methods and results: In a prospective pilot study, we enrolled 30 patients with HFpEF. In Phase 1, patients were treated with medical therapy for 6 months. Thereafter, all patients underwent CD34+ cell transplantation. Using electroanatomical mapping, we measured local mechanical diastolic delay and myocardial viability to guide the targeting of cell injections. Patients were followed for 6 months after cell transplantation (Phase 2), and the primary endpoint was the difference in change in E/e' between Phase 1 and Phase 2. In Phase 1, the decrease in E/e' was significantly less pronounced than in Phase 2 (-0.33 ± 1.72 vs. -3.77 ± 2.66, p = 0.001). During Phase 1, there was no significant change in global systolic strain (GLS; from -12.5 ± 2.4% to -12.8 ± 2.6%, p = 0.77), N-terminal pro-B-type natriuretic peptide (NT-proBNP; from 1463 ± 1247 pg/ml to 1298 ± 931 pg/ml, p = 0.31), or 6-min walk test (6MWT; from 391 ± 75 m to 402 ± 93 m, p = 0.42). In Phase 2, an improvement was noted in NT-proBNP (from 1298 ± 931 pg/ml to 887 ± 809 pg/ml, p = 0.02) and 6MWT (from 402 ± 93 m to 438 ± 72 m, p = 0.02). Although GLS did not change significantly in Phase 2 (from -12.8 ± 2.6% to -13.8 ± 2.7%, p = 0.36), we found improved local systolic strain at cell injection sites (-3.4 ± 6.8%, p = 0.005).

Conclusions: In this non-randomized trial, transendocardial CD34+ cell therapy in HFpEF was associated with an improvement in E/e', NT-proBNP, exercise capacity, and local myocardial strain at the cell injection sites.

Clinical trial registration: ClinicalTrials.gov NCT02923609.

Keywords: Cell therapy; Diastolic function; Heart failure; Heart failure with preserved ejection fraction.

© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Figures

Figure 1

Flow‐chart of the study design. After enrolment all patients were treated with optimization of medical therapy for 6 months (Phase 1). Thereafter, all patients received transendocardial CD34+ cell therapy, and were followed for another 6 months (Phase 2). At the time of enrolment (6 months before cell therapy), at the time of cell therapy, and 6 months thereafter we performed detailed clinical evaluation, laboratory assays, echocardiography, 6‐min walk test, and measured plasma levels of N‐terminal pro‐B‐type natriuretic peptide.

Figure 2

Measurement of local mechanical diastolic delay and myocardial viability. (A) Exemplary electroanatomical mapping of the left ventricle with measurement of local mechanical diastolic delay. (B) Examples of mapping points with (top) and without (bottom) local mechanical diastolic delay. (C) Schematic presentation of the local mechanical diastolic delay measurements from panel B. Prior to stem cell application, we performed electroanatomical mapping of the left ventricle consisting of at least 150 mapping points. At each point we measured local movement of left ventricular wall (white lines in panels B and C). Local mechanical diastolic delay (red arrows in panel C) was defined as timing difference between maximum local diastolic time and end‐diastolic time based on left ventricular volume (yellow lines in panels B and C). In panel (A), blue and purple areas represent regions with increased local mechanical diastolic delay; red, yellow and green areas represent the regions without significant local mechanical diastolic delay. Green lines in panels (B) and (C) represent local action potential. (E) Exemplary unipolar voltage map: red and yellow areas represent regions with decreased viability; green, blue and purple areas represent regions with preserved viability. (D) Distribution of local mechanical diastolic delay in mapping points with decreased viability. (F) Distribution local mechanical diastolic delay in points with preserved viability. Overall, we found a significantly increased local mechanical diastolic delay in regions with decreased viability. Stem cell injections (brown dots in panel E) were performed targeting the areas with increased local mechanical diastolic delay and preserved myocardial viability.

Figure 3

Changes in E/e′. The chart displays individual changes in E/e′ between baseline (6 months before cell therapy), the time of cell therapy, and 6 months thereafter. The decrease in E/e′ was significantly more pronounced in Phase 2 than in Phase 1 (p = 0.001). SC, stem cell.

Figure 4

Changes in global and local longitudinal strain, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), and exercise capacity. In Phase 1, we found no change in global longitudinal strain (GLS); although GLS showed a trend of decrease in Phase 2, the changes did not reach statistical significance (A). Levels of NT‐proBNP remained stable throughout Phase 1 but decreased significantly in Phase 2 (B). In Phase 1, 6‐min walk test (6MWT) distance did not change; however, we found a significant improvement in 6MWT distance in Phase 2 (C). SC, stem cell.