Myocardial Injury as a New Target for Cell Therapy in Patients with Chronic Heart Failure

While cell therapy in patients with chronic heart failure has been safe, its efficacy has been modest with considerable variability across trials (1,2). This may be attributed to a wide variety of factors including cell type and dose, cell function-in particular autologous cells, method of delivery, cell processing issues and the etiology of heat failure. However, important factors rarely considered are individual patient characteristics that may be predictive of the clinical response to therapy and recovery of left-ventricular (LV) function. Knowledge of these characteristics would be helpful in selecting patients for cell therapy trials and further identifying mechanisms of benefit.

In patients with recent STEMI who received bone marrow mononuclear stem cells (BMCs), several clinical characteristics from the TIME Trial (3) and it’s pilot study (4) predicted improved LV function at 6-months (defined as a > 10% absolute improvement in LV ejection fraction (LVEF)). Not surprisingly, patients with shorter ischemic times, smaller infarcts and those with pre-infarction angina had significant recovery of LV function. Conversely, patients with larger infarcts and increased LV mass experienced a decline in LVEF over time. Additionally, the presence of microvascular obstruction on baseline MRI was most predictive of adverse LV remodeling. These changes in LV function were observed irrespective of treatment with BMCs or placebo.

Identifying those patients in a chronic heart failure population who would benefit from cell therapy may be more challenging given the chronicity of the disease and decline in stem cell homing signals. The chemokine stromal-derived factor-1 (SDF-1) and its CXCR4 ligand are important mediators of tissue repair and stem cell homing. SDF-1 is briefly up-regulated in response to tissue injury such as myocardial infarction and may enhance the homing of circulating stem cells to the myocardium (5). Unfortunately, SDF-1 expression in the myocardium may only be transiently elevated following injury such that it is not effective in chronic heart failure despite evidence that circulating SDF-1 levels are increased in these patients (6) and that certain stem cell fractions may have enhanced expression of SDF-1 (7). In support of this reduced expression in heart failure, a recent clinical trial using gene therapy (plasmid) to over-express SDF-1 in chronic heart failure patients was safely completed and revealed several trends of efficacy in LVEF and LV volumes in those patients with the most depressed LVEF compared to placebo (8).

Given the growing societal and economic burden of the heart failure population, it would be valuable to identify clinical factors that would convey benefit to cell therapy. To date, several studies have retrospectively examined the composition of the delivered cell product to determine what cell types may lead to greater efficacy. For example, in FOCUS-CCTRN (9) the improvement in LVEF was inversely related to age and directly proportional to the percentage of CD34⁺ cells. The recently initiated ischemic cardiomyopathy trial (CardiAMP^™) sponsored by Biocardia Inc. (NCT02438306) may represents a step forward by screening patient’s bone marrow for favorable cellular composition prior to allowing enrollment in the main trial.

The recent development of high sensitivity troponin T (hs-TnT) assays indicates that many patients with chronic heart failure who are stable and without obvious ischemia have detectable levels of troponin in their serum. Although the cause of this release is not entirely clear, it suggests a low-level of ongoing myocardial injury. This finding has portended an adverse prognosis in multiple clinical trials (10). In this issue of Circulation Research, Luu and colleagues (11) hypothesized that this low-level of myocardial injury might result in enhanced expression of chemoattractants such as SDF-1that could render the myocardium more receptive to repair via cell therapy.

The authors treated 157 chronic heart failure patients secondary to remote myocardial infarction (mean=7 years) and normal renal function with intracoronary autologous BMCs between 2003 and 2011. The vast majority of patients were NYHA Class 2/3 (81%) and the median LVEF was 39%. The median baseline values of both NT-proBNP (629 pg/ml) and hs-TnT levels (10.2 pg/ml) were significantly elevated prior to bone marrow harvest. Surprisingly, only 31 patients had hs-TnT levels below the level of detection of the assay (<3 pg/ml). The authors observed that subjects with the higher levels of TnT were older, had higher NYHA class and had lower LVEFs associated with the greatest levels of NT-proBNP. At 4 months, they report that the patients with the highest tertile of hs-TnT levels at baseline demonstrated the most benefit as manifested by a significant decline in NT-proBNP. While using this method would be challenging to demonstrate improvement in patients with normal levels at baseline, the authors performed a second analysis in 58 patients with elevated baseline NT-proBNP (> 1000 pg/ml) and observed a strong trend for reduction in mortality with patients who had a reduction in NT-proBNP. The authors conclude that patients with chronic heart failure and elevated hs-TnT levels represent a group of patients most likely to benefit from BMC therapy based on a significant reduction in NT-proBNP levels at 4 months post-delivery.

Because NT-proBNP levels were their only measurement of efficacy, it is important to determine how levels of this peptide vary over time in patients with chronic CHF. Araujo et al. (12) measured serial NT-proBNP levels in a population of stable CHF outpatients and observed that those with elevated levels at baseline (>1300 pg/ml, n=30) had a subsequent change of −29 to +38% on a second blood draw 3 weeks later without change in medications or clinical status. In the present study, the median change in NT-proBNP (38 pts decreased, 14 pts decreased) was a 250 pg/ml decrease from a median baseline of 1611 pg/ml, a 16% decline that falls within the range of clinical stability observed in the Araujo study.

To add mechanistic insight to this observational study, the authors examined a previous study (13) where they infused ¹¹¹Indium oxine-labeled autologous cultured circulating progenitor cells (CPCs) to patients with previous myocardial infarction (5 days – 17 years) and measured their retention by serial PET imaging. They found that retention in the heart of the CPCs following intracoronary infusion progressively decreased over time from infarction consistent with a temporal decline in homing signals and loss of progenitor cell activity that is known to occur with chronic heart disease. Using stored serum samples from the subgroup of those same patients, the authors demonstrated a significant correlation of hs-TnT serum levels with ¹¹¹Indium oxine-labeled uptake in the heart. Although this certainly strengthens their hypothesis, it is uncertain if the BMCs delivered in this registry study will have similar retention in the heart as the cultured CPCs delivered in the sub-study.

What are we to make of these findings? They are certainly hypothesis generating. Data from the ACT-34 trial using intramyocardial-delivered CD34⁺ cells for patients with refractory angina supports this hypothesis (14). In Act-34, placebo patients with elevated troponin had an increased MACE rate while cell treated patients with elevated troponin had very low event rates similar to patients without troponin elevation. On the other hand, it is paradoxical that patients with heart failure who chronically release troponins do much more poorly than those patients who do not when they should have increased expression of SDF-1 or other chemo-attractants to increase recruitment of circulating stem cells and repair the myocardium as postulated by the authors? In the Val-HeFT trial (10) of 4053 patients, hs-TnT was detectable in 92% of patients (mean=0.018 ng/ml). Subjects with troponin levels above median were older, male, diabetic, had lower LVEF and higher neurohormone levels. Two-year mortality stratified by hs-TnT level was 7.8% in the lowest quartile but rose to 35.6% in the highest quartile of hs-TnT. In contrast, the present study observed that those patients with the highest troponins actually had much better survival than predicted, the distinction being that they received cell therapy! Perhaps this again demonstrates the inadequate endogenous repair mechanisms endowed in the human heart.

Conclusions

In this interesting observational study of registry patients with chronic heart failure, the authors have identified a subgroup of higher risk patients with chronic elevations in hs-TnT levels who respond favorably to cell therapy as evidenced by a decline in NT-proBNP levels and a trend towards improved mortality. Perhaps this represents the identification of a novel target for patients who should receive this therapy going forward, something needed in the field of cell therapy for heart failure. We look forward to the author’s upcoming clinical trial in this patient population where this hypothesis will be tested prospectively for the first time.