To the best of our knowledge, this is the first study assessing the impact of CRT on circulating EPCs levels.
The main findings of the present work can be summarized as follows. First, the etiology of heart failure seems to influence EPCs levels, with lower number of circulating EPCs in the ischemic patients. Second, circulating levels of CD34+KDR+ and CD133+KDR+ cells significantly increase after CRT, independently of patient’s response. Third, baseline EPCs numbers seem not to correlate with long-term outcome after CRT.
Heart failure with reduced ejection fraction (HFrEF) is a very common disease with a poor prognosis. The prevalence of HF can be estimated at approximately 1–2% of the adult population in developed countries and the incidence approaches 5–10 per 1000 persons per year.10
Over the last two decades, CRT has revolutionized the treatment of selected patients who have HFrEF. CRT improves cardiac performance in appropriately selected patients and reduces morbidity and mortality.11 Several studies have demonstrated the efficacy of CRT in counteracting ventricular remodeling through the recovery of synchronous muscle contractility.12 However, the exact mechanisms leading to the long-term benefits of CRT are not yet fully understood and other mechanisms beyond left ventricular reverse remodeling are likely involved, explaining the discordance frequently observed between clinical and remodeling response to CRT and also between CRT response and long-term outcomes.13
End-stage HF is the final common pathway for several different diseases, with ischemic aetiology being responsible for the vast majority of cases, in developed countries.14
Previous studies have suggested that patients with ischemic etiology have a lower probability of response to CRT than non-ischemic patients.8, 15 The reasons for the lack of response to CRT are not well understood. In ischemic etiology, LV desynchrony may be related to segmental wall motion abnormalities due to the presence of myocardial scars or perfusion defects that cannot be resynchronized.15 Here, we verify that patients with ICM express significantly lower levels of circulating EPCs, suggesting that this pauperization may justify why ICM patients typically benefit less from CRT. However, several studies conducted in recent years have found that the benefits of CRT appear to be similar in HF regardless of the underlying cause. Therefore, presently, the decision to indicate CRT is not influenced by the etiology of HF.14
Endothelial dysfunction has been extensively reported in patients with HF.16 Endothelial damage or ischemia leads to liberation of several mediators, such as VEGF, stromal cell-derived factor 1 (SDF-1) or nitric oxide synthase (NOS). This cascade activation seems to stimulate the proliferation of EPCs in bone marrow and their release to bloodstream. Circulating EPCs adhere to the injured endothelium, playing a crucial role in vascular repair.17 During recent years, accumulating evidence revealed that circulating EPCs showed reduced numbers and functional impairment within several cardiovascular diseases. Valgimigli et al. were the first to evaluate the role of circulating EPCs in HF patients. They showed decreasing EPC levels with more advanced stages of congestive HF indicated by higher NYHA classes and elevated NT-proBNP levels.18 Nonaka-Sarukawa et al. also showed that HF patients present lower EPCs counts than controls.2 The reduction of circulating EPCs levels in advanced HF can be justified by diffuse and severe endothelial damage. However, conflicting results about the behaviour of circulating EPCs in advanced HF have been published. Theiss et al. found that circulating EPCs were lower in patients with ICM than DCM but still higher than healthy controls.19 Heeschen et al. observed a functional impairment of bone marrow-derived EPCs leading to a reduced migratory capacity into the circulation of patients with ischemic HF compared to healthy controls.20 However, findings from other investigators groups indicate that the etiology of HF does not differentially affect circulating EPCs.18 In our study, despite the greater use of statins (a stimulus for EPCs) in patients with ischemic etiology, they showed significantly lower levels of circulating EPCs when compared to non-ischemic patients. This reduced circulating EPCs levels were observed for both the CD34+KDR+ cells and for the more immature CD133+KDR+ population. That difference could potentially explain why ICM patients typically benefit less from CRT and the worse prognosis generally associated with ischemic etiology compared to non-ischemic causes of HF.
Long-term outcome after CRT
Low circulating EPC levels are associated with adverse outcomes in patients with coronary artery disease.5 However, regarding CHF, Michowitz et al. showed that higher levels of EPCs independently predicted all-cause mortality.21 In contrast, Koller et al. showed that EPCs defined as CD34+CD45dimKDR+ cells were a strong and independent inverse predictor of mortality in patients with chronic HF.22 Similarly, Samman Tahhan et al. demonstrated that lower EPCs counts were strongly and independently predictive of mortality.23 On other hand, another study found that CD34+KDR+ levels were not related with the risk of mortality, composite outcomes, or hospital admissions in patients with ambulatory left ventricular ejection fraction < 40%.24 However, the potential impact of circulating EPCs on clinical outcomes after CRT had not yet been studied. In our study, baseline EPCs levels were not related with long-term outcomes in HF submitted to CRT.
Evolution of EPC levels after CRT
An important observation of our study is that numbers of both EPCs populations (CD34+KDR+ cells and CD133+KDR+ cells) significantly increase after CRT. We can speculate that this increase in EPCs is a result of effective CRT which may translate in an improved capacity of endothelial repair mediated by EPCs. However, the significance of this finding remains to be determined.
In recent years the role of EPCs in cardiovascular disease as well as the interplay between inflammation and endothelial progenitor cell biology have been discussed. In patients at an increased cardiovascular risk (diabetes mellitus, systemic hypertension and hyperlipidemia) EPCs show a decreased proliferative capacity, and present reduced levels in peripheral circulation.6,25 In patients with advanced CHF, the majority of studies indicate that circulating EPCs levels are profoundly decreased.2,18,20
HF is characterized by a chronic inflammatory status with elevated pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. This inflammatory milieu can negatively impact on circulating EPCs.26,27
Previous studies have shown that CRT reduces the inflammatory milieu of chronic HF.26,27 Theodorakis et al. showed that IL-6 and TNF-α were reduced after 3 months of biventricular pacing.26 In the present study, circulating EPCs significantly increase after CRT. Therefore, we can speculate that this anti-inflammatory action of CRT can be translated into increase in circulating levels of CD34+KDR+ and CD133+KDR EPCs. However, these findings need confirmation and possible mechanisms to explain this association need further investigation.
Limitations
This study had a relatively small sample size and future larger studies would be important to confirm that circulating EPCs do not influence long-term prognosis of HF patients submitted to CRT. Another limitation of the study is the absence of a healthy control group, which could help to understand whether or not the increase in EPCs levels after CRT means a return towards normal levels.
We were not able to explore other functional characteristics of EPCs that might provide further understanding about the role of CRT on EPCs response and its contribution to HF pathogenesis.