**3. Inflammation and cytokines**

#### **3.1 Tumor necrosis factor-alpha**

Reports on inflammatory profiles in HF patients and LVAD recipients have recently been comprehensively summarized by Radley *et al.* [42]. Tumor necrosis factor-alpha (TNF-α) is a protein expressed in the myocardium that stimulates cardiac growth and cell death [43, 44]. High levels of TNF-α are found in patients with severe HF [45]. Expression of *TNF-α* mRNA and protein were both elevated in the heart and serum of VAD candidates with severe HF [46]. Moreover, interleukin 1 beta (IL-1β), IL-6, procaspase-9, and active caspase-9 were increased in the heart of those deteriorating patients who required VAD support. Torre-Amione *et al.* reported that prolonged MCS results in significant reductions in intracardiac TNF-α, with a greater reduction in myocardial TNF-α in VAD-treated patients with recovered cardiac function *versus* those who required cardiac transplantation [43].

### **3.2 Metallothionein**

Metallothionein (MT) is a highly conserved cytokine-inducible protein whose role is the detoxification of heavy metals through the regulation of their metabolism [47]. High metal affinity to cadmium (Cd) of MT in renal tissue plays a major role in the kinetics and balance between CdMT and non-bound Cd, which is highly neurotoxic [48]. A study of heart transplant patients by Baba *et al.* demonstrated that MT expression correlated with IL-6 elevation in blood vessels and a decrease in plasma IL-2 [49]. *Myocardial Remodeling with Ventricular Assist Devices DOI: http://dx.doi.org/10.5772/intechopen.110814*

Moreover, MT expression was associated with lower fractional shortening, increase in LV end-systolic diameter, and lower mean arterial pressure in the absence of rejection in transplant patients, implicating the role of MT in cellular stress response. Further immunohistochemical studies by the same group demonstrated a decrease of MT-positive cardiomyocytes and vessels in the subendocardial and subepicardial regions of the myocardium in 17 HF patients during prolonged VAD compared to pre-VAD state [50]. In addition, ventricular unloading leads to regression of cellular hypertrophy and a reversal of MT expression in the failing heart, suggesting the remodeling process with reduction of MT expression is due to diminished wall stress and improved blood supply. The authors also observed that MT reactivity was substantially lower in the hearts of patients supported longer than 88 days as compared to patients supported less than 88 days [50].

#### **3.3 C-reactive protein and interleukins**

C-reactive protein (CRP) is a protein that is produced in response to the release of pro-inflammatory cytokines when the body is in an inflammatory condition [51]. Patients with end-stage HF have almost 8-fold higher levels of circulating CRP (cCRP) in serum compared to normal references [52]. Batra *et al.* studied pre- and post-implant VAD patients and found that one-third of post-VAD patients have persistently high CRP levels. They concluded that high CRP levels are linked with high mortality risk and a higher possibility of having a stroke during VAD support. Longer VAD therapy (60 days after implantation) resulted in a 50% reduction of CRP levels compared to pre-VAD values, suggesting improved inflammatory status over time [53].

Interleukins (IL) are a group of small molecules and peptides secreted by a wide variety of body cells or cytokines that function in cellular signaling and communication. Serum levels of members of IL-1 family cytokines, IL-1β and IL-33, are highly elevated in HF and remained elevated after MCS [54]. Increased expression of IL-1β and correlated patterns of IL-1 receptors indicate enhanced IL-1β signaling in MCS patients, while expression of IL-33 correlates with CRP plasma levels in HF, but not in patients on MCS. Suppression of tumorigenicity 2 (ST2) is a receptor of IL-33 and coupling of IL-33 with its ST2 receptor (IL-33/ST2) triggers dangerassociated cellular responses playing a pivotal role in tissue repair in many organs [55]. In the heart, IL-33 is expressed by activated cardiac fibroblasts and cardiomyocytes during cardiac stretch and then is released into the extracellular matrix (ECM), promoting cell survival by blocking pro-fibrotic intracellular signaling [56, 57]. A significant decrease in soluble ST2 (sST2) levels was observed in endstage HF patients after VAD implantation, suggesting a lessening of fibrosis and inflammation [58]. Levels of other cytokines, including IL-6 and IL-8, were also linked to the severity of clinical course in end-stage HF patients and correlated with outcome after VAD implantation [59]. A significant correlation of those cytokines was also found with ET-1 and relaxin (RLX)-2, the vasoactive mediators involved in neurohormonal system responses in VAD-supported HF patients [60]. Elevated levels of galectin-3 (GAL-3) were associated with the severity of HF and dynamic changes in GAL-3 levels predicted post-VAD survival [61]. Although unloading with continuous-flow LVAD results in a decrease of GAL-3 levels early post-implant, GAL-3 levels become elevated after 6 months of VAD implantation [61, 62], suggesting that levels of GAL-3 may represent a higher risk of death in HF patients with long-term VAD support.
