**2. Neurohormonal remodeling during LVAD therapy**

HF is a highly complex clinical syndrome characterized by cardinal symptoms due to structural and/or functional abnormality of the heart, resulting in elevated intracardiac pressures and/or inadequate cardiac output [23]. The clinical symptoms of HF develop and progress through prolonged dyshomeostasis in the heart in response to various stressors, which include alterations of regulatory neurohormonal systems associated with the release of natriuretic peptides, proinflammatory cytokines as well as activations of the sympathetic nervous system (SNS), which in turn activates the renin-angiotensin-aldosterone system (RAAS) [8]. Some of these alterations appear to be reversible by VAD treatment in response to a decrease in cardiac pressure, volume overload, and ventricular wall tension and stretch [24]. These events lead to reduced cardiomyocyte hypertrophy, improved coronary perfusion, and decreased chronic ischemia in the heart [25]. Therefore, mechanical unloading of the failing heart by LVADs, coupled with neurohormonal and anti-inflammatory therapy, may further promote reverse remodeling and recovery of myocardial function.

#### **2.1 Natriuretic peptides**

The natriuretic peptide family consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) [26]. Under normal conditions, ANP is produced in the atrium and BNP is synthesized primarily by the

#### *Myocardial Remodeling with Ventricular Assist Devices DOI: http://dx.doi.org/10.5772/intechopen.110814*

ventricles in response to cardiac mechanical stretch. Circulating in the plasma, ANP and BNP play compensatory diuretic roles by decreasing salt and water retention and inhibiting vasoconstrictor peptides. In contrast to ANP, levels of BNP are significantly elevated in plasma of HF patients in response to chronic volume overload and BNP concentration correlates with the status of ventricular dysfunction with high concentrations predicting poor long-term survival. Support with VAD in patients with endstage HF reduces the myocardial wall stress and thereby may change BNP levels in the heart. Sodian *et al.* studied 21 patients with nonischemic cardiomyopathy on VAD support and demonstrated a significant decrease in BNP levels in plasma after initiation of MCS, reaching normal levels within the first week after VAD implantation [27]. Especially, an early decrease of BNP in plasma was indicative of cardiac function recovery during VAD support. The significant decrease in BNP serum concentration after VAD support coincides with a decrease in *BNP* messenger RNA (mRNA) and protein expression in the heart of patients with severe HF supported by VAD. They also showed a decrease in BNP production not only by cardiomyocytes, but also by endothelial cells, T cells, and macrophages infiltrating the heart [28].

ANP and BNP also exert local antihypertrophic, antifibrotic, and lusitropic effects in the heart *via* their interactions with guanylyl cyclase-A receptor (CG-AR) [29]. Comparative analysis of cardiac *ANP* and *BNP* mRNAs expression in patients with HF revealed normalization of *ANP, BNP,* and the NP-metabolizing *NPR-C* receptor after VAD support, while *GC-AR* mRNA expression levels remained intact, suggesting that reverse remodeling is associated with the local protective effects of ANP and BNP.

In chronic HF, expression of ANP and BNP serves as clinical markers of cardiac hypertrophy, decompensation, hypertension, and myocardial infarction. Acute coronary syndromes are linked with the expression of chromogranin A (CgA), CD56/NCAM (neural cell adhesion molecule), and endothelin-1 (ET-1) [30, 31]. Investigation of 33 paired myocardial and plasma samples demonstrated significantly increased ANP, BNP, and CgA in congestive HF (CHF) patients before LVAD support, and all of these indicators were significantly decreased by VAD support [32]. Concentrations of plasma ANP and BNP also depend on different types of devices and durations of MCS. The time courses of ANP and BNP concentration have been studied in patients supported by Thoratec (8 patients), TCI Heartmate (6 patients), Novacor (7 patients), and Lionheart (3 patients) by Milting *et. al* [33]. All patients supported with Novacor, and some patients supported by TCI Heartmate, showed a steady decrease in plasma BNP levels, reaching normal ranges at 30 to 50 days. In contrast, only few patients supported by Thoratec or Lionheart reached normal BNP plasma values during the entire duration of support, suggesting recognition of different time points in ANP and BNP decrease among various types of devices when weaning from MCS in patients without heart transplant is suggested.

In pediatric cohort, it has been demonstrated that BNP and N-terminal pro-BNP (NT-proBNP) were modified differently by MCS compared to adults, showing an increase up to 1 day after VAD implant with a subsequent decrease to the pre-VAD levels in one month. Another pediatric study found levels of BNP and NT-pro-BNP correlated with severity and unfavorable outcomes of acute decompensated HF and an incremental increase of those peptides within 48 hours of admission predicted the need for MCS [34]. Short-term VAD support in children with severe HF significantly decreased BNP levels in plasma from pre-VAD to post-VAD and reduced markers of apoptosis [35].

#### **2.2 Renin angiotensin aldosterone system**

Reduced blood supply causes renal hypoperfusion and stimulation of SNS and RAAS [36]. The key molecule that mediates RAAS activation is angiotensin II (Ang II), a potent vasoconstrictor. In early stages of HF, RAAS activation functions as a compensatory mechanism to increase cardiac output. However, with the HF progression, RAAS activation plays a detrimental role in myocardial ischemia, hypertrophy, and arrhythmia [37]. In end-stage HF, G-protein-coupled receptors (GPCRs) of RAAS, such as Ang receptors, AT1R and AT2R, are downregulated, while angiotensin-converting enzymes (ACE and ACE2), GPCR kinase (GRK), and β-arrestin are upregulated [38]. Following VAD support, a significant downregulation of Ang I, ACE2, GRK, and β-arrestin has been documented, while AT2R, JNK, and p38 were upregulated, indicating divergent and incomplete molecular reverse remodeling. Combined MCS with neurohormonal blockade drug therapy (NHBDT) improved survival and reduced adverse cardiac events in HF [39]. For example, ACE inhibition (ACEI) during VAD support was linked with decreased Ang II, cardiac collagen content, and myocardial stiffness [17, 40], demonstrating the pathophysiological benefits of combined therapy compared with VAD support alone. The ISHLT Mechanically Assisted Circulatory Support (IMACS) registry suggested positive effects for ACEI and angiotensin II receptor blockers (ARBs) therapy in adult HF patients with VAD implantation [41]. Among patients treated with an ACEI/ARB, significantly lower risk of cardiovascular death, gastrointestinal bleeding, and levels of creatinine has been demonstrated compared to those in patients treated with mineralocorticoid receptor antagonist (MRA).
