Characterization of biventricular alterations in myocardial (reverse) remodelling in aortic banding-induced chronic pressure overload

Abstract

Aortic Stenosis (AS) is the most frequent valvulopathy in the western world. Traditionally aortic valve replacement (AVR) has been recommended immediately after the onset of heart failure (HF) symptoms. However, recent evidence suggests that AVR outcome can be improved if performed earlier. After AVR, the process of left ventricle (LV) reverse remodelling (RR) is variable and frequently incomplete. In this study, we aimed at detecting mechanism underlying the process of LV RR regarding myocardial structural, functional and molecular changes before the onset of HF symptoms. Wistar-Han rats were subjected to 7-weeks of ascending aortic-banding followed by a 2-week period of debanding to resemble AS-induced LV remodelling and the early events of AVR-induced RR, respectively. This resulted in 3 groups: Sham (n = 10), Banding (Ba, n = 15) and Debanding (Deb, n = 10). Concentric hypertrophy and diastolic dysfunction (DD) were patent in the Ba group. Aortic-debanding induced RR, which promoted LV functional recovery, while cardiac structure did not normalise. Cardiac parameters of RV dysfunction, assessed by echocardiography and at the cardiomyocyte level prevailed altered after debanding. After debanding, these alterations were accompanied by persistent changes in pathways associated to myocardial hypertrophy, fibrosis and LV inflammation. Aortic banding induced pulmonary arterial wall thickness to increase and correlates negatively with effort intolerance and positively with E/e′ and left atrial area. We described dysregulated pathways in LV and RV remodelling and RR after AVR. Importantly we showed important RV-side effects of aortic constriction, highlighting the impact that LV-reverse remodelling has on both ventricles.

The Degree of Cardiac Remodelling before Overload Relief Triggers Different Transcriptome and miRome Signatures during Reverse Remodelling (RR)—Molecular Signature Differ with the Extent of RR

“…After debanding, we observed a normalization of passive tension in cardiomyocytes from both debanding subgroups, suggesting that myocardial fibrosis is the principal contributor for diastolic function impairment predominantly observed in DEB1. Accordingly, we also found a partial regression of cardiomyocytes stiffness and no regression of fibrosis in a similar rat experimental study [36]. In the context of the present study, reduction of cardiomyocyte stiffness can be interpreted as a compensatory response to pressure-overload relief of the "fibrotic" myocardium of the DEB1 subgroup, as previously reported in myocardium from HF patients [42].…”

“…Furthermore, after LVAD implantation, the circulatory levels of inflammation mediators (e.g., increased IL6 and IL8), the macrophage activation (e.g., increased levels of macrophage-1 antigen expression), and the adaptive immune cell deactivation (e.g., increased T-cell apoptosis and defective T-cell response to pathogens) increased and were associated to the worst prognosis of HF patients [ 50 ]. Together, these reports suggest that despite pressure-overload relief, insistent activation of various cardiac inflammatory pathways likely precede the fibrotic pattern and, consequently, the unimproved diastolic function observed in DEB1 as we previously demonstrated in an analogous rat model [ 36 ].…”

“…Likewise, we cannot exclude the contribution of post-translational protein modifications in the process of cardiac RR, which can influence the state of activation/inhibition of hypertrophic pathways, as it happens with calcineurin/NFAT signalling [ 33 , 36 ]. In the present study, we did not carry out these types of studies, and therefore, we cannot rule out their involvement in the phenotype observed in different groups.…”

“…Regarding the DEB2 group, we observed signs of partial metabolic improvement, corroborated by increased Oxidative phosphorylation, TCA signalling pathways, and preserved mitochondrial structure compared to BA. In a similar rat RR model, we found that the attenuation of cardiac hypertrophy and oxidative stress allowed myocardial energetics, LV hypertrophy, and diastolic dysfunction to recover, despite the persistence of increased markers of autophagy and mitophagy [ 36 ]. Also, in the clinical context, cardiac unloading induced by LVAD [ 59 ] or by AVR [ 7 ] was associated with a partial reversal of the depressed metabolic gene expression and with a significant improvement of postoperative myocardial phosphocreatine/adenosine triphosphate ratio (PCr/ATP) in parallel with a better LV diastolic function.…”

Protection of Sacubitril/Valsartan against Pathological Cardiac Remodeling by Inhibiting the NLRP3 Inflammasome after Relief of Pressure Overload in Mice

“…Emerging clinical trials have established transcatheter aortic valve replacement (TAVR), which exhibits lower invasiveness, risk, and all-cause mortality rate, as the main interventional treatment for AS [ 2 , 3 ]. However, left ventricular reverse remodeling following successful TAVR is incomplete and is characterized by persistent cardiac fibrosis, inflammation, and hypertrophy, leading to a poor prognosis [ 4 ]. Therefore, better strategies for promoting the recovery of early cardiac function post-TAVR are essential to delay heart failure and improve clinical outcomes.…”