Heart and lung aquaporins play a major role in severity of heart failure with preserved ejection fraction in mice and differs between comorbidities
Authors: Villalba-Orero M , Marti-Gomez-Aldaravi C , Lopez-Olaneta M , Camarero-Cadenas C , Gonzalez-Garcia M.E , Hernandez-Luzardo A.A , Martin-Torres J.M , Camafeita-Fernandez E , Garcia-Pavia P , Pascual-Figal D , Vazquez J , Lara-Pezzi E 
Published: November 2020

Abstract

Introduction
Heart failure (HF) is a major public health problem worldwide. To date, HF with preserved ejection fraction (EF, HFpEF) represents half of all HF patients and its prevalence is increasing. HFpEF is associated with multiple comorbidities, including diabetes mellitus, pulmonary and systemic hypertension and obesity, mainly in elderly population. Accurately phenotyping HFpEF is crucial for the development of new therapies, appropriate patient stratification and the implementation of a personalised medicine. Cardiac and pulmonary remodelling play a major role in HFpEF severity but the specific mechanisms underlying cardiac failure and lung congestion, the last stage in HFpEF, in each comorbidity are incompletely understood, precluding the development of effective therapies. Aquaporins (AQP) are membrane proteins serving as water channels across the plasma membrane and control intra- and extracellular fluid volume and prompt to tissue oedema in many organs. However, its specific contribution in HFpEF has not been explored.

Purpose
We aimed to identify cardiac and pulmonary molecular changes associated to dysfunction and oedema in HFpEF, specific for each comorbidity.

Methods
A total of 48 C57BL/6 mice 10 weeks old were randomised to the following groups: control (Ctl; n=9), type I diabetes (Db; n=9), chronic hypoxia (PAH; n=10), obesity (Ob; n=10) and systemic arterial hypertension (SAH; n=10). Mice were followed for up to 2.5 years by echocardiography and lung ultrasound until they developed pulmonary oedema (HF) or died naturally. Lungs and heart were extracted and changes were determined by proteomic, immunohistochemistry and qRT-PCR.

Results
Diastolic dysfunction was observed in all comorbidities and above 50% of those mice developed HF. Db presented the highest ratio in developing HF. Db also showed the earliest mortality (47 weeks), whereas PAH, Ob and SAH mice survived for 82, 92 and 99 weeks, respectively (p&lt;0.001 vs Ctl). A common finding in all groups was the development of different degrees o perivascular fibrosis. Db mice, the HFpEF severest group, showed an increase in pulmonary AQP1 and 5 (p&lt;0.05 and p&lt;0.001, respectively, vs Ctl). Upregulation of AQPs correlated with increased ventricular filling pressures (E/E', r2=07). Cardiac AQP4 was also markedly elevated in Db mice in left and right ventricle (p&lt;0.001 and p=0.01, respectively, vs Ctl).

Conclusion
Increased AQPs in the lung is associated with a more aggressive development of congestion and HFpEF. In addition, increased AQP4 in the heart in the most aggressive form of HFpEF suggests a relevant role in cardiac oedema. Targeting AQPs in HFpEF may prevent oedema and decompensation.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported from the Spanish Ministerio de Economía y Competitividad (RTI2018-096961-B-I00, SAF2015-65722-R and SAF2012-31451 to E.L-P. and Juan de la Cierva Incorporaciόn to M,V-O). The CNIC is supported by the Ministerio de Ciencia, Innovaciόn y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).