1Charité - Universitätsmedizin Berlin CC 11: Med. Klinik für Kardiologie Berlin, Deutschland; 2Carl von Ossietzky Universität Oldenburg Pharmakologie Oldenburg, Deutschland; 3Carl von Ossietzky Universität Oldenburg Abteilung Pharmakologie und Toxikologie Oldenburg, Deutschland; 4Deutsches Herzzentrum der Charite (DHZC) Innere Medizin-Kardiologie Berlin, Deutschland
Background: Obesity has been established as a major risk factor for heart failure due to lipid accumulation, oxidative stress and inflammation which results in cardiac remodelling. Protease-activated receptors (PAR1-4) are activated by serine proteases such as factor Xa (FXa) and have been linked to various cardiovascular and inflammatory diseases.
Methods: In the experimental mouse study, we used 1-year old ApoE−/− and ApoE−/− PAR2−/− mice on a C57Bl/6 background on a Western diet (n=5/ group). Cell culture experiments were performed with human primary cardiac fibroblasts and HepG2 hepatocytes. Patients (n=48) included in the clinical study had a BMI ≥ 25kg/m², symptoms of heart failure (HF) and endomyocardial biopsy (EMB) that confirmed the absence of active myocarditis or amyloidosis. Cardiac PAR2 expression was measured via RT-PCR in the EMB. Patients were divided into PAR2low and PARhigh based on the median value of the cohort. Cardiac function was assessed via echocardiographic strain imaging.
Results: HF-fed dko mice showed 10% less cardiac necrosis (p≤0.05), which also correlated with cardiac PAR2 expression (r=0.63; p≤0.04), hepatic PAR1 (r=0.76; p≤0.007) and hepatic PAR2 expression (r=0.58; p≤0.06). Complement C1q, C3, C4, C5 and C9 expression were reduced by 99% (p≤0.014), respectively, in the liver, C3 by 57% and C4 by 66% in the heart. Stimulation with lipopolysaccharide (LPS) increased complement C3, PAR1 and PAR2 gene expression in hepatocytes and primary cardiac fibroblasts. PAR2low patients with BMI≥25kg/m² (n=48) had a higher left ventricular ejection fraction (LVEF) (64.5 [54.3; 75.5] vs 54 [43.5; 60.3] %; p≤0.03), lower LV global longitudinal strain (GLS) (-15.3 [-19.9; -8.3] vs -8.0 [-12.6; -5.6] %; p≤0.02), lower bone-natriuretic peptide (BNP) (474 [85; 1489] vs 1169 [429; 3614] mg/dl; p≤0.05) and smaller left atrial (LA) diameter (44 [39.3; 46.3] vs 48 [44; 57] mm; p≤0.1) than PAR2high patients. PAR2low patients with BMI≥30kg/m² (n=18) had a higher LVEF (44 [39.5; 59.5] vs 31 [24; 41] %; p≤0.03), lower LV GLS ( -11.8 [-19.9; -8.1] vs -5.6 [-10.4; -4.6]%; p≤0.14), smaller LA (42 [41; 43] vs 46.5 [43.8; 49] %; p≤0.07) and smaller left ventricular enddiastolic diameter (LVEDD) (53 [45; 63.5] vs 66.5 [60.3; 69] %; p≤0.03).
Conclusion: PAR1 and PAR2 expression is associated with more cardiac damage in the metabolic mouse model. Genetic deletion of PAR2 reduced cardiac necrosis in the mouse model. PAR2low overweight patients showed better cardiac function and less cardiac morphological changes. Anti-FXa treatment might prove useful in obesity-related HF to reduce inflammation-associated cardiac damage.