Myeloperoxidase and related biomarkers are suggestive footprints of endothelial microvascular inflammation in HFpEF patients

Abstract

Aims In heart failure (HF) with preserved ejection fraction (HFpEF), microvascular inflammation is proposed as an underlying mechanism. Myeloperoxidase (MPO) is associated with vascular dysfunction and prognosis in congestive HF. Methods and results MPO, MPO-related biomarkers, and echocardiography were assessed in 86 patients, 4-8 weeks after presentation with acute HF (EF ≥ 45%), and in 46 healthy controls. Patients were followed up for median 579 days (Q1;Q3 276;1178) regarding the composite endpoint all-cause mortality or HF hospitalization. Patients were 73 years old, 51% were female, EF was 64% (Q1;Q3 58;68), E/e′ was ratio 10.8 (8.3;14.0), and left atrial volume index (LAVI) was 43 mL/m 2 (38;52). Controls were 60 (57;62) years old (vs. patients; P < 0.001), 24% were female (P = 0.005), and left ventricular EF was 63% (59;66; P = 0.790). MPO was increased in HFpEF compared with controls, 101 (81;132) vs. 86 (74;101 ng/mL, P = 0.015), as was uric acid 369 (314;439) vs. 289 (252;328 μmol/L, P < 0.001), calprotectin, asymmetric dimethyl arginine (ADMA), and symmetric dimethyl arginine (SDMA), while arginine was decreased. MPO correlated with uric acid (r = 0.26; P = 0.016). In patients with E/e′ > 14, uric acid and SDMA were elevated (421 vs. 344 μM, P = 0.012; 0.54 vs. 0.47 μM, P = 0.039, respectively), and MPO was 121 vs. 98 ng/mL (P = 0.090). The ratios of arginine/ADMA (112 vs. 162; P < 0.001) and ADMA/SDMA (1.36 vs. 1.17; P = 0.002) were decreased in HFpEF patients, suggesting reduced NO availability and increased enzymatic clearance of ADMA, respectively. Uric acid independently predicted the endpoint [hazard ratio (HR) 3.76 (95% CI 1.19-11.85; P = 0.024)] but not MPO [HR 1.48 (95% CI 0.70-3.14; P = 0.304)] or the other biomarkers. Conclusions In HFpEF, MPO-dependent oxidative stress reflected by uric acid and calprotectin is increased, and SDMA is associated with diastolic dysfunction and uric acid with outcome. This suggests microvascular neutrophil involvement mirroring endothelial dysfunction, a central component of the HFpEF syndrome and a potential treatment target.

NETosis as a Pathogenic Factor for Heart Failure

“…More than a decade ago, several studies have reported that an increase in circulating MPO, as an independent risk factor, may play a key role in the occurrence and maintenance of chronic HF [ 37 – 39 ]. Furthermore, a recent study revealed that MPO is closely related to microvascular endothelial inflammation and dysfunction in HFpEF [ 40 ]. These findings indicate that circulating MPO derived from neutrophils may lead to the chlorination or nitration of protein tyrosine, causing protein dysfunction and vascular endothelial damage [ 39 ] and that the MPO-DNA complex may form NETs in HF tissues [ 41 , 42 ].…”

Sarcopenic Obesity in Heart Failure With Preserved Ejection Fraction

“…Certainly, inflammation is characteristic of this HFpEF that is augmented by SO is a likely major contributor to increased levels of oxidative stress (60,61). Cardiac ischemia and tissue hypoxia have also been implicated to play a role in HFpEF related oxidative stress (61,62). In this respect, hypoxia related increases in uric acid have been reported in these patients (62).…”

“…Cardiac ischemia and tissue hypoxia have also been implicated to play a role in HFpEF related oxidative stress (61,62). In this respect, hypoxia related increases in uric acid have been reported in these patients (62). Therefore, xanthine oxidase, the ROS generating enzyme the catalyzes the oxidation of xanthine to uric acid could be a potential source of oxidative stress in HFpEF.…”

“…Mitochondrial dysfunction that is consistently reported in HFpEF is an additional source of oxidative stress ( 63 ). Uncoupled endothelial nitric oxide synthesis (eNOS) due to reduced levels of the NO precursor L-Arginine and increased levels of the L-Arginine competitor asymmetric dimethylarginine is also a likely source of oxidative stress in these patients ( 62 ). Whether an activated renin angiotensin aldosterone system (RAAS) leading to increased levels of Angiotensin II is a source of oxidative stress in these patients remains controversial ( 64 , 65 ).…”

Rationale for the Use of Pirfenidone in Heart Failure With Preserved Ejection Fraction

“…Histological studies on LV endomyocardial biopsy samples from HFpEF patients showed high level of expression of inflammatory endothelial adhesion molecules including VCAM1, high numbers of CD3, CD11, and CD45-positive leucocytes in the myocardium, increased expression of TGF-β in inflammatory cells and increased levels of collagen I and III (14). Hage et al (15) found that myeloperoxidase-dependent oxidative stress, reflected by uric acid and calprotectin, is increased in HFpEF patients, suggesting microvascular neutrophil involvement mirroring endothelial dysfunction as a central component of the HFpEF syndrome. Moreover, Pentraxin 3, a biomarker of inflammation, was found to be significantly elevated in HFpEF patients and its levels at the coronary sinus significantly higher than at the aortic root, suggesting a production in the coronary circulation in patients with LV diastolic dysfunction (16).…”