Abstract 9013: Myeloperoxidase is Critically Linked to the Development of Diastolic Heart Failure Following Pressure Overload
Background: Plasma levels of the leukocyte derived enzyme myeloperoxidase (MPO) are elevated in patients with heart failure (HF). We have shown previously that MPO promotes vasoconstriction, leukocyte recruitment and myocardial fibrosis - suggesting that MPO may be mechanistically linked to the pathophysiology of HF. Here we assessed whether MPO is modulating systolic and diastolic myocardial performance in a pressure overload model.
Methods and Results: C57Bl/6-Wild-type (WT) and MPO-deficient (Mpo-/-) mice were subjected to mild transverse aortic constriction (TAC, Δp max: 50 ±10 mmHg). After 6 weeks, echocardiography revealed significantly reduced left ventricular (LV) ejection fraction (EF) in TAC-treated animals as compared to sham operated controls. In vivo hemodynamic assessment of left ventricular function using pressure-volume loops revealed an upward shift of enddiastolic pressure volume relation (EDPVR) in both TAC groups as compared to sham animals (p< 0.001). Of note WT-TAC revealed a significantly higher upward shift than Mpo-/- TAC (3.18 ±0.74 mmHg/µl vs. 1.17 ±0.17 mmHg/µl; n=8; p=0.02). Enddiastolic pressure was higher in WT-TAC as compared to Mpo-/- TAC (6.23 ±1.88 mmHg vs. 2.82 ±0.33 mmHg; n=8; p = 0.05). In WT-TAC heart weight and lung weight normalized on tibia length was significantly increased as compared to Mpo-/- TAC mice (15.21 ±0.67 mg/mm vs. 12.65 ±0.79 mg/mm; n=10; p<0.02; respectively 20.15 ±2.65 mg/mm vs. 10.78 ±1.00 mg/mm; n=10; p=0.006). mRNA of matrix metalloproteinase 9 was increased in WT-TAC mice compared to Mpo-/- TAC (2.58 ±0,84 vs. 0,95 ±0,15, n=11; p=0,06). In accordance with this experimental observations MPO plasma levels of 5,000 patients enrolled in the Gutenberg Health Study were associated with left ventricular hypertrophy (median (IQR): 310pmol/l (240/384) vs. 297pmol/l (237/369); p=0.034).
Conclusions: The current data reveal that MPO is critically linked to impaired diastolic compliance during pressure overload. This suggests that leukocyte activation in general and MPO release in particular is not only a prognostic marker in heart failure but evolves as an important pathophysiological link and potential pharmacological target in this disease.
- © 2011 by American Heart Association, Inc.