Abstract 15194: Multiple Co-morbidities Produce Left Ventricular Diastolic Dysfunction in a Large Animal Model
More than 50% of patients with heart failure have preserved ejection fraction (HFpEF) characterized by diastolic dysfunction. HFpEF usually occurs in female patients with multiple comorbidities such as obesity, hypercholesterolemia, diabetes mellitus (DM) and hypertension. Here we studied the effects of DM, high fat diet (HFD), and chronic kidney disease (CKD) on diastolic dysfunction in swine.
In 11 female swine, DM type 2 (3x50mg/kg iv streptozotocin), hypercholesterolemia (HFD 1% cholesterol) and CKD by renal artery embolization (38-42μm polyethylene beads), were induced (DM+HFD+CKD). Swine were followed for 6 months. Eight female healthy swine on normal pig-chow, matched for age were used as controls (CON).
The DM+HFD+CKD showed hyperglycemia (22.7±0.9mmol/l in DM+HFD+CKD vs 6.1±0.67mmol/l in CON), hypercholesterolemia (16.9±3.4 vs 2.2±0.1mmol/l), hypertriglyceridemia (1.20±0.36 vs 0.28±0.05mmol/l) and hypertension (awake mean arterial pressure: 108±6 vs 84±3mmHg; all P≤0.05). These co-morbidities resulted in chronic systemic inflammation (TNF-α: 231±64 vs 74±24pg/ml), impaired coronary small artery endothelium-dependent vasodilation to bradykinin, capillary rarefaction (cap./fiber ratio 0.58 vs 0.99) and increased myocardial superoxide production (14.8±0.9 vs 6.4±0.3 RLU/sec/g), due to increased NOX activity (all P≤0.05). The coronary microvascular abnormalities were associated with increased myocardial collagen content (4.7±0.3 vs 2.4±0.2%) and elevated passive cardiomyocyte force, (both P≤0.05), resulting in reduced E/A ratio (0.99±0.14 vs 1.53±0.23), measured with cardiac MRI, and increased LV end-diastolic stiffness (0.79±0.19 vs 0.29±0.03 mmHg/ml/mg) derived from LV pressure-volume relations obtained with a conductance catheter (both P≤0.05). In contrast, ejection fraction was maintained, (45±4 vs 54±3%, P=NS).
In summary, multiple comorbidities, including DM, hypercholesterolemia, CKD and hypertension in female swine trigger a series of events, starting with systemic inflammation, increased oxidative stress and coronary microvascular dysfunction, resulting in myocardial stiffening, and leading to diastolic dysfunction.
Author Disclosures: O. Sorop: None. I. Heinonen: None. M. van Kranenburg: None. V.J. de Beer: None. Y. Octavia: None. R.M. van Geuns: None. A.H. van den Meiracker: None. J. van der Velden: None. J.A. Danser: None. D. Merkus: None. D.J. Duncker: None.
- © 2015 by American Heart Association, Inc.