Abstract 15877: Titin-isoform Shift May Underlie Distinct Ventricular Responses to Pressure and Volume Overloads in Type 2 Diabetic Heart
Background: How diabetes modifies ventricular responses to pressure loading and volume loading remains uncharacterized. Here, we examined this issue using a rat model of obese modestly hypertensive type 2 diabetes (T2DM), OLETF.
Methods and Results: Pressure-volume relationships (PVRs) were determined by a conductance catheter and catheter-tip monomer in OLETF, LETO (non-diabetic control) and LETO with hypertension induced by renal artery stenosis (LETOHT). Blood pressure in OLETF was significantly higher than that in LETO and similar to that in LETOHT (161±4, 124±3 and 157±8 mmHg, respectively). Pressure overloading and volume overloading were performed by phenylephrine with target peak systolic pressure being 200 to 250 mmHg and by saline infusion (5% body weight over 30 min), respectively. Changes in the slope/position of PVRs were assessed by systolic and diastolic ventricular volumes at pre-defined pressures (ESV125 and EDV20). Baseline EDV20 and left ventricular end-diastolic pressure (LVEDP) were similar in the study groups. During pressure overloading, systolic reserves assessed by changes in ESV125 and stroke work were preserved in OLETF, but EDV20 was reduced only in OLETF and LVEDP was higher in OLETF than in LETO and LETOHT (14.1±1.8 vs. 5.9±2.1 and 6.0±2.1 mmHg, respectively, p<0.05) . In contrast, acute volume overload induced a right-downward shift of end-diastolic PVRs similarly in all study groups. Interstitial collagen volumes and mRNA levels of types 1 and 3 collagens were comparable in OLETF and LETO. Protein expression of SERCA2a was reduced in OLETF, and its restoration by a chemical chaperone did not normalize PVR response to pressure overload. RT-PCR showed that compliant N2BA-to-stiff N2B ratio of titin isoforms was significantly higher by 21% in OLETF than in LETO, though levels of total titin and Rbm20, a modulator of titin splicing, were similar in the two group.
Conclusions: Latent ventricular diastolic stiffness, which is unmasked by increased afterload, is present in T2DM hearts with preserved distensibility to volume overload. Isoform shift of titin, together with reported modification of titin stiffness by phosphorylation and Ca2+ binding, may be involved in the changes in the ventricular diastolic properties.
- © 2012 by American Heart Association, Inc.