OR-02 SAXAGLIPTIN PREVENTS INCREASED CORONARY ARTERIAL STIFFNESS AND ADVANCED GLYCATION END PRODUCT EXPRESSION IN A MINIATURE SWINE MODEL OF HEART FAILURE WITH PRESERVED EJECTION FRACTION

Abstract Background and Aims Inflammation contributes to progressive renal dysfunction and increases cardiovascular mortality of patients with chronic kidney disease (CKD). The association of CKD and heart failure with preserved ejection fraction (HFpEF) is observed in up to 50%, suggesting the possibility of a shared pathophysiology. CKD and HFpEF are commonly associated with inflammation. Using a novel swine model of CKD and HFpEF, we propose that a renal-cardio inflammatory axis drives diastolic dysfunction and HFpEF in CKD and that targeting renal inflammation will improve cardiac health and reduce cardiovascular risk. Methods We developed a biopolymer-fused peptide of nuclear-factor kappa (NFk)B (ELP-p50i) that we show it blocks its activity in vitro and in vivo. NFkB is a key pro-inflammatory transcription factor that is upregulated in CKD. To test our hypothesis, we induced CKD in 10 pigs via bilateral renovascular disease and dyslipidemia. Pigs were observed for 6 weeks, renal hemodynamics quantified (multi-detector CT), then randomized to single intra-renal ELP-p50i or placebo (n=5 each), and studies repeated 8 weeks later accompanied by echocardiographic assessment. Blood pressure was continuously measured (telemetry). Blood was collected to measure circulating TNF-α and biomarkers of HF (ANP, BNP). Furthermore, kidneys and hearts were used to quantify expression of factors involved in NFkB signaling. Results CKD led to a significant loss of renal function, accompanied by left ventricular hypertrophy and diastolic dysfunction with pEF, increased renal mRNA expression of TNF-α and canonical and non-canonical mediators of NFkB signaling, and elevated systemic TNF-α, ANP, and BNP, indicating renal and cardiac dysfunction. Most of these changes were improved after intra-renal ELP-p50i, although cardiac inflammatory signaling was unchanged (Figure) suggesting the kidney as a source of inflammation that can target the heart in CKD. Conclusion We show that a renal anti-inflammatory strategy via targeted inhibition of renal NFkB improves renal and cardiac function in CKD, suggesting an inflammatory renal-cardio axis. The translational pathological features of CKD and HFpEF combined with the predictive power of the model may contribute to advance the field towards new treatments targeting renal inflammation to reduce cardiovascular risk in CKD.

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Carotid Arterial Stiffness and Its Relationship to Exercise Intolerance in Older Patients With Heart Failure and Preserved Ejection Fraction

Hypertension ◽

10.1161/hypertensionaha.111.00163 ◽

2013 ◽

Vol 61 (1) ◽

pp. 112-119 ◽

Cited By ~ 62

Author(s):

Dalane W. Kitzman ◽

David M. Herrington ◽

Peter H. Brubaker ◽

J. Brian Moore ◽

Joel Eggebeen ◽

...

Keyword(s):

Heart Failure ◽

Arterial Stiffness ◽

Ejection Fraction ◽

Older Patients ◽

Exercise Intolerance ◽

Preserved Ejection Fraction ◽

Patients With Heart Failure ◽

Carotid Arterial

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Heart failure with preserved ejection fraction: chronic low-intensity interval exercise training preserves myocardial O2 balance and diastolic function

Journal of Applied Physiology ◽

10.1152/japplphysiol.01059.2012 ◽

2013 ◽

Vol 114 (1) ◽

pp. 131-147 ◽

Cited By ~ 41

Author(s):

Kurt D. Marshall ◽

Brittany N. Muller ◽

Maike Krenz ◽

Laurin M. Hanft ◽

Kerry S. McDonald ◽

...

Keyword(s):

Heart Failure ◽

Exercise Training ◽

Ejection Fraction ◽

Diastolic Function ◽

Myocardial Oxygen Consumption ◽

Preserved Ejection Fraction ◽

Miniature Swine ◽

Interval Exercise ◽

Low Intensity ◽

Physiol Heart Circ

We have previously reported chronic low-intensity interval exercise training attenuates fibrosis, impaired cardiac mitochondrial function, and coronary vascular dysfunction in miniature swine with left ventricular (LV) hypertrophy (Emter CA, Baines CP. Am J Physiol Heart Circ Physiol 299: H1348–H1356, 2010; Emter CA, et al. Am J Physiol Heart Circ Physiol 301: H1687–H1694, 2011). The purpose of this study was to test two hypotheses: 1) chronic low-intensity interval training preserves normal myocardial oxygen supply/demand balance; and 2) training-dependent attenuation of LV fibrotic remodeling improves diastolic function in aortic-banded sedentary, exercise-trained (HF-TR), and control sedentary male Yucatan miniature swine displaying symptoms of heart failure with preserved ejection fraction. Pressure-volume loops, coronary blood flow, and two-dimensional speckle tracking ultrasound were utilized in vivo under conditions of increasing peripheral mean arterial pressure and β-adrenergic stimulation 6 mo postsurgery to evaluate cardiac function. Normal diastolic function in HF-TR animals was characterized by prevention of increased time constant of isovolumic relaxation, normal LV untwisting rate, and enhanced apical circumferential and radial strain rate. Reduced fibrosis, normal matrix metalloproteinase-2 and tissue inhibitors of metalloproteinase-4 mRNA expression, and increased collagen III isoform mRNA levels ( P < 0.05) accompanied improved diastolic function following chronic training. Exercise-dependent improvements in coronary blood flow for a given myocardial oxygen consumption ( P < 0.05) and cardiac efficiency (stroke work to myocardial oxygen consumption, P < 0.05) were associated with preserved contractile reserve. LV hypertrophy in HF-TR animals was associated with increased activation of Akt and preservation of activated JNK/SAPK. In conclusion, chronic low-intensity interval exercise training attenuates diastolic impairment by promoting compliant extracellular matrix fibrotic components and preserving extracellular matrix regulatory mechanisms, preserves myocardial oxygen balance, and promotes a physiological molecular hypertrophic signaling phenotype in a large animal model resembling heart failure with preserved ejection fraction.

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