Receptor tyrosine kinase signaling in heart failure with preserved ejection fraction

The "phenotype" of patients with chronic heart failure is gradually changing from a dilated, poorly contracting left ventricle (LV) to a non-dilated, "thickened" ventricle (called "concentric" hypertrophy) with a normal global pump function (referred to as "heart failure with a preserved ejection fraction" or "HFPEF"). The reason for this phenotypic shift is unclear but relates to aging of the population and the increasing incidence of obesity, hypertension and type II diabetes, especially in postmenopausal women. How these risk factors, mostly in combination, promote HFPEF is unknown. Clinically, HFPEF is a diagnostic challenge and requires the development of novel therapeutic strategies, as traditional heart failure treatments have no proven benefit in HFPEF. In this project we will develop a new animal model of HFPEF by step-wise introducing risk factors (diabetes, hypertension, post-menopausal female gender and aging). The pathophysiology of HFPEF is incompletely understood but impaired LV filling due to slow LV relaxation and reduced LV compliance (altogether described as "diastolic dysfunction") seems to be a predominant mechanism. We predict that abovementioned risk factors accelerate the development of diastolic dysfunction and HFPEF. Next, we hypothesize that the risk factors for HFPEF direct the heart versus this HFPEF phenotype by affecting the balance between adaptive and disease-inducing signaling pathways in the heart. Changing this balance may prevent LV dilatation and pump failure but at the cost of developing concentric hypertrophy with impaired LV diastolic function. We will analyze the behavior of two important cardioprotective pathways, namely insulin like growth factor-1 (IGF1) and neuregulin-1(NRG1)/ErbB during the development of HFPEF induced by its specific risk factors. The cardioprotective nature of these pathways has been established under several cardiovascular diseases but their behavior and role in the development of HFPEF is completely unknown. IGF1 and NRG1 both rely on tyrosine kinase receptors and subsequent Akt activation to promote growth and stress-resistance of cardiac cells. This way they can protect the heart against LV dilation and pump failure, but may contain the risk of promoting concentric hypertrophy and HFPEF instead. On the other hand, however, IGF1 or NRG1 may ameliorate LV compliance and diastolic function by affecting the sarcomeric protein titin and by activation of the endothelial nitric oxide synthase, both powerful determinants of LV compliance. To unravel this apparent paradox, we will inhibit and activate these pathways using recombinant proteins and specific tyrosine kinase inhibitors respectively to examine whether the HFPEF phenotype is accentuated or soothed. Over the past decade IGF1 and NRG1 came forward as powerful cardioprotective agents failure in conditions of myocardial ischemia and phase I clinical trials have been initiated. Therefore uncovering the effects of IGF1 and NRG1 on diastolic function and the development of HFPEF is clinically very important. In summary, the presented research project will shed light on the correlation between specific risk factors such as hypertension, type II diabetes, aging and postmenopausal female gender and the HFPEF phenotype. Next, this project is the first to investigate the effects IGF1 and NRG1/ErbB pathways on diastolic function and the development of HFPEF.

Keywords:MOUSE MODELS, REMODELLING, DIASTOLIC HEART FAILURE, GROWTH FACTORS

Disciplines:Cardiac and vascular medicine, Physiology