Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction

Franssen, Constantijn; Chen, H. Sophia; Unger, Andreas; Korkmaz, Halil İbrahim; Keulenaer, Gilles W. De; Tschöpe, Carsten; Leite‐Moreira, Adelino F.; Musters, René J.P.; Niessen, Hans W.M.; Linke, Wolfgang A.; Paulus, Walter J.; Hamdani, Nazha

doi:10.1016/j.jchf.2015.10.007

Cited by 439 publications

(431 citation statements)

References 30 publications

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“…Previous data showed that diastolic dysfunction can be determined in the HFpEF animal model ZDF rat 23, 24. In accord with the literature we observed a significant increase in LV stiffness and prolonged relaxation time by pressure–volume analysis in our model.…”

Section: Discussionsupporting

confidence: 92%

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

Mátyás

Németh

Oláh

et al. 2016

European J of Heart Fail

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AimsHeart failure with preserved ejection fraction (HFpEF) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate (cGMP) signalling has been intensively investigated in HFpEF. Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including diabetic cardiomyopathy. We investigated the effect of long‐term preventive application of the phosphodiesterase‐5A (PDE5A) inhibitor vardenafil in diabetic cardiomyopathy‐associated HFpEF.Methods and resultsZucker diabetic fatty (ZDF) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular (LV) pressure–volume analysis and echocardiography at week 32. Cardiomyocyte force measurements were performed. The key markers of cGMP signalling, nitro‐oxidative stress, apoptosis, myocardial hypertrophy and fibrosis were examined. The ZDF animals showed diastolic dysfunction (increased LV/cardiomyocyte stiffness, prolonged LV relaxation time), preserved systolic performance, decreased myocardial cGMP level coupled with impaired protein kinase G (PKG) activity, increased nitro‐oxidative stress, enhanced cardiomyocyte apoptosis, and hypertrophic and fibrotic remodelling of the myocardium. Vardenafil effectively prevented the development of HFpEF by maintaining diastolic function (decreased LV/cardiomyocyte stiffness and LV relaxation time), by restoring cGMP levels and PKG activation, by lowering apoptosis and by alleviating nitro‐oxidative stress, myocardial hypertrophy and fibrotic remodelling.ConclusionsWe report that vardenafil successfully prevented the development of diabetes mellitus‐associated HFpEF. Thus, PDE5A inhibition as a preventive approach might be a promising option in the management of HFpEF patients with diabetes mellitus.

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Section: Discussionsupporting

confidence: 92%

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

Mátyás

Németh

Oláh

et al. 2016

European J of Heart Fail

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“…The subsequent inflammation could lead to frailty and could also negatively effect myocardial function ‘from a distance’ via the negative inotropic effects of the circulating cytokines (Mann, 2015). Interestingly, chronic inflammation and associated vascular dysfunction have also recently been linked to HFpEF (Paulus & Tschope, 2013; Glezeva et al ., 2015; Franssen et al ., 2016), the most common form of HF in the older adults (Upadhya et al ., 2015). Systemic inflammation can also accelerate skeletal muscle apoptosis and promote sarcopenia (Muscaritoli et al ., 2010).…”

Section: How Aging Frailty and Hf Interact To Induce Inflammationmentioning

confidence: 99%

Pathophysiology of heart failure and frailty: a common inflammatory origin?

et al. 2017

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SummaryFrailty, a clinical syndrome that typically occurs in older adults, implies a reduced ability to tolerate biological stressors. Frailty accompanies many age‐related diseases but can also occur without overt evidence of end‐organ disease. The condition is associated with circulating inflammatory cytokines and sarcopenia, features that are shared with heart failure (HF). However, the biological underpinnings of frailty remain unclear and the interaction with HF is complex. Here, we describe the inflammatory pathophysiology that is associated with frailty and speculate that the inflammation that occurs with frailty shares common origins with HF. We discuss the limitations in investigating the pathophysiology of frailty due to few relevant experimental models. Leveraging current therapies for advanced HF and current known therapies to address frailty in humans may enable translational studies to better understand the inflammatory interactions between frailty and HF.

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“…Moreover, expression of both vascular cell adhesion molecule (VCAM) and E-selectin by endothelial cells favors migration of monocytes into the subendothelium, resulting in increased levels of TGF-␤ release and myocardial deposition of collagen (185,269). Recently, Franssen et al (71) provided comprehensive evidence for microvascular endothelial activation, high oxidative stress, endothelial nitric oxide synthase (eNOS) uncoupling, and low NO levels in the LV myocardium of HFpEF patients. These findings were reproduced in obese ZSF1 rats, which develop HFpEF at 20 wk of age, in contrast to lean ZSF1 rats (hypertensive controls), which maintain normal LV function after a similar time period.…”

Section: Altered Signaling Pathways In Hfpef As Potential Targets Formentioning

confidence: 99%

Myocardial reverse remodeling: how far can we rewind?

Gonçalves-Rodrigues

Leite‐Moreira

Falcão-Pires

2016

American Journal of Physiology-Heart and Circulatory Physiology

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Heart failure (HF) is a systemic disease that can be divided into HF with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). HFpEF accounts for over 50% of all HF patients and is typically associated with high prevalence of several comorbidities, including hypertension, diabetes mellitus, pulmonary hypertension, obesity, and atrial fibrillation. Myocardial remodeling occurs both in HFrEF and HFpEF and it involves changes in cardiac structure, myocardial composition, and myocyte deformation and multiple biochemical and molecular alterations that impact heart function and its reserve capacity. Understanding the features of myocardial remodeling has become a major objective for limiting or reversing its progression, the latter known as reverse remodeling (RR). Research on HFrEF RR process is broader and has delivered effective therapeutic strategies, which have been employed for some decades. However, the RR process in HFpEF is less clear partly due to the lack of information on HFpEF pathophysiology and to the long list of failed standard HF therapeutics strategies in these patient's outcomes. Nevertheless, new proteins, protein-protein interactions, and signaling pathways are being explored as potential new targets for HFpEF remodeling and RR. Here, we review recent translational and clinical research in HFpEF myocardial remodeling to provide an overview on the most important features of RR, comparing HFpEF with HFrEF conditions.

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Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction

Abstract: HFpEF is associated with coronary microvascular endothelial activation and oxidative stress. These lead to a reduction of NO-dependent signalling from endothelial cells to cardiomyocytes, which can contribute to the high cardiomyocyte stiffness and hypertrophy observed in HFpEF.

Cited by 439 publications

References 30 publications

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

Pathophysiology of heart failure and frailty: a common inflammatory origin?

Myocardial reverse remodeling: how far can we rewind?

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