Heart Failure with Preserved Ejection Fraction Linked with Metabolic Risk-Induced Inflammation

Patients with heart failure with preserved ejection fraction had high levels of coronary microvascular endothelial activation and oxidative stress, which may be induced by obesity and/or diabetes.

Patients with heart failure with preserved ejection fraction (HFpEF) were found to have high levels of coronary microvascular endothelial activation and oxidative stress, which may be induced by metabolic comorbidities such as obesity and diabetes, according to research published in JACC: Heart Failure.1

Previous researchled to the increased recognition of metabolic risk as a significant contributor to diastolic left ventricular (LV) dysfunction and HFpEF.

One study established the connection between diastolic LV stiffness and body mass index (BMI), concluding that reduction of weight and abdominal fat might prevent diastolic LV dysfunction and HFpEF development. In another trial, high BMI was the strongest predictor for the development of HFpEF in patients with arterial hypertension, which the current authors reported “was consistent with the high prevalence of overweight/obesity in large HFpEF outcome trials or registries, which almost uniformly reported a median BMI value of HFpEF patients in excess of 30 kg/m2.”

The MEDIA European HFpEF registry, for example, reported that 85% of patients met criteria for metabolic syndrome. The authors noted that the “prominent involvement of metabolic risk and endothelial inflammatory activation recently led to a new paradigm for HFpEF development,” as described in a 2013 paper2 proposing that “metabolic comorbidities drive LV remodeling and dysfunction in HFpEF through coronary microvascular endothelial inflammation, which alters paracrine signalling from endothelial 5 cells to surrounding cardiomyocytes.”

The current study was conducted to establish the validity of that proposed paradigm.

Researchers sought to determine whether the chronic inflammation associated with metabolic risk contributes to the development of HFpEF. First, they examined myocardial biopsies from 36 HFpEF patients to assess inflammatory endothelial activation, myocardial oxidative stress, nitric oxide (NO) bioavailability and cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling. These were compared with biopsies from 43 patients with heart failure with reduced ejection fraction (HFrEF) and 67 patients with aortic stenosis (AS).

Biopsies from each group were procured while patients were hospitalized to undergo procedures related to their respective conditions. To validate their findings, the researchers investigated the same variables in obese Zucker diabetic fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1)-HFpEF rats and compared them with lean ZSF1 rats with normal diastolic LV function.

Hypertension occurred in more patients with HFpEF than patients with HFrEF, and diabetes was more prevalent in HFpEF compared with AS. BMI values were also higher in the HFpEF group vs AS group. In all patient groups, LV end diastolic pressures were equally elevated. NOX2 was compared between HFpEF patients and controls (n=4) and myocardium from HFpEF patients contained more NOX2 expressing macrophages. Meanwhile, the ZSF1-HFpEF rats had cGMP concentrations lower in myocardium compared with the control group.

Based on both the human and rodent samples, the authors reported that “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.”

They recommended that future treatment approaches for HFpEF should target the chronic inflammation of the myocardial microvasculature that is induced by metabolic risk.


  1. Franssen C, Chen S, Unger A, et al. Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure with Preserved Ejection Fraction.  JACC Heart Fail. 2015. doi:10.1016/j.jchf.2015.10.007.
  2. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):2631-271. doi: 10.1016/j.jacc.2013.02.092.