Biomarkers of stable and decompensated phases of heart failure with preserved ejection fraction
Graphical abstract
Introduction
Heart disease is a significant health problem linked to aging. Most elderly patients suffer from heart failure with preserved ejection fraction (HFpEF) [1,2]. The course of the disease is progressive, with several episodes of acute decompensation [3].
Changes in energy metabolism, comorbidities, and inflammation are considered to have a role in the origin and progression of heart failure (HF) [4]. However, it is difficult to distinguish abnormalities associated with aging from those linked to HF [1]. Thus, pathophysiology of HFpEF is not completely understood, nor is the change occurring during stable and decompensated periods. Previous studies have shown a mitochondrial dysfunction in HFpEF. However, most of this research has been performed in skeletal and cardiac muscle cells during the stable phase [5]. Invasive and highly specialized endomyocardial biopsy has a very limited value for clinical use. Sensitive, consistent, and easy to obtain biomarkers are thus needed. However, classical blood biomarkers in HFpEF, including N-terminal pro B-type natriuretic peptide (NT-pro-BNP), have been questioned and therefore new and more reliable ones are currently under investigation [6]. Recently, circulating white blood cells have been claimed to represent a liquid biopsy reflecting intra-cardiac metabolic condition. This may be particularly true for peripheral blood mononuclear cells (PBMCs), as supported by several lines of evidence that include the reactive oxygen species (ROS) level, mitochondrial morphology, and RNA and protein expression [6]. A relevant example is the correlation between PBMCs and lymphocyte mitochondrial ROS levels in chronic HF with disease severity and plasma BNP and NT-pro-BNP [7,8]. Another method to search for these markers in blood is metabolomics [9]. Considering that HFpEF is presently viewed as a systemic aged-related condition [1], these holistic approaches may be particularly relevant. However, a comparative analysis of functional changes in acute (AHFpEF) versus stable (SHFpEF) phases in very old patients (ie 80 years of age and older) with HFpEF in the context of aging is lacking. In particular, it would be clinically useful to detect these changes in peripheral blood and to compare them to age-related ones. This would allow to better understand and monitor this condition.
The present study aimed to describe biomarkers related to mitochondrial function and cell metabolism using peripheral blood analysis between AHFpEF and SHFpEF among very old patients in comparison with individuals of the same age and young controls.
Section snippets
Patients
A total of 29 consecutive patients at least 80 years old who were admitted to the Emergency department of a Tertiary University Hospital with decompensated HF were enrolled in the study. They were diagnosed according to the European Society of Cardiology (ESC) guidelines [10] and met all of the following criteria: clinical signs and symptoms of HF, signs of pulmonary congestion on chest X-ray or pulmonary ultrasound, and value of NT-proBNP of >1300 pg/mL. Patients with left ventricular ejection
Subject characteristics
First, eight patients (five males and three females) with PBMC and plasma samples were studied. Their median age was 87 years (83–96 range). The mean time between samples in acute and stable phases was 192 ± 50 days. ECs were 88.5 (80–100) years old (cases vs. controls p = 0.673) and YCs were 28 (22–44) years old. All groups had the same number of individuals and sex ratio. Four additional female patients only had plasma samples. Thus, all 12 patients and appropriate controls (four extra
Discussion
The present pilot prospective study assessed mitochondrial and metabolic biomarkers in blood during acute and stable phases among older patients with HFpEF. Serial patient samples were compared at each disease phase with both age-matched and young controls to differentiate adaptations to aging from HF-specific changes. Our data show metabolic stress modifications in the acute phase supported by higher mitochondrial mass, ROS production, and glycolysis: reduced expression of LDHB and
Conclusions
We found increased mitochondrial superoxide and data for enhanced glycolysis in the decompensated HFpEF phase in comparison to the stable phase in PBMCs. In addition, acute patients had congestive mitochondria with a higher mitochondrial mass. On the other hand, the stable phase was characterized by a high mtDNA content and low formate level (Fig. 3E). Formate, lactate, and histidine distinguished both of the HFpEF phases. When these markers were compared in these very old HFpEF patients with
Funding
This study was supported by Hay Esperanza foundation and by grants from the Instituto de Salud Carlos III funded by the Spanish Ministry of Health and FEDER (PI15/00773 and PI18/00456).
Authors contribution
A.C., C.R.-A., and N.M.-M. performed experiments, acquired and analyzed data, and drafted the manuscript. N.M.-M., N.A., G.L.-G.,M. M.S.-C. and M.M. selected patients, acquired and analyzed data, and drafted the work; N.M.-M., N.A., M.J.T., F.J.C., J.G.C., F.J.M.-S. and E.A. interpreted data and revised the manuscript critically. E. A. designed the work and wrote the final version of the paper. E.A. F.J.C. and F.J.M.-S. acquired the funding. All the authors approved the final version to be
Declaration of Competing Interest
N.A. is stock owner of Biosfer Teslab and has a patent to commercialize the lipoprotein and glycoprotein profile described in the present manuscript. The other authors report no conflicts of interest.
Acknowledgements
The authors would like to thank Hospital Clínico San Carlos Biobank.
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