Elsevier

International Journal of Cardiology

Volume 361, 15 August 2022, Pages 91-100
International Journal of Cardiology

Biomarkers of stable and decompensated phases of heart failure with preserved ejection fraction

https://doi.org/10.1016/j.ijcard.2022.05.004Get rights and content

Highlights

  • Acute HFpEF patients have higher mitochondrial mass and normal for the age mtDNA.

  • These “congestive-like mitochondria” have elevated ROS production.

  • Increased mtDNA and low formate are marks of HFpEF stable phase.

  • Acute phase LDHB drop and lactate increase worsen the glycolytic pattern of aging.

  • Formate, lactate and histidine distinguish acute and stable HFpEF.

Abstract

Background

Heart failure with preserved ejection fraction (HFpEF) is a disorder related to patient comorbidities and aging. Whether mitochondrial dysfunction is present during HFpEF decompensation versus the stable phase is largely unknown. The aim of the present study was to identify mitochondrial and cell metabolism blood biomarkers in older patients with acute and stable HFpEF.

Methods

Peripheral blood biomarkers were investigated in a group of eight to 12 patients aged 80–96 years and diagnosed with HFpEF first when they were in decompensated phase and then at least three months later in stable phase. Their data were compared to two control groups with an equal number of participants and sex proportions. One group was age matched and the other included individuals aged between 22 and 44 years.

Results

Decompensated patients experienced an increased mitochondrial superoxide production and mitochondrial mass, lower mitochondrial DNA copy number and LDHB expression, and higher lactate level compared to the stable stage. The stable phase was characterized by a sharp reduction in formate level. Multivariate analysis indicated that formate, lactate, and histidine can distinguish both of the HFpEF phases. Many of these parameters, including LDHB, lactate, formate, and mitochondrial mass, followed an age-related pattern, with acute HFpEF at its apex or nadir, suggesting that it represents an exacerbation of an aging-related process.

Conclusions

We identified distinct blood biomarkers of chronic and decompensated HFpEF phases. The data underlined the relationship between HFpEF and aging. These findings could be used to monitor patients and might be therapeutically targeted.

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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