Metabolomic Profile in HFpEF vs HFrEF Patients

doi:10.1016/j.cardfail.2020.07.010

Journal of Cardiac Failure

Volume 26, Issue 12, December 2020, Pages 1050-1059

https://doi.org/10.1016/j.cardfail.2020.07.010 Get rights and content

ABSTRACT

Background

Heart failure with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are associated with metabolic derangements, which may have different pathophysiological implications.

Methods and Results

In new-onset HFpEF (EF of ≥50%, n = 46) and HFrEF (EF of <40%, n = 75) patients, 109 endogenous plasma metabolites including amino acids, phospholipids and acylcarnitines were assessed using targeted metabolomics. Differentially altered metabolites and associations with clinical characteristics were explored. Patients with HFpEF were older, more often female with hypertension, atrial fibrillation, and diabetes compared with patients with HFrEF. Patients with HFpEF displayed higher levels of hydroxyproline and symmetric dimethyl arginine, alanine, cystine, and kynurenine reflecting fibrosis, inflammation and oxidative stress. Serine, cGMP, cAMP, l-carnitine, lysophophatidylcholine (18:2), lactate, and arginine were lower compared with patients with HFrEF. In patients with HFpEF with diabetes, kynurenine was higher (P = .014) and arginine lower (P = .014) vs patients with no diabetes, but did not differ with diabetes status in HFrEF. Decreasing kynurenine was associated with higher eGFR only in HFpEF (P_interaction = .020).

Conclusions

Patients with new-onset HFpEF compared with patients with new-onset HFrEF display a different metabolic profile associated with comorbidities, such as diabetes and kidney dysfunction. HFpEF is associated with indices of increased inflammation and oxidative stress, impaired lipid metabolism, increased collagen synthesis, and downregulated nitric oxide signaling. Together, these findings suggest a more predominant systemic microvascular endothelial dysfunction and inflammation linked to increased fibrosis in HFpEF compared with HFrEF. Clinical Trial Registration: ClinicalTrials.gov NCT03671122 https://clinicaltrials.gov

Section snippets

Patients

From 2015 to 2018 patients with new-onset HF were recruited to the Preserved and Reduced Ejection Fraction Epidemiological Regional Study (PREFERS study) at five hospital-based HF clinics in Stockholm. The study protocol has previously been described.¹². The present analysis includes patients enrolled in 2015 and 2016. In brief, patients with previously undiagnosed HF presented to hospital either with acute signs and symptoms of HF or in stable condition at the outpatient clinic with an N

Results

The clinical characteristics of the 46 patients with HFpEF and 75 patients with HFrEF are presented in Table 1. Most patients were in New York Heart Association functional class II at the time of assessment. Patients with HFpEF were more than 10 years older, more often female with a nonsignificantly higher body mass index, and a higher prevalence of hypertension, atrial fibrillation, and diabetes compared with HFrEF. Filling pressure estimates were moderately increased in both groups with a

Discussion

In this exploratory study, patients with new-onset HFpEF had a diverging metabolite pattern compared with patients with new-onset HFrEF, reflecting potential differences in pathophysiologic mechanisms. First, patients with HFpEF displayed elevated hydroxyproline reflecting fibrosis, elevated SDMA indicating oxidative stress, and elevated alanine, cystine, and kynurenine, reflecting a state of increased inflammation compared with patients with HFrEF. Second, patients with HFpEF had lower levels

Serine

We found lower serine levels in HFpEF compared with HFrEF replicating similar findings on sphingomyelins in HFpEF⁹ and atrial fibrillation. In HFpEF mouse models, serine deficiency has been associated with oxidative stress²³ and reversely serine supply to decrease cardiac fibrosis and left ventricular mass index may be due to decreased transforming growth factor-β signaling.²⁴ In addition to lower levels of lysoPC (18:2) in our patients with HFpEF, our findings indicate further dysregulation in

Limitations

The PREFERS study was designed before the European Society of Cardiology HFpEF criteria were established in 2016 and therefore did not include specific requirements for structural impairments. However, in the HFpEF group 84% fulfilled the diagnostic criteria for HFpEF according to European Society of Cardiology guidelines.¹ It would have been valuable to have had healthy subjects as controls; however, this option was not available at the time. We provide two methods (OPLS-DA and logistic

Conclusions

In patients with new-onset HF, HFpEF was associated with increased hydroxyproline, SDMA, alanine, cystine, and kynurenine and decreased cGMP, cAMP, serine, l-carnitine, lysoPC (18:2), lactate, and arginine compared with HFrEF. In HFpEF but not in HFrEF, metabolites were modulated by comorbidities such as diabetes and kidney dysfunction. The overall HFpEF metabolic profile in this exploratory study reflects increased inflammation and oxidative stress, impaired lipid metabolism, increased

Disclosures

CH reports consulting fees from Novartis and Roche Diagnostics and speaker and honoraria from MSD; CL reports research grants, speaker honoraria and consulting fees from Medtronic, Abbot, Impulse Dynamics, Novartis, Bayer, Vifor, Microport, Boston Scientific, AstraZeneca and Orion Pharma. HP reports research grants from AstraZeneca; HW reports speakers fee from Bayer AG and Fujimori Kogyo Co, and research grants from Boehringer Ingelheim and Fujimori Kogyo Co. ME reports consulting fee and

Acknowledgments

The authors are grateful to Ulrika Löfström (MD), Ulla Wedén (MD), Carin Corovic Cabrera (MD), Per Eldhagen (MD), Jenny Stenudd (JS), Eva Andersson (RN), Karin Karlsson (RN), Fauzia Abdullahi-Moalim (RN), Gunnel Löfgren (RN), and Emma Berg (RN) for organizational work at the HF clinics and taking care of patients.

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Myeloperoxidase, carnitine, and derivatives of reactive oxidative metabolites in heart failure with preserved versus reduced ejection fraction: A meta-analysis
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Understanding the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF) continues to be challenging. Several inflammatory and metabolic biomarkers have recently been suggested to be involved in HFpEF.
The purpose of this review was to synthesize the evidence on non-traditional biomarkers from metabolomic studies that may distinguish HFpEF from heart failure with reduced ejection fraction (HFrEF) and controls without HF.
A systematic search was conducted using Medline and PubMed with search terms such as “HFpEF” and “metabolomics”, and a meta-analysis was conducted.
Myeloperoxidase (MPO) levels were significantly (p < 0.001) higher in HFpEF than controls without HF, but comparable (p = 0.838) between HFpEF and HFrEF. Carnitine levels were significantly (p < 0.0001) higher in HFrEF than HFpEF, but comparable (p = 0.443) between HFpEF and controls without HF. Derivatives of reactive oxidative metabolites (DROMs) were not significantly (p = 0.575) higher in HFpEF than controls without HF.
These data suggest that MPO is operative in HFpEF and HFrEF and may be a biomarker for HF. Furthermore, circulating carnitine levels may distinguish HFrEF from HFpEF.
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Heart failure with preserved ejection (HFpEF) and diabetes mellitus (DM) commonly co-exist. However, it is unclear if DM modifies the haemodynamic and cardiometabolic phenotype in patients with HFpEF. We aimed to interrogate the haemodynamic and cardiometabolic effects of DM in HFpEF.
We compared the haemodynamic and metabolic profiles of non-DM patients and patients with DM–HFpEF at rest and during exercise using right heart catheterisation and mixed venous blood gas analysis.
Of 181 patients with HFpEF, 37 (20%) had DM. Patients with DM displayed a more adverse exercise haemodynamic response vs HFpEF alone (mean pulmonary arterial pressure: 47 mmHg [interquartile range {IQR} 42–55] vs 42 [38–47], p<0.001; workload indexed pulmonary capillary wedge pressure indexed: 0.80 mmHg/W [0.44–1.23] vs 0.57 [0.43–1.01], p=0.047). HFpEF–DM patients had a lower mixed venous oxygen saturation at rest (70% [IQR 66–73] vs 72 [69–75], p=0.003) and were unable to enhance O₂ extraction to the same extent (Δ-28% [-33 to -15] vs -29 [-36 to -21], p=0.029), this occurred at a 22% lower median workload. Resting mixed venous lactate levels were higher in those with DM (1.5 mmol/L [IQR 1.1–1.9] vs 1 [0.9–1.3], p<0.001), and during exercise indexed to workload (0.09 mmol/L/W [0.06–0.13] vs 0.08 [0.05–0.11], p=0.018).
Concurrent diabetes and HFpEF was associated with greater metabolic responses at rest, with enhanced wedge driven pulmonary hypertension and relative lactataemia during exercise without appropriate augmentation of oxygen consumption.
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Cardiac macrophages are essential mediators of cardiac development, tissue homeostasis, and response to injury. Cell-intrinsic shifts in metabolism and availability of metabolites regulate macrophage function. The human and mouse heart contain a heterogeneous compilation of cardiac macrophages that are derived from at least two distinct lineages. In this review, we detail the unique functional roles and metabolic profiles of tissue-resident and monocyte-derived cardiac macrophages during embryonic development and adult tissue homeostasis and in response to pathologic and physiologic stressors. We discuss the metabolic preferences of each macrophage lineage and how metabolism influences monocyte fate specification. Finally, we highlight the contribution of cardiac macrophages and derived metabolites on cell–cell communication, metabolic health, and disease pathogenesis.
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Traditional Chinese medicine theory believes that qi deficiency and blood stasis are the key pathogenesis of heart failure with preserved ejection fraction (HFpEF). As a representative prescription for replenishing qi and activating blood, QiShenYiQi dripping pills (QSYQ) has been used for treating heart diseases. However, the pharmacological mechanism of QSYQ in improving HFpEF is not well understood.
The objective of the study is to investigate the cardioprotective effect and mechanism of QSYQ in HFpEF using the phenotypic dataset of HFpEF.
HFpEF mouse models established by feeding mice combined high-fat diet and N^ω-nitro-L-arginine methyl ester drinking water were treated with QSYQ. To reveal causal genes, we performed a multi-omics study, including integrative analysis of transcriptomics, proteomics, and metabolomics data. Moreover, adeno-associated virus (AAV)-based PKG inhibition confirmed that QSYQ mediated myocardial remodeling through PKG.
Computational systems pharmacological analysis based on human transcriptome data for HFpEF showed that QSYQ could potentially treat HFpEF through multiple signaling pathways. Subsequently, integrative analysis of transcriptome and proteome showed alterations in gene expression in HFpEF. QSYQ regulated genes involved in inflammation, energy metabolism, myocardial hypertrophy, myocardial fibrosis, and cGMP-PKG signaling pathway, confirming its function in the pathogenesis of HFpEF. Metabolomics analysis revealed fatty acid metabolism as the main mechanism by which QSYQ regulates HFpEF myocardial energy metabolism. Importantly, we found that the myocardial protective effect of QSYQ on HFpEF mice was attenuated after RNA interference-mediated knock-down of myocardial PKG.
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: Funding: Supported by a collaborative grant from Astra Zeneca; Gothenburg, Sweden to the Science for Life Laboratory (No. 1377).

View full text

Metabolomic Profile in HFpEF vs HFrEF Patients

ABSTRACT

Background

Methods and Results

Conclusions

Section snippets

Patients

Results

Discussion

Serine

Limitations

Conclusions

Disclosures

Acknowledgments

J Am Coll Cardiol

JACC Heart Fail

Pharmacol Ther

Pharmacol Ther

JACC Heart Fail

J Am Coll Cardiol

Biochim Biophys Acta Mol Basis Dis

J Am Coll Cardiol

J Card Fail

J Am Coll Cardiol

Nutrition

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

Eur J Heart Fail

The prognostic significance of diabetes and microvascular complications in patients with heart failure with preserved ejection fraction

Diabetes Care

Microvascular endothelial dysfunction in heart failure with preserved ejection fraction

Heart

Metabolomic fingerprint of heart failure with preserved ejection fraction

PLoS One

Metabolic dysfunction in heart failure: diagnostic, prognostic, and pathophysiologic insights from metabolomic profiling

Curr Heart Fail Rep

Rationale and design of the PREFERS (Preserved and Reduced Ejection Fraction Epidemiological Regional Study) Stockholm heart failure study: an epidemiological regional study in Stockholm county of 2.1 million inhabitants

Eur J Heart Fail

Orthogonal projections to latent structures (O-PLS)

J Chemometrics

OPLS discriminant analysis: combining the strengths of PLS-DA and SIMCA classification

J Chemometrics