Camilla Hage1, Lars Löfgren2, Filippos Michopoulos3, Ralph Nilsson2, Pia Davidsson2, Chanchal Kumar2, Mattias Ekström4, Maria J Eriksson5, Patrik Lyngå6, Bengt Persson7, Hakan Wallén4, Li Ming Gan8, Hans Persson4, Cecilia Linde9. 1. Karolinska Institutet, Department of Medicine, Cardiology unit, Stockholm, Sweden. Electronic address: camilla.hage@sll.se. 2. Translational Science and Experimental Medicine; Research and early Development, Cardiovascular, Renal and Metabolism, Biopharmaceutical R&D, AstraZeneca, Gothenburg, Sweden. 3. Bioscience, Early Oncology R&D, AstraZenenca, Cambridge, UK. 4. Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine Stockholm, Sweden. 5. Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden. 6. Karolinska Institutet, Department of Clinical Science and Education, Sodersjukhuset, Stockholm, Sweden. 7. Uppsala University, Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala, Sweden. 8. Early Clinical Development, Research and early Development, Cardiovascular, Renal and Metabolism, Biopharmaceutical R&D, AstraZeneca, Gothenburg, Sweden. 9. Karolinska Institutet, Department of Medicine, Cardiology unit, Stockholm, Sweden.
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 (Pinteraction = .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.
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 (Pinteraction = .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.
Authors: Milton Packer; Javed Butler; Faiez Zannad; Gerasimos Filippatos; Joao Pedro Ferreira; Stuart J Pocock; Peter Carson; Inder Anand; Wolfram Doehner; Markus Haass; Michel Komajda; Alan Miller; Steen Pehrson; John R Teerlink; Sven Schnaidt; Cordula Zeller; Janet M Schnee; Stefan D Anker Journal: Circulation Date: 2021-08-29 Impact factor: 29.690
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