The circadian clock remains intact, but with dampened hormonal output in heart failure

Sandra Crnko, Markella I. Printezi, Peter Paul M. Zwetsloot, Laurynas Leiteris, Andrew I. Lumley, Lu Zhang, Isabelle Ernens, Tijn P.J. Jansen, Lilian Homsma, Dries Feyen, Martijn van Faassen, Bastiaan C. du Pré, Carlo A.J.M. Gaillard, Hans Kemperman, Marish I.F.J. Oerlemans, Pieter A.F.M. Doevendans, Anne M. May, Nicolaas P.A. Zuithoff, Joost P.G. Sluijter, Yvan DevauxLinda W. van Laake*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)

Abstract

Background: Circadian (24-h) rhythms are important regulators in physiology and disease, but systemic disease may disrupt circadian rhythmicity. Heart failure (HF) is a systemic disease affecting hormonal regulation. We investigate whether HF affects the rhythmic expression of melatonin and cortisol, main endocrine products of the central clock, and cardiac-specific troponin in patients. We corroborate the functionality of the peripheral clock directly in the organs of translational models, inaccessible in human participants.

Methods: We included 46 HF patients (71.7% male, median age of 60 years, NYHA class II (32.6%) or III (67.4%), ischemic cardiomyopathy (43.5%), comorbidities: diabetes 21.7%, atrial fibrillation 30.4%), and 24 matched controls. Blood was collected at seven time-points during a 24-h period (totalling 320 HF and 167 control samples) for melatonin, cortisol, and cardiac troponin T (cTnT) measurements after which circadian rhythms were assessed through cosinor analyses, both on the individual and the group level. Next, we analysed peripheral circadian clock functionality using cosinor analysis in male animal HF models: nocturnal mice and diurnal zebrafish, based on expression of core clock genes in heart, kidneys, and liver, every 4 h during a 24-h period in a light/darkness synchronised environment.

Findings: Melatonin and cortisol concentrations followed a physiological 24-h pattern in both patients and controls. For melatonin, acrophase occurred during the night for both groups, with significantly decreased amplitude (median 5.2 vs 8.8, P = 0.0001) and circadian variation ([maximum]/[minimum]) in heart failure patients. For cortisol, mesor showed a significant increase for HF patients (mean 331.9 vs 275.1, P = 0.017) with a difference of 56.8 (95% CI 10.3–103.3) again resulting in a relatively lower variation: median 3.9 vs 6.3 (P = 0.0058). A nocturnal blood pressure dip was absent in 77.8% of HF patients. Clock gene expression profiles (Bmal, Clock, Per, Cry) were similar and with expected phase relations in animal HF models and controls, demonstrating preserved peripheral clock functionality in HF. Furthermore, oscillations in diurnal zebrafish were expectedly in opposite phases to those of nocturnal mice. Concordantly, cTnT concentrations in HF patients revealed significant circadian oscillations. Interpretation: Central clock output is dampened in HF patients while the molecular peripheral clock, as confirmed in animal models, remains intact. This emphasises the importance of taking timing into account in research and therapy for HF, setting the stage for another dimension of diagnostic, prognostic and therapeutic approaches.

Funding: Hartstichting.

Original languageEnglish
Article number104556
Number of pages17
JournalEBioMedicine
Volume91
DOIs
Publication statusPublished - May 2023

Bibliographical note

Funding Information:
Hartstichting.The authors would like to thank Hilde Schutte and Lena Bosch for their assistance with patient inclusions, Leanne Smit and Loes Peters for their help with processing blood samples, Walid al Hedni for performing cTnT analysis, Sophie Bots and Manon van der Meer for their assistance with initial statistical analysis, and all of the volunteers in this study as well as the nursing staff at the University Medical Centre Utrecht that helped with blood sampling. This work was supported by the Jacob Jongbloed Talent Society Grant (Circulatory Health, UMC Utrecht; to SC) and by Horizon 2020 ERC-2016-COG EVICARE (725229 to JPGS). This work has been partly funded by the Ministry of Research and Higher Education of Luxembourg and the Fondation Coeur—Daniel Wagner. LWvL is supported by the Dutch Heart Foundation, Dekker Clinical Scientist 2013, grant agreement No 2013T056, Dekker Senior Clinical Scientist 2019, grant agreement No 2019T056. The authors acknowledge the support from Innovation and the Netherlands CardioVascular Research Initiative (CVON): The Dutch Heart Foundation; the Dutch Federation of University Medical Centres; the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Science.

Funding Information:
This work was supported by the J acob Jongbloed Talent Society Grant (Circulatory Health, UMC Utrecht; to SC) and by Horizon 2020 ERC-2016-COG EVICARE ( 725229 to JPGS). This work has been partly funded by the Ministry of Research and Higher Education of Luxembourg and the Fondation Coeur—Daniel Wagner. LWvL is supported by the Dutch Heart Foundation , Dekker Clinical Scientist 2013, grant agreement No 2013T056 , Dekker Senior Clinical Scientist 2019, grant agreement No 2019T056 . The authors acknowledge the support from Innovation and the Netherlands CardioVascular Research Initiative (CVON): The Dutch Heart Foundation; the Dutch Federation of University Medical Centres ; the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Science .

Publisher Copyright:
© 2023 The Author(s)

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