PUBLICATION
The circadian clock remains intact, but with dampened hormonal output in heart failure
- Authors
- Crnko, S., Printezi, M.I., Zwetsloot, P.M., Leiteris, L., Lumley, A.I., Zhang, L., Ernens, I., Jansen, T.P.J., Homsma, L., Feyen, D., van Faassen, M., du Pré, B.C., Gaillard, C.A.J.M., Kemperman, H., Oerlemans, M.I.F.J., Doevendans, P.A.F.M., May, A.M., Zuithoff, N.P.A., Sluijter, J.P.G., Devaux, Y., van Laake, L.W.
- ID
- ZDB-PUB-230420-65
- Date
- 2023
- Source
- EBioMedicine 91: 104556104556 (Journal)
- Registered Authors
- Keywords
- Circadian rhythms, Cortisol, Human heart failure, Melatonin, Mouse, Zebrafish
- MeSH Terms
-
- Animals
- Circadian Clocks*/physiology
- Circadian Rhythm/genetics
- Female
- Heart Failure*
- Humans
- Hydrocortisone
- Male
- Melatonin*
- Mice
- Middle Aged
- Zebrafish/metabolism
- PubMed
- 37075492 Full text @ EBioMedicine
Citation
Crnko, S., Printezi, M.I., Zwetsloot, P.M., Leiteris, L., Lumley, A.I., Zhang, L., Ernens, I., Jansen, T.P.J., Homsma, L., Feyen, D., van Faassen, M., du Pré, B.C., Gaillard, C.A.J.M., Kemperman, H., Oerlemans, M.I.F.J., Doevendans, P.A.F.M., May, A.M., Zuithoff, N.P.A., Sluijter, J.P.G., Devaux, Y., van Laake, L.W. (2023) The circadian clock remains intact, but with dampened hormonal output in heart failure. EBioMedicine. 91:104556104556.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping