Implications of the cardiomyocyte stress response on protein homeostasis in atrial fibrillation

Boezemfibrilleren is de meest voorkomende en aanhoudende ritmestoornis van het hart, die de kans op sterven verhoogt. Oudere mensen hebben vaker last van deze ziekte en doordat mensen steeds ouder worden, zal boezemfibrilleren in de toekomst steeds meer voorkomen. De huidige behandelingen voor boezemfibrilleren zijn niet effectief genoeg. Dit komt omdat deze behandelingen alleen proberen een normaal hartritme terug te krijgen, maar niet ingrijpen op de schadelijke structurele veranderingen. Deze structurele veranderingen omvatten de afbraak van eiwitten die nodig zijn voor de structuur en contractie van de hartspiercellen. De mechanismes die de structurele veranderingen in boezemfibrilleren veroorzaken zijn niet compleet bekend. Eerder onderzoek heeft laten zien dat de verstoring van de eiwit homeostase (aanmaak, functie en afbraak van eiwitten) een belangrijke rol speelt bij de structurele veranderingen in boezemfibrilleren. In dit proefschrift laten we zien dat boezemfibrilleren specifieke eiwit stress routes en eiwit afbraak routes activeert. De activatie van deze routes draagt bij aan de verstoring van de eiwit homeostase in boezemfibrilleren. Door de identificatie van specifieke routes die bijdragen aan het ziekteproces, hebben we verschillende nieuwe, potentiële therapeutische aangrijpingspunten gevonden die de eiwit homeostase in stand houden in de gebruikte experimentele modellen. Deze aangrijpingspunten zouden in de toekomst gebruikt kunnen worden om het ziekteproces in patiënten te verminderen en misschien zelfs te voorkomen

Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca2+-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased mitochondrial Ca2+-influx through partial blocking or downregulation of the mitochondrial calcium uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these results show that conservation of the mitochondrial function protects against tachypacing-induced cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target

Endoplasmic Reticulum Stress Is Associated With Autophagy and Cardiomyocyte Remodeling in Experimental and Human Atrial Fibrillation

BACKGROUND: Derailment of proteostasis, the homeostasis of production, function, and breakdown of proteins, contributes importantly to the self-perpetuating nature of atrial fibrillation (AF), the most common heart rhythm disorder in humans. Autophagy plays an important role in proteostasis by degrading aberrant proteins and organelles. Herein, we investigated the role of autophagy and its activation pathway in experimental and clinical AF. METHODS AND RESULTS: Tachypacing of HL-1 atrial cardiomyocytes causes a gradual and significant activation of autophagy, as evidenced by enhanced LC3B-II expression, autophagic flux and autophagosome formation, and degradation of p62, resulting in reduction of Ca(2+) amplitude. Autophagy is activated downstream of endoplasmic reticulum (ER) stress: blocking ER stress by the chemical chaperone 4-phenyl butyrate, overexpression of the ER chaperone-protein heat shock protein A5, or overexpression of a phosphorylation-blocked mutant of eukaryotic initiation factor 2α (eIF2α) prevents autophagy activation and Ca(2+)-transient loss in tachypaced HL-1 cardiomyocytes. Moreover, pharmacological inhibition of ER stress in tachypaced Drosophila confirms its role in derailing cardiomyocyte function. In vivo treatment with sodium salt of phenyl butyrate protected atrial-tachypaced dog cardiomyocytes from electrical remodeling (action potential duration shortening, L-type Ca(2+)-current reduction), cellular Ca(2+)-handling/contractile dysfunction, and ER stress and autophagy; it also attenuated AF progression. Finally, atrial tissue from patients with persistent AF reveals activation of autophagy and induction of ER stress, which correlates with markers of cardiomyocyte damage. CONCLUSIONS: These results identify ER stress-associated autophagy as an important pathway in AF progression and demonstrate the potential therapeutic action of the ER-stress inhibitor 4-phenyl butyrate

Evaluating Serum Heat Shock Protein Levels as Novel Biomarkers for Atrial Fibrillation

Background: Staging of atrial fibrillation (AF) is essential to understanding disease progression and the accompanied increase in therapy failure. Blood-based heat shock protein (HSP) levels may enable staging of AF and the identification of patients with higher risk for AF recurrence after treatment. Objective: This study evaluates the relationship between serum HSP levels, presence of AF, AF stage and AF recurrence following electrocardioversion (ECV) or pulmonary vein isolation (PVI). Methods: To determine HSP27, HSP70, cardiovascular (cv)HSP and HSP60 levels, serum samples were collected from control patients without AF and patients with paroxysmal atrial fibrillation (PAF), persistent (PeAF) and longstanding persistent (LSPeAF) AF, presenting for ECV or PVI, prior to intervention and at 3-, 6- and 12-months post-PVI. Results: The study population (n = 297) consisted of 98 control and 199 AF patients admitted for ECV (n = 98) or PVI (n = 101). HSP27, HSP70, cvHSP and HSP60 serum levels did not differ between patients without or with PAF, PeAF or LSPeAF. Additionally, baseline HSP levels did not correlate with AF recurrence after ECV or PVI. However, in AF patients with AF recurrence, HSP27 levels were significantly elevated post-PVI relative to baseline, compared to patients without recurrence. Conclusions: No association was observed between baseline HSP levels and the presence of AF, AF stage or AF recurrence. However, HSP27 levels were increased in serum samples of patients with AF recurrence within one year after PVI, suggesting that HSP27 levels may predict recurrence of AF after ablative therap

Derailed Proteostasis as a Determinant of Cardiac Aging

Age comprises the single most important risk factor for cardiac disease development. The incidence and prevalence of cardiac diseases, which represents the main cause of death worldwide, will increase even more because of the aging population. A hallmark of aging is that it is accompanied by a gradual derailment of proteostasis (eg, the homeostasis of protein synthesis, folding, assembly, trafficking, function, and degradation). Loss of proteostasis is highly relevant to cardiomyocytes, because they are postmitotic cells and therefore not constantly replenished by proliferation. The derailment of proteostasis during aging is thus an important factor that preconditions for the development of age-related cardiac diseases, such as atrial fibrillation. In turn, frailty of proteostasis in aging cardiomyocytes is exemplified by its accelerated derailment in multiple cardiac diseases. Here, we review 2 major components of the proteostasis network, the stress-responsive and protein degradation pathways, in healthy and aged cardiomyocytes. Furthermore, we discuss the relation between derailment of proteostasis and age-related cardiac diseases, including atrial fibrillation. Finally, we introduce novel therapeutic targets that might possibly attenuate cardiac aging and thus limit cardiac disease progression

Microscopic images produced by the SARS-CoV-2 application of the Biotrack-MED analyzer in saliva samples.

Examples of a negative (a), weak positive (b), medium positive (c) and highly positive (d) test result. The arrows indicate white blood cells positive for SARS-CoV-2 in (b), (c) and (d). In the case of (d), almost all white blood cells appear to show SARS-CoV-2 particles. The images from the Biotrack-MED analyzer are 1392 x 1040 pixels, which converts to 448.9 x 335.4 μm. The insert (b, c and d) shows a positive white blood cell that is zoomed in from the original image. A white blood cell is approximately 12–15 μm in diameter.</p

Symptoms of mild- and moderate-COVID-19-symptomatic patients.

Symptoms of mild- and moderate-COVID-19-symptomatic patients.</p

Results of the saliva samples of the SARS-CoV-2 application of the Biotrack-MED® analyzer.

Results of the saliva samples of the SARS-CoV-2 application of the Biotrack-MED® analyzer.</p