Low Circulating Levels of Mitochondrial and High Levels of Nuclear DNA Predict Mortality in Chronic Heart Failure

Dhondup, Yangchen; Ueland, Thor; Dahl, Christen P.; Askevold, Erik T.; Sandanger, Øystein; Fiane, Arnt E.; Ohm, Ingrid Kristine; Sjaastad, Ivar; Finsen, Alexandra Vanessa; Wæhre, Anne; Gullestad, Lars; Aukrust, Pål; Yndestad, Arne; Vinge, Leif Erik

doi:10.1016/j.cardfail.2016.06.013

Cited by 19 publications

(22 citation statements)

References 147 publications

(186 reference statements)

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“…90,91 Sequence-based qPCR detection methods allow to distinguishing nDNA from mtDNA, with a detection limit in the picogram range. 104 Using qPCR several studies identified both nDNA and mtDNA in plasma samples, 59,67,76,82 indicat-ing that ceDNA comprises a pool of mitochondrial and nDNA. These data suggest that ceDNA in patients probably originates from dying and injured cells, which release intracellular contents including nuclei and mitochondria into the circulation.…”

Section: Discussionmentioning

confidence: 99%

“…75 In line with these results, levels of nDNA and mtDNA were found to be increased in plasma from CHF patients compared with healthy controls. 76 Levels of nDNA, but not mtDNA, were associated with mortality within 2 years in CHF patients. 76 These studies suggest nDNA and nucleosomes as prognostic marker or mortality in CHF.…”

Section: Myocardial Infarctionmentioning

confidence: 91%

“…76 Levels of nDNA, but not mtDNA, were associated with mortality within 2 years in CHF patients. 76 These studies suggest nDNA and nucleosomes as prognostic marker or mortality in CHF. 75,76 Stroke Several independent studies showed an association of ceDNA with stroke in patients.…”

Section: Myocardial Infarctionmentioning

confidence: 91%

“…76 These studies suggest nDNA and nucleosomes as prognostic marker or mortality in CHF. 75,76 Stroke Several independent studies showed an association of ceDNA with stroke in patients. Plasma levels of nDNA were found to be increased in patients with acute stroke and correlated with the size of ischemic lesions in the brain.…”

Section: Myocardial Infarctionmentioning

confidence: 95%

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Circulating Extracellular DNA: Cause or Consequence of Thrombosis?

Jiménez-Alcázar

Kim

Fuchs

2017

Semin Thromb Hemost

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Thrombosis leads to ischemic organ damage in cardiovascular and thromboembolic diseases. Neutrophils promote thrombosis in vitro and in vivo by releasing neutrophil extracellular traps (NETs). NETs are composed of DNA filaments coated with histones and neutrophil enzymes such as myeloperoxidase (MPO). Circulating extracellular DNA (ceDNA) is widely used as a surrogate marker to monitor NET formation in thrombosis. This narrative review summarizes the association of ceDNA with human thrombosis. Levels of ceDNA indicate the extent and outcome of several cardiovascular and thromboembolic diseases, including myocardial infarction, stroke, and venous thromboembolism. ceDNA correlates with markers of coagulation and platelet consumption, thus supporting the hypothesis that ceDNA may be a surrogate marker of thrombus formation. In addition, ceDNA levels correlate with markers of cell injury and size of ischemic lesions, suggesting that ceDNA does not derive from NETs but is probably released from damaged organs. Few studies identified NET-specific biomarkers such as DNA-MPO complexes in the blood of patients with thrombosis. In conclusion, it remains to be established whether ceDNA in patients derives from NETs and is a cause or consequence of thrombosis.

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Section: Discussionmentioning

confidence: 99%

Section: Myocardial Infarctionmentioning

confidence: 91%

Section: Myocardial Infarctionmentioning

confidence: 91%

Section: Myocardial Infarctionmentioning

confidence: 95%

See 2 more Smart Citations

Circulating Extracellular DNA: Cause or Consequence of Thrombosis?

Jiménez-Alcázar

Kim

Fuchs

2017

Semin Thromb Hemost

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“…The quest for such a mechanistic explanation must be the basis for future studies. It is, however, intriguing that we also have clinical data suggesting a correlation between high plasma levels of the endogenous TLR9 ligand mtDNA and survival [23]. …”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 9 Promotes Survival in SERCA2a KO Heart Failure Mice

Dhondup

Sjaastad

Sandanger

et al. 2017

Mediators of Inflammation

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Aim. Inflammation is important in heart failure (HF). The role of the immune receptor toll-like receptor 9 (TLR9) in HF is not understood and not investigated in diastolic HF. We investigated the role of TLR9 in a murine diastolic HF model caused by cardiomyocyte SERCA2a excision. Methods and Results. We crossed SERCA2a KO and TLR9 KO mice to generate four mouse lines. Tamoxifen-induced cardiomyocyte SERCA2a gene excision was carried out in mice, causing diastolic HF. After 7.6 weeks, cardiac functions and dimensions were analyzed by echocardiography and heart tissues were processed. HF mice depleted of TLR9 demonstrated reduced survival compared to SERC2a KO mice, with a median life expectancy of 58 days compared to 63 days. Both HF groups displayed increased left atrium size, lung weight, fetal gene expressions, monocyte/macrophage infiltration, and fibrosis. However, there were no significant differences between the groups. Conclusion. In mice with SERCA2a KO-induced diastolic HF, the absence of TLR9 reduced median life expectancy. The cause remains elusive, as all investigated HF parameters were unaltered. Still, these findings support a salutary role of TLR9 in some subsets of HF conditions and underline the importance for future studies on the mechanisms of TLR9 in diastolic HF.

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Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy

et al. 2022

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Aims The role of necroptosis in dilated cardiomyopathy (DCM) remains unclear. Here, we examined whether phosphorylation of mixed lineage kinase domain‐like protein (MLKL), an indispensable event for execution of necroptosis, is associated with the progression of DCM. Methods and results Patients with DCM (n = 56, 56 ± 15 years of age; 68% male) were enrolled for immunohistochemical analyses of biopsies. Adverse events were defined as a composite of death or admission for heart failure or ventricular arrhythmia. Compared with the normal myocardium, increased signals of MLKL phosphorylation were detected in the nuclei, cytoplasm, and intercalated discs of cardiomyocytes in biopsy samples from DCM patients. The phosphorylated MLKL (p‐MLKL) signal was increased in enlarged nuclei or nuclei with bizarre shapes in hypertrophied cardiomyocytes. Nuclear p‐MLKL level was correlated negatively with septal peak myocardial velocity during early diastole (r = −0.327, P = 0.019) and was correlated positively with tricuspid regurgitation pressure gradient (r = 0.339, P = 0.023), while p‐MLKL level in intercalated discs was negatively correlated with mean left ventricular wall thickness (r = −0.360, P = 0.014). During a median follow‐up period of 3.5 years, 10 patients (18%) had adverse events. To examine the difference in event rates according to p‐MLKL expression levels, patients were divided into two groups by using the median value of nuclear p‐MLKL or intercalated disc p‐MLKL. A group with high nuclear p‐MLKL level (H‐nucMLKL group) had a higher adverse event rate than did a group with low nuclear p‐MLKL level (L‐nucMLKL group) (32% vs. 4%, P = 0.012), and Kaplan–Meier survival curves showed that the adverse event‐free survival rate was lower in the H‐nucMLKL group than in the L‐nucMLKL group (P = 0.019 by the log‐rank test). Such differences were not detected between groups divided by a median value of intercalated disc p‐MLKL. In δ‐sarcoglycan‐deficient (Sgcd−/−) mice, a model of DCM, total p‐MLKL and nuclear p‐MLKL levels were higher than in wild‐type mice. Conclusion The results suggest that increased localization of nuclear p‐MLKL in cardiomyocytes is associated with left ventricular diastolic dysfunction and future adverse events in DCM.

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Low Circulating Levels of Mitochondrial and High Levels of Nuclear DNA Predict Mortality in Chronic Heart Failure

Cited by 19 publications

References 147 publications

Circulating Extracellular DNA: Cause or Consequence of Thrombosis?

Circulating Extracellular DNA: Cause or Consequence of Thrombosis?

Toll-Like Receptor 9 Promotes Survival in SERCA2a KO Heart Failure Mice

Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy

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