Rising Cardiac Troponin: A Prognostic Biomarker for Mortality After Acute Ischemic Stroke.

BACKGROUND: Elevated cardiac troponin (cTn) is detected in 10% to 30% of patients with acute ischemic stroke (AIS) and correlates with poor functional outcomes. Serial cTn measurements differentiate a dynamic cTn pattern (rise/fall >20%), specific for acute myocardial injury, from elevated but stable cTn levels (nondynamic), typically attributed to chronic cardiac/noncardiac conditions. We investigated if the direction of the cTn change (rising versus falling) affects mortality and outcome. METHODS AND RESULTS: We retrospectively screened consecutive patients with AIS admitted to 5 stroke centers for elevated cTn at admission and at least 1 additional cTn measurement within 48 hours. The pattern of cTn was defined as rising if >20% increase from baseline, falling if >20% decrease, or nondynamic if ≤20% change in either direction. Logistic regression analyses were performed to assess the association of cTn patterns and 7-day mortality and unfavorable discharge disposition. Of 3789 patients with AIS screened, 300 were included. Seventy-two had a rising pattern, 66 falling, and 162 nondynamic. In patients with AIS with rising cTn, acute ischemic myocardial infarction was present in 54%, compared with 33% in those with falling cTn (P<0.01). Twenty-two percent of patients with a rising pattern had an isolated dynamic cTn in the absence of any ECG or echocardiogram changes, compared with 53% with falling cTn. A rising pattern was associated with higher risk of 7-day mortality (adjusted odds ratio [OR]=32 [95% CI, 2.5-415.0] rising versus aOR=1.3 [95% CI, 0.1-38.0] falling versus nondynamic as reference) and unfavorable discharge disposition (aOR=2.5 [95% CI, 1.2-5.2] rising versus aOR=0.6 [95% CI, 0.2-1.5] versus falling). CONCLUSIONS: Rising cTn is independently associated with increased mortality and unfavorable discharge disposition in patients with AIS.

Stroke-Heart Syndrome: Does Sex Matter?

Background Cardiovascular complications after acute ischemic stroke (AIS) can be related to chronic/comorbid cardiac conditions or acute disruption of the brain-heart autonomic axis (stroke-heart syndrome). Women are known to be more vulnerable to certain stress-induced cardiac complications, such as Takotsubo cardiomyopathy. We investigated sex differences in cardiac troponin (cTn) elevation, cardiac events, and outcomes after AIS. Methods and Results We retrospectively analyzed consecutive patients with AIS from 5 stroke centers. Patients with AIS with elevated baseline cTn and at least 2 cTn measurements were included, while patients with acute comorbid conditions that could impact cTn levels were excluded. Poststroke acute myocardial injury was defined as the presence of a dynamic cTn pattern (rise/fall >20% in serial measurements) in the absence of acute atherosclerotic coronary disease (type 1 myocardial infarction) or cardiac death (type 3 myocardial infarction). From a total cohort of 3789 patients with AIS, 300 patients were included in the study: 160 were women (53%). Women were older, had a lower burden of cardiovascular risk factors, and more frequently had cardioembolic stroke and right insula involvement (P values all <0.05). In multivariate analysis, women were more likely to have a dynamic cTn pattern (adjusted odds ratio, 2.1 [95% CI, 1.2-3.6]) and develop poststroke acute myocardial injury (adjusted odds ratio, 2.1 [95% CI, 1.1-3.8]). Patients with poststroke acute myocardial injury had higher 7-day mortality (adjusted odds ratio, 5.5 [95% CI, 1.2-24.4]). Conclusions In patients with AIS with elevated cTn at baseline, women are twice as likely to develop poststroke acute myocardial injury, and this is associated with higher risk of short-term mortality. Translational studies are needed to clarify mechanisms underlying sex differences in cardiac events and mortality in AIS.

Cep55: abscission boss or assistant?

Abscission is the second stage of cytokinesis. Cep55, a coiled-coil protein, is thought to recruit endosomal sorting complexes required for transport (ESCRTs) to the midbody to complete abscission. However, recent studies of Cep55-knockout mice reveal that most cells can complete abscission without Cep55. More work is needed to understand abscission mechanisms in different cell types.

Loss of Coiled-Coil Protein Cep55 Impairs Neural Stem Cell Abscission and Results in p53-Dependent Apoptosis in Developing Cortex.

To build the brain, embryonic neural stem cells (NSCs) tightly regulate their cell divisions, undergoing a polarized form of cytokinesis that is poorly understood. Cytokinetic abscission is mediated by the midbody to sever the daughter cells at the apical membrane. In cell lines, the coiled-coil protein Cep55 was reported to be required for abscission. Mutations of Cep55 in humans cause a variety of cortical malformations. However, its role in the specialized divisions of NSCs is unclear. Here, we elucidate the roles of Cep55 in abscission and brain development. KO of Cep55 in mice causes abscission defects in neural and non-neural cell types, and postnatal lethality. The brain is disproportionately affected, with severe microcephaly at birth. Quantitative analyses of abscission in fixed and live cortical NSCs show that Cep55 acts to increase the speed and success rate of abscission, by facilitating ESCRT recruitment and timely microtubule disassembly. However, most NSCs complete abscission successfully in the absence of Cep55 Those that fail show a tissue-specific response: binucleate NSCs and neurons elevate p53, but binucleate fibroblasts do not. This leads to massive apoptosis in the brain, but not other tissues. Double KO of both p53 and Cep55 blocks apoptosis but only partially rescues Cep55-/- brain size. This may be because of the persistent NSC cell division defects and p53-independent premature cell cycle exit. This work adds to emerging evidence that abscission regulation and error tolerance vary by cell type and are especially crucial in neural stem cells as they build the brain.SIGNIFICANCE STATEMENT During brain growth, embryonic neural stem cells (NSCs) must divide many times. In the last step of cell division, the daughter cell severs its connection to the mother stem cell, a process called abscission. The protein Cep55 is thought to be essential for recruiting proteins to the mother-daughter cell connection to complete abscission. We find that Cep55 mutants have very small brains with disturbed structure, but almost normal size bodies. NSC abscission can occur, but it is slower than normal, and failures are increased. Furthermore, NSCs that do fail abscission activate a signal for programmed cell death, whereas non-neural cells do not. Blocking this signal only partly restores brain growth, showing that regulation of abscission is crucial for brain development.

Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease.

The failure of DNA ligases to complete their catalytic reactions generates cytotoxic adenylated DNA strand breaks. The APTX RNA-DNA deadenylase protects genome integrity and corrects abortive DNA ligation arising during ribonucleotide excision repair and base excision DNA repair, and APTX human mutations cause the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1). How APTX senses cognate DNA nicks and is inactivated in AOA1 remains incompletely defined. Here, we report X-ray structures of APTX engaging nicked RNA-DNA substrates that provide direct evidence for a wedge-pivot-cut strategy for 5'-AMP resolution shared with the alternate 5'-AMP processing enzymes POLß and FEN1. Our results uncover a DNA-induced fit mechanism regulating APTX active site loop conformations and assembly of a catalytically competent active center. Further, based on comprehensive biochemical, X-ray and solution NMR results, we define a complex hierarchy for the differential impacts of the AOA1 mutational spectrum on APTX structure and activity. Sixteen AOA1 variants impact APTX protein stability, one mutation directly alters deadenylation reaction chemistry, and a dominant AOA1 variant unexpectedly allosterically modulates APTX active site conformations.