All-Cause Mortality Differentials by Diabetes Status and Serum Neurofilament Light Chain Levels in U.S. General Adults.

CONTEXT: Neurofilament light chain (sNFL) increases in patients with diabetes and is associated with death. OBJECTIVE: To examine whether sNFL mediates associations of diabetes with all-cause mortality and the extent of interaction or joint relations of sNFL and diabetes with mortality. DESIGN: Population based cohort study. SETTING: 2013-2014 cycle of National Health and Nutrition Examination Survey. PARTICIPANTS: 2071 adults aged 20 to 75 years with measurements of sNFL. INTERVENTION(S): sNFL was lg transformed (LgNfl). Participants were featured whether LgNfl was higher than 1.48pg/ml or diagnosed with diabetes. MAIN OUTCOME MEASURE: All-cause mortality was the primary outcome obtained through linkage to registries. RESULTS: During a median follow-up of 6.1years, 85 participants died. Incidence rates [per 1000 person-years (95% CI)] of all-cause mortality were 27.78 (19.98∼35.58) in adults with LgNfl>1.48pg/ml and diabetes, 9.01 (1.99∼16.03) in adults with LgNfl>1.48pg/ml but no diabetes, 3.07 (1.01∼5.13) in adults with diabetes and LgNfl≤1.48pg/ml, and 2.21 (1.15∼3.27) in adults without diabetes and LgNfl≤1.48pg/ml. Significant interaction but not mediation was observed between LgNfl and diabetes. Compared with adults of no diabetes and LgNfl≤1.48pg/ml, those with diabetes and LgNfl > 1.48pg/ml had higher risks of all-cause mortality (Hazard ratio, 95%CI; 7.06, 3.52∼14.16). CONCLUSIONS: In general US adults with diabetes, elevated sNFL associated with higher all-cause mortality specifically, supporting an important role of sNFL in predicting health outcome in those with diabetes.

Increased Renal Dysfunction, Apoptosis, and Fibrogenesis Through Sympathetic Hyperactivity After Focal Cerebral Infarction.

Sympathetic nervous system plays an important role in secondary injury of diseases. Accumulating evidence has observed association between ischemic stroke and renal dysfunction, but the mechanisms are incompletely clear. In this study, we investigated whether sympathetic hyperactivity can cause the development of renal dysfunction, apoptosis, and fibrogenesis after focal cerebral infarction. To determine the renal consequences of focal cerebral ischemia, we subjected a mice model of transient middle cerebral artery occlusion (tMCAO) and examined systolic blood pressure, heart rate, renal structure and function, serum catecholamine, and cortisol levels, and the expression of active caspase-3 bcl-2, bax, and phosphorylated p38 MAPK after 8 weeks. We also analyzed the relationship between insular cortex infarction and acute kidney injury (AKI) in 172 acute anterior circulation ischemic stroke (ACIS) patients. Transient right middle cerebral artery occlusion induced sympathetic hyperactivity, renal dysfunction, upregulation of apoptosis, and fibrogenesis in kidneys of mice. Metoprolol treatment relieves the development of renal injury. Study in stroke patients demonstrated that insular cortex infarction, especially the right insular cortex infarction, is an independent risk factor of AKI. Focal cerebral ischemia in mice leads to the development of renal injury driven by sympathetic hyperactivity. Right insular cortex infarction is an independent risk factor of AKI in older patients. Understanding the brain-kidney interaction after stroke would have clinical implications for the treatment and overall patient outcome.

Anxiety is associated with increased risk for atrial cardiopathy.

Anxiety is common in patients with atrial fibrillation (AF). The mutual causal effect between anxiety and AF is expected with limited evidence. Atrial cardiopathy is a term to describe structural or electrophysiological atrium abnormality that precedes the onset of AF. This study aimed to investigate the association of anxiety with atrial cardiopathy, giving a clue to the causal relationship of this mind-heart link. This cross-sectional study analyzed 532 patients who were free of AF, atrial flutter, stroke, acute coronary syndrome and valvular heart disease. Atrial cardiopathy was defined as P-wave terminal force in lead V1 > 5000 µV·ms on electrocardiogram or severe left atrial enlargement on echocardiogram. Generalized anxiety disorder was ascertained by a score of > 17/56 on Hamilton anxiety rating scale. Multivariable logistic regression was used to explore the association of anxiety with atrial cardiopathy. A total of 65(12.2%) patients had atrial cardiopathy and 53(10.0%) had generalized anxiety disorder, respectively. Those with atrial cardiopathy were older (74.0 vs 67.0, P < 0.001), had a bigger left ventricular posterior wall thickness (10.1 vs 9.7 mm, P = 0.030), and had a higher prevalence of hypertension (83.1% vs 65.5%, P = 0.005), premature complexes (20.0% vs 6.2%, P < 0.001), and generalized anxiety disorder (20.0% vs 8.6%, P = 0.004), respectively. Multivariable logistic regression showed the significant association of anxiety with atrial cardiopathy (OR 2.788; 95% CI 1.304-5.960, P = 0.008), independent of confounding factors. Anxiety is independently associated with atrial cardiopathy. This association indicates the triggering effect of anxiety on atrial remodeling.

Association between advanced interatrial block and small vessel diseases in the brain.

BACKGROUND: The latest evidence shows the association of atrial cardiopathy with embolic strokes of undetermined source. Advanced interatrial block (aIAB) is an electrophysiological mark of atrial cardiopathy. This study investigated the relationship between aIAB and the burden of silent cerebral small vessel diseases (SVD) on magnetic resonance imaging in the absence of atrial fibrillation (AF) and atrial flutter. METHODS: This cross-sectional study included 499 patients with normal left ventricular ejection fraction (LVEF), who were free of AF, atrial flutter, stroke, and acute coronary syndrome in our hospital. aIAB was ascertained by digital electrocardiograms. Left atrial diameter, LVEF, and left ventricular posterior wall thickness (LVPWT) were measured on echocardiograms. Based on the presence of 4 manifestations of SVD, including white matter hyperintensity (WMH), lacunes, microbleeds, and enlarged perivascular spaces (EPVS) on magnetic resonance imaging, an ordinal SVD score (range, 0-4) was devised to reflect the total burden of cerebral SVD. The ordinal regression model was used to explore the association of aIAB with SVD burden after adjusting for confounding factors. RESULTS: The mean age was 67.7 years, and 327 (65.5%) were male. A total of 23 (4.6%) patients had aIAB. The number of patients with cerebral SVD scores of 0, 1, 2, 3, and 4 was 92 (18.4%), 122 (24.4%), 190 (38.1%), 83 (16.6%), and 12 (2.4%), respectively. After adjusting for age, sex, hypertension, diabetes, hyperlipidemia, left atrial diameter, LVEF, and LVPWT, the regression model showed a significant association of aIAB with cerebral SVD score (OR =2.408, 95% CI, 1.082-5.366). CONCLUSIONS: Atrial cardiopathy indexed by aIAB was independently associated with a high burden of SVD in the brain.

Resveratrol Delivery by Albumin Nanoparticles Improved Neurological Function and Neuronal Damage in Transient Middle Cerebral Artery Occlusion Rats.

Human serum albumin (HSA) is an intrinsic protein and important carrier that transports endogenous as well as exogenous substances. It is demonstrated in this study that the regional accumulation of albumin in the ischemia-reperfusion (I/R) brain may lead in the application of HSA based nanoparticles in the study of cerebral I/R injury. Resveratrol (RES) is potential in the treatment of cerebral I/R injury but is restricted for its water insolubility and short half-life in vivo. In our study, RES loaded HSA nanoparticles (RES-HSA-NPs) were prepared to facilitate the application of RES in protection from cerebral I/R injury. RES-HSA-NPs demonstrated spherical shape, a diameter about 100 nm, a highest RES encapsulation efficiency of 60.9 ± 5.07%, and controlled release pattern with the maximum release ratio of 50.2 ± 4.91% [in pH = 5.0 phosphate buffered saline (PBS)] and 26. 2 ± 2.73% (in pH = 7.4 PBS), respectively, after 90 h incubation at 37°C. After intravenous injection into transient middle cerebral artery occlusion (tMCAO) rats, RES-HSA-NPs improved neurological score and decreased infarct volume at 24 h after tMCAO in a dose dependent manner. A single dose of 20 mg/kg RES-HSA-NPs via tail vein improved neurological outcomes and decreased infarct volume at 24 and 72 h in tMCAO rats. I/R increased oxidative stress (indicated by products of lipid peroxidation, MDA) and neuronal apoptosis (indicated by yellow-brown TUNEL-positive cells), RES-HSA-NPs significantly attenuated oxidative stress and neuronal apoptosis. These results demonstrated the potential of RES-HSA-NPs in the therapy of cerebral I/R injury.

TGF-ß1 prevents blood-brain barrier damage and hemorrhagic transformation after thrombolysis in rats.

Transforming growth factor-beta1 (TGF-ß1) is well known to promote extracellular matrix accumulation. Recent studies demonstrated that TGF-ß1 protects against blood-brain barrier (BBB) disruption in the condition of inflammatory pain and stroke. In the present study, we investigated whether TGF-ß1 can maintain BBB integrity and prevent hemorrhagic transformation (HT) after recombinant tissue plasminogen activator (rt-PA) treatment in a rat model of thromboembolic middle cerebral artery occlusion (MCAO). Three hours after MCAO, rats were given saline, rt-PA alone or rt-PA combined with TGF-ß1 intravenously. Animals were sacrificed 24h after surgery. HT was calculated as hemorrhagic score. Evans blue dye extravasation was measured for BBB disruption. Basement membrane damage was observed by electron microscopy and quantified by collagen IV and laminin immunostaining. Gelatin zymography was used to measure the activities of matrix metalloproteinase (MMP)-2 and MMP-9. Western blot was performed for the expressions of MMP-2, MMP-9 and plasminogen activator inhibitor type-1 (PAI-1). Rats treated with rt-PA showed elevations in basement membrane damage, BBB disruption and HT. These phenomena were reduced in rats treated by TGF-ß1. We also showed that TGF-ß1 inhibited rt-PA mediated induction of MMP-2 and MMP-9. Meanwhile, TGF-ß1 upregulated PAI-1 expression which was reduced by rt-PA. Taken together, these results suggest that TGF-ß1 can reduce rt-PA induced basement membrane degradation, BBB disruption and HT. One possible mechanism is associated with the elevation of PAI-1. Suppression of MMP-2 and MMP-9 elevated by rt-PA may be another mechanism contributing to the protective effects of TGF-ß1.