Aim: To investigate the influence of trimetazidine, which is known to be an antioxidant and modulator of metabolism, on cardiac function and the development of diabetic cardiomyopathy in db/db mouse. Methods: Trimetazidine was administered to db/db mice for eight weeks. Cardiac function was measured by inserting a Millar catheter into the left ventricle, and oxidative stress and AMP-activated protein kinase (AMPK) activity in the myocardium were evaluated. Results: Untreated db/db mice exhibited a significant decrease in cardiac function compared to normal C57 mice. Oxidative stress and lipid deposition were markedly increased in the myocardium, concomitant with inactivation of AMPK and increased expression of peroxisome proliferator-activated receptor coactivator-1α (PGC-1α). Trimetazidine significantly improved systolic and diastolic function in hearts of db/db mice and led to reduced production of reactive oxygen species and deposition of fatty acid in cardiomyocytes. Trimetazidine also caused AMPK activation and reduced PGC-1α expression in the hearts of db/db mice. Conclusion: The data suggest that trimetazidine significantly improves cardiac function in db/db mice by attenuating lipotoxicity and improving the oxidation status of the heart. Activation of AMPK and decreased expression of PGC-1α were involved in this process. Furthermore, our study suggests that trimetazidine suppresses the development of diabetic cardiomyopathy, which warrants further clinical investigation.

Ischemic postconditioning (IPOC) could be ineffective or even detrimental if the index ischemic duration is either too short or too long. The present study is to demonstrate that oxygen supply and metabolism defines a salvageable ischemic time window of IPOC in mice. C57BL/6 mice underwent coronary artery occlusion followed by reperfusion (I/R), with or without IPOC by three cycles of 10 s/10 s R/I. In vivo myocardial tissue oxygenation was monitored with electron paramagnetic resonance oximetry. Regional blood flow (RBF) was measured with a laser Doppler monitor. At the end of 60 min reperfusion, tissue from the risk area was collected, and mitochondrial enzyme activities were assayed. Tissue oximetry demonstrated that I/R induced a reperfusion hyperoxygenation state in the 30- and 45-min but not 15- and 60-min ischemia groups. IPOC attenuated the hyperoxygenation with 45 but not 30 min ischemia. RBF, eNOS phosphorylation, and mitochondrial enzyme activities were suppressed after I/R with different ischemic time, and IPOC afforded protection with 30 and 45 but not 60 min ischemia. Infarct size measurement indicated that IPOC reduced infarction with 30 and 45 min but not 60 min ischemia. Clearly, IPOC protected mouse heart with a defined ischemic time window between 30 and 45 min. This salvageable time window was accompanied by the improvement of RBF due to increased phosphorylated eNOS and the preservation of mitochondrial oxygen consumption due to conserved mitochondrial enzyme activities. Interestingly, this salvageable ischemic time window was mirrored by tissue hyperoxygenation status in the postischemic heart.

Background and purpose: Current evidence supports the involvement of lipids in brain aging. A range of serum lipids is explored in association with brain structure and cognitive function amongst rural-dwelling older adults. Methods: This population-based cross-sectional study included 184 rural-dwelling adults (age ≥ 65 years, 39.1% women) in Shandong, China. In 2014-2016, data on demographics, lifestyle, health conditions and serum lipids were collected. Volumes of gray matter, white matter, ventricles, hippocampus and white matter hyperintensity were automatically estimated on brain magnetic resonance imaging. Global cognitive function was assessed with the Mini-Mental State Examination (MMSE), and mild cognitive impairment (MCI) was defined according to Petersen's criteria. Data were analyzed using the general linear regression, logistic regression and mediation models. Results: Of the 184 participants, 47 were defined with MCI. Low high-density lipoprotein cholesterol (HDL-C; <1.55 vs. ≥1.55 mmol/l) was significantly associated with reduced volumes of total white matter (multi-adjusted β = −9.77, 95% confidence interval −19.48-0.06) and hippocampus (−0.23, −0.46-0.01), a lower MMSE score (−1.49, −2.67-0.31) and a higher likelihood of MCI (multi-adjusted odds ratio 3.21, 95% confidence interval 1.42-7.29). The mediation effects of structural brain measures on the associations between a low level of HDL-C and MMSE score or MCI were not statistically significant (p > 0.05).Conclusions: This study suggests that low HDL-C may be involved in structural brain aging and cognitive dysfunction amongst rural-dwelling older adults in China, but the association of low HDL-C with cognitive aging phenotypes appears not to be mediated by brain structure. How to cite this article: Wang M, Li Y, Cong L, et al. Highdensity lipoprotein cholesterol and brain aging amongst rural-dwelling older adults: a population-based magnetic resonance imaging study.

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Background and Purpose: Cerebral small vessel disease, as a potential mechanism underlying the association between atrial fibrillation (AF) and dementia, remains poorly investigated. In this cohort study, we sought to examine the association between AF and cerebral small vessel disease markers among older adults. Methods: Data on 336 participants (age ≥60 years, mean 70.2 years; 60.2% women) free of dementia, disability, and cerebral infarcts were derived from the population-based Swedish National Study on Aging and Care in Kungsholmen. Structural brain magnetic resonance imaging examinations were performed at baseline (2001–2004) and follow-ups (2004–2007 and 2007–2010). Magnetic resonance imaging markers of cerebral small vessel disease included perivascular spaces, lacunes, and volumes of white matter hyperintensities, lateral ventricles, and total brain tissue. AF was assessed at baseline and follow-ups through clinical examinations, electrocardiogram, and medical records. Data were analyzed using linear mixed-effects models. Results: At baseline, 18 persons (5.4%) were identified to have prevalent AF and 17 (5.6%) developed incident AF over the 6-year follow-up. After multivariable adjustment, AF was significantly associated with a faster annual increase in white matter hyperintensities volume (β coefficient=0.45 [95% CI, 0.04–0.86]) and lateral ventricular volume (0.58 [0.13–1.02]). There was no significant association of AF with annual changes in perivascular spaces number (β coefficient=0.53 [95% CI, −0.27 to 1.34]) or lacune number (−0.01 [−0.07 to 0.05]). Conclusions: Independent of cerebral infarcts, AF is associated with accelerated progression of white matter lesions and ventricular enlargement among older adults.

Background and purpose Little is known about whether nonalcoholic fatty liver disease (NAFLD) is associated with dementia or the role of serum proinflammatory cytokines in the association. We aimed to investigate the interrelationships of NAFLD, serum cytokines, and dementia among rural‐dwelling older adults. Methods This population‐based cross‐sectional study included 5129 participants (aged ≥60 years; 61.79% women) who were living in rural communities and examined in March 2018–September 2018. NAFLD was defined through transabdominal ultrasound examination in the absence of hepatitis B or excessive alcohol consumption. Serum cytokines were measured in a subsample (n = 1686). Dementia, Alzheimer disease (AD), and vascular dementia (VaD) were diagnosed following international criteria. Data were analyzed with logistic regression and mediation models. Results Of the 5129 participants, 455 (8.87%) were detected with moderate‐to‐severe NAFLD, and 292 (5.69%) were diagnosed with dementia (188 with AD and 96 with VaD). The multivariable adjusted odds ratios associated with moderate‐to‐severe (vs. no‐to‐mild) NAFLD were 2.22 (95% confidence interval [CI] = 1.41–3.49) for all‐cause dementia, 1.88 (95% CI = 1.01–3.50) for AD, and 2.62 (95% CI = 1.33–5.17) for VaD. In the cytokine subsample, controlling for multiple potential confounders, moderate‐to‐severe NAFLD was significantly associated with higher levels of serum monocyte chemotactic protein‐1, interleukin‐17A, interleukin‐6 (IL‐6), interleukin‐8, and tumor necrosis factor‐α (P < 0.05). The mediation analysis showed that IL‐6 mediated 12.56% of the association between NAFLD and VaD. Conclusions Moderate‐to‐severe nonalcoholic fatty liver disease is associated with dementia and AD, especially with VaD, among rural‐dwelling Chinese older adults, in which the association with VaD is partly mediated by serum inflammatory cytokines.

Background and Objective:The Life’s Simple 7 approach was proposed to define cardiovascular health (CVH) metrics. We sought to investigate the associations between behavioral, biological, and genetic markers for CVH and vascular brain aging in older adults.Methods:This population-based cohort study included participants who had repeated brain MRI measures from 2001-2003 to 2007-2010 (i.e., count of perivascular spaces, volumes of white-matter hyperintensity [WMH] and grey matter, and lacunes). At baseline, global, behavioral, and biological CVH metrics were defined and scored following the Life’s Simple 7 approach and categorized into unfavorable, intermediate, and favorable profiles according to tertiles. The metabolic genetic risk score was calculated by counting 15 risk alleles associated with hypertension, diabetes, or dyslipidemia. Data were analyzed using linear mixed-effects and Cox proportional-hazards models, adjusting for age, sex, and education.Results:The study sample consisted of 317 participants (age ≥60 years; 61.8% women). Favorable and intermediate (vs. unfavorable) global CVH profiles were related to slower WMH progression, with β-coefficients (95% CI) being -0.019(-0.035–-0.002) and -0.018(-0.034–-0.001), respectively. Favorable and intermediate (vs. unfavorable) biological CVH profiles were significantly related to slower WMH increase only in people aged 60-72 years. CVH profiles were not related to progression of other brain measures. Furthermore, a higher metabolic genetic risk score (range: 6-21) was associated with faster WMH increase (β-coefficient=0.005; 95% CI: 0.003–0.008). There were statistical interactions of metabolic genetic risk score with global and behavioral CVH profiles on WMH accumulation. A higher metabolic genetic risk score was related to faster WMH accumulation, with β-coefficients being 0.015(0.007–0.023), 0.005(0.001–0.009), and 0.003(-0.001–0.006) among people with unfavorable, intermediate, and favorable global CVH profiles, respectively; the corresponding β-coefficients were 0.013(0.006–0.020), 0.006(0.003–0.009), and 0.002(-0.002–0.006) among people with unfavorable, intermediate, and favorable behavioral CVH profiles.Discussion:Intermediate-to-favorable global CVH profiles in older adults are associated with slower vascular brain aging. The association of metabolic genetic risk load with accelerated vascular brain aging was evident among people with unfavorable-to-intermediate, but not favorable, CVH profiles. These findings highlight the importance of adhering to favorable CVH profiles, especially healthy behaviors, in vascular brain health.

Objectives eNOS-derived NO induces acute phase tissue hyperoxia in vivo and hyperoxia induces fibroblast trans-differentiation in vitro. However, little is known about the effect of reperfusioninduced hyperoxia on myocardial infarct healing. The current study is to determine how late phase reperfusion hyperoxia and NO regulate cardiac myofibroblast formation. Methods C57BL/6 wild-type, eNOS −/− and iNOS −/− mice were subjected to 30-min LAD occlusion followed by 14-days of reperfusion. Myocardial tissue PO 2 was monitored with electron paramagnetic resonance oximetry. Protein expression of TGF-beta1, p-Smad2/3, t-Smad2/3, p21 and α-SMA were measured with ELISA and western blot. Results There was an acute phase overshoot of tissue Po 2 in the WT and iNOS −/− but not eNOS −/− mice. After 60 min reperfusion, tissue hyperoxia was observed in all three groups and peaked at day 3 with significantly lower PO 2 in the eNOS −/− mice than that in the WT and iNOS −/− mice (22.4±0.8 vs 39.8±1.13 and 26.9±1.3 mm Hg). Protein expression of the total and active TGF-β1, p-Smad2/3 over t-Smad2/3 ratio, p21 and α-SMA were significantly increased after reperfusion in the WT mice. Knockout of eNOS or iNOS further increased the expression of these signals. Immunohistochemical staining indicated the expression of α-SMA in the infarct area. Immunoprecipitation demonstrated the nitration of TGF-β RII. Carbogen (95% O 2 +5% CO 2) treatment increased the expression of p-Smad2/3 over t-Smad2/3 which was inhibited by EUK134 (10006329 EUK 134) and sodium nitroprusside. Conclusions Late phase reperfusion tissue hyperoxia promoted while eNOS-/iNOS-derived NO/ONOO − inhibited cardiac TGF-β1 signalling and myofibroblast trans-differentiation. These findings may provide new targets to improve myocardial infarct healing and repair.