Left ventricular hypertrophy phenotype to predict incident atrial fibrillation: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIM: Left ventricular hypertrophy (LVH) has been shown to be associated with the occurrence of atrial fibrillation (AF). However, the predictive value of the LVH phenotype for incident AF remains uncertain. This study aimed to investigate the predictive value of LVH phenotype for incident AF. METHODS AND RESULTS: This study utilized the Multi-Ethnic Study of Atherosclerosis (MESA) data. LVH was defined by cardiac magnetic resonance measured LV mass index. Isolated LVH was determined as LVH without elevated cardiac biomarker and malignant LVH was determined as LVH with at least 1 elevated biomarker. Receiver-operating characteristic (ROC) analysis was performed to calculate areas under the curves (AUC) for predicting AF. A total of 4983 community-dwelling participants were included, with a mean age of 61.5 years. 279 (5.6 %) had isolated LVH, and 222 (4.5 %) had malignant LVH. During a median follow-up of 8.5 years, 272 incident AF was observed. Compared to participants without LVH and elevated cardiac biomarkers, those with isolated LVH (HR, 1.82; 95 % CI, 1.03-3.20) and malignant LVH (HR, 4.13; 95 % CI, 2.77-6.16) had a higher risk of incident AF. Malignant LVH carried a 1.5-fold increased risk of AF compared to isolated LVH (HR: 2.48, 95 % CI: 1.30-4.73). Including the LVH phenotype in the CHARGE-AF model improved model discrimination (AUC increase: 0.03, p < 0.001). CONCLUSIONS: The risks of AF incidence varied across LVH phenotypes. Malignant LVH carried the highest risk among LVH phenotypes. LVH phenotype provides incremental predictive value over the variables included in the CHARGE-AF model.

Association between 5-year change in cardiovascular risk and the incidence of atherosclerotic cardiovascular diseases: a multi-cohort study.

BACKGROUND: The influence of the historical cardiovascular risk status on future risk of atherosclerotic cardiovascular disease (ASCVD) is poorly understood. We aimed to investigate the association between 5-year changes in cardiovascular risk and ASCVD incidence. METHODS: We analyzed pooled data from seven community-based prospective cohort studies with up to 20 years of follow-up data. The study populations included White or Black participants aged 40-75 years without prevalent ASCVD. Cardiovascular risk was assessed using the pooled cohort equation and was categorized into non-high (< 20%) or high risk (≥ 20%). Changes in cardiovascular disease (CVD) risk over a 5-year interval were recorded. The main outcome was incident ASCVD. RESULTS: Among 11,026 participants (mean [SD] age, 60.0 [8.1] years), 4272 (38.7%) were female and 3127 (28.4%) were Black. During a median follow-up period of 9.9 years, 2560 (23.2%) ASCVD events occurred. In comparison with individuals showing a consistently high CVD risk, participants whose CVD risk changed from non-high to high (hazard ratio [HR], 0.67; 95% confidence interval [CI] 0.59-0.77) or high to non-high (HR, 0.57; 95% CI 0.41-0.80) and those with a consistently non-high risk (HR, 0.33; 95% CI 0.29-0.37) had a lower risk of incident ASCVD. In comparison with individuals showing a consistently non-high CVD risk, participants whose CVD risk changed from high to non-high (HR, 1.74; 95% CI 1.26-2.41) or from non-high to high risk (HR, 2.04; 95% CI 1.84-2.27) and those with a consistently high risk (HR 3.03; 95% CI 2.69-3.42) also showed an increased risk of incident ASCVD. CONCLUSIONS: Individuals with the same current CVD risk status but different historical CVD risks exhibited varying risks of future ASCVD incidents. Dynamic risk evaluation may enable more accurate cardiovascular risk stratification, and decision-making regarding preventive interventions should take the historical risk status into account.

Weigh change across adulthood is related to the presence of NAFLD: results from NHANES III.

BACKGROUND: Obesity is a widely recognized driving factor of Non-alcoholic fatty liver disease (NAFLD), it remains unclear whether historical weight status was associated with the presence of NAFLD. The study aimed to explore the relationship between weight change across adulthood and the presence of NAFLD. METHODS: Data from the National Health and Nutrition Examination Survey III included 6586 participants. Weight change was assessed according to body mass index (BMI) at baseline, at 25 years old, and 10 years before baseline. Obesity was defined as BMI ≥ 30 kg/m2. NAFLD was assessed by hepatic ultrasonography. RESULTS: The prevalence of NAFLD was highest among stable obese participants (48.1%), and the lowest among stable non-obese participants (18.9%). Among non-obese participants, those who get obese in early adulthood had a higher risk for the presence of NAFLD than those who were never obese (odds ratio [OR], 1.82; 95% confidence interval [CI] 1.17-2.92). Among obese participants, those who become obese in middle-late adulthood had a lower risk of NAFLD (OR, 0.79; 95% CI 0.65-0.96) than those with stable obesity. A weight gain of more than 12 kg and 4 kg since early and middle-late adulthood respectively were associated with increased risks of NAFLD. CONCLUSION: Among current nonobese individuals, those with a history of obesity in their early adulthood had a higher risk of NAFLD than those never obese. Among the currently obese population, those who became obese after mid-adulthood have a significantly lower risk of NAFLD compared with those who were stable obese.

Association of Life's Essential 8 with all-cause and cardiovascular mortality among US adults: A prospective cohort study from the NHANES 2005-2014.

BACKGROUND AND AIMS: This study aims to investigate the association of Life's Essential 8 (LE8), the recently updated algorithm for quantifying cardiovascular health (CVH) by the American Heart Association (AHA), with long-term outcomes among US adults. METHODS AND RESULTS: This population-based prospective cohort study analyzed data of 23,110 participants aged 20 years or older from the National Health and Nutrition Examination Survey from 2005 to 2014 and their linked mortality data through December 2019. LE8 score (range 0-100) was measured according to AHA definitions and was categorized into low (0-49), moderate (50-79), and high (80-100) CVH. The weighted mean age of the study population was 47.0 years (95% confidence interval [CI], 46.4-47.5 years), and 11,840 were female (weighted percentage, 51.5%; 95% CI, 50.9-52.1%). During a median follow-up period of 113 months (up to 180 months), 2942 all-cause deaths occurred, including 738 CVD deaths. The LE8 score was significantly and inversely related to mortality from all causes (adjusted hazard ratio [HR] for per 10-score increase in LE8 score, 0.86; 95% CI, 0.82-0.90) and cardiovascular disease (adjusted HR for per 10-score increase in LE8 score, 0.81; 95% CI, 0.75-0.87). Compared with participants having low CVH, those having high CVH had a reduction of 40% (adjusted HR, 0.60; 95% CI, 0.48-0.75) in the risk for all-cause mortality and 54% (adjusted HR, 0.46; 95% CI, 0.31-0.68) in the risk for cardiovascular mortality. CONCLUSIONS: Higher LE8 score was independently associated with lower risks of all-cause and cardiovascular mortality among US adults.

Novel metabolic phenotypes for extrahepatic complication of nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Phenotypic heterogeneity among patients with NAFLD is poorly understood. We aim to identify clinically important phenotypes within NAFLD patients and assess the long-term outcomes among different phenotypes. METHODS: We analyzed the clinical data of 2311 participants from the Third National Health and Nutrition Examination Survey (NHANES III) and their linked mortality data through December 2019. NAFLD was diagnosed by ultrasonographic evidence of hepatic steatosis without other liver diseases and excess alcohol use. A 2-stage cluster analysis was applied to identify clinical phenotypes. We used Cox proportional hazard models to explore all-cause and cause-specific mortality between clusters. RESULTS: We identified 3 NAFLD phenotypes. Cluster 1 was characterized by young female patients with better metabolic profiles and lower prevalence of comorbidities; Cluster 2 by obese females with significant insulin resistance, diabetes, inflammation, and advanced fibrosis and Cluster 3 by male patients with hypertension, atherogenic dyslipidemia, and liver and kidney damage. In a median follow-up of 26 years, 989 (42.8%) all-cause mortality occurred. Cluster 1 patients presented the best prognosis, whereas Cluster 2 and 3 had higher risks of all-cause (Cluster 2-adjusted HR: 1.48, 95% CI: 1.16-1.90; Cluster 3-adjusted HR: 1.29, 95% CI: 1.01-1.64) and cardiovascular (Cluster 2-adjusted HR: 2.01, 95% CI: 1.18-3.44; Cluster 3-adjusted HR: 1.75, 95% CI: 1.03-2.97) mortality. CONCLUSIONS: Three phenotypically distinct and clinically meaningful NAFLD subgroups have been identified with different characteristics of metabolic profiles. This study reveals the substantial disease heterogeneity that exists among NAFLD patients and underscores the need for granular assessments to define phenotypes and improve clinical practice.

Associations between life's essential 8 and non-alcoholic fatty liver disease among US adults.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is closely associated with Cardiovascular disease (CVD). We aim to examine the association of Life's Essential 8 (LE8), the recently updated measurement of cardiovascular health (CVH), with the presence of NAFLD among US adults. METHODS: This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey in 2017-2018 and included adults 20 years or older. LE8 score (range 0-100) was measured according to American Heart Association definitions and was categorized into low (0-49), moderate (50-79), and high (80-100) CVH. NAFLD was determined by transient elastography measured hepatic steatosis in the absence of other liver diseases and excess alcohol use. Multivariable logistic and restricted cubic spline models were used to assess the associations. RESULTS: Among 3588 participants included (weighted mean age, 48.0 years; 95% confidence interval [CI] 46.4-49.7 years), 1839 were female (weighted percentage, 51.6%; 95% CI 49.0-54.2%) and 1483 were determined to have NAFLD (weighted percentage, 36.5%; 95% CI 33.3-39.7%). The weighted mean LE8 score of the study population was 67.9 (95% CI 66.6-69.2). After the adjustment of potential confounders, higher LE8 scores were associated with reduced odds of NAFLD (odds ratio [OR] for per 10 score increase, 0.67; 95% CI 0.59-0.76) and a nonlinear dose-response relationship was observed. Similar patterns were also identified in the association of health behavior and health factor scores with NAFLD. The inversed association of LE8 score and NAFLD was significantly stronger among younger, Asian, and participants with higher education and income level. CONCLUSIONS: LE8 and its subscales scores were negatively associated with the presence of NAFLD in non-linear fashions. Promoting adherence to optimal CVH levels may be beneficial to reduce the burden of NAFLD as well as CVD.

Caffeine and Parkinson's Disease: Multiple Benefits and Emerging Mechanisms.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by dopaminergic neurodegeneration, motor impairment and non-motor symptoms. Epidemiological and experimental investigations into potential risk factors have firmly established that dietary factor caffeine, the most-widely consumed psychoactive substance, may exerts not only neuroprotective but a motor and non-motor (cognitive) benefits in PD. These multi-benefits of caffeine in PD are supported by convergence of epidemiological and animal evidence. At least six large prospective epidemiological studies have firmly established a relationship between increased caffeine consumption and decreased risk of developing PD. In addition, animal studies have also demonstrated that caffeine confers neuroprotection against dopaminergic neurodegeneration using PD models of mitochondrial toxins (MPTP, 6-OHDA, and rotenone) and expression of α-synuclein (α-Syn). While caffeine has complex pharmacological profiles, studies with genetic knockout mice have clearly revealed that caffeine's action is largely mediated by the brain adenosine A2A receptor (A2AR) and confer neuroprotection by modulating neuroinflammation and excitotoxicity and mitochondrial function. Interestingly, recent studies have highlighted emerging new mechanisms including caffeine modulation of α-Syn degradation with enhanced autophagy and caffeine modulation of gut microbiota and gut-brain axis in PD models. Importantly, since the first clinical trial in 2003, United States FDA has finally approved clinical use of the A2AR antagonist istradefylline for the treatment of PD with OFF-time in Sept. 2019. To realize therapeutic potential of caffeine in PD, genetic study of caffeine and risk genes in human population may identify useful pharmacogenetic markers for predicting individual responses to caffeine in PD clinical trials and thus offer a unique opportunity for "personalized medicine" in PD.

Chronic Caffeine Treatment Protects Against α-Synucleinopathy by Reestablishing Autophagy Activity in the Mouse Striatum.

Despite converging epidemiological evidence for the inverse relationship of regular caffeine consumption and risk of developing Parkinson's disease (PD) with animal studies demonstrating protective effect of caffeine in various neurotoxin models of PD, whether caffeine can protect against mutant α-synuclein (α-Syn) A53T-induced neurotoxicity in intact animals has not been examined. Here, we determined the effect of chronic caffeine treatment using the α-Syn fibril model of PD by intra-striatal injection of preformed A53T α-Syn fibrils. We demonstrated that chronic caffeine treatment blunted a cascade of pathological events leading to α-synucleinopathy, including pSer129α-Syn-rich aggregates, apoptotic neuronal cell death, microglia, and astroglia reactivation. Importantly, chronic caffeine treatment did not affect autophagy processes in the normal striatum, but selectively reversed α-Syn-induced defects in macroautophagy (by enhancing microtubule-associated protein 1 light chain 3, and reducing the receptor protein sequestosome 1, SQSTM1/p62) and chaperone-mediated autophagy (CMA, by enhancing LAMP2A). These findings support that caffeine-a strongly protective environment factor as suggested by epidemiological evidence-may represent a novel pharmacological therapy for PD by targeting autophagy pathway.

The Corticostriatal Adenosine A2A Receptor Controls Maintenance and Retrieval of Spatial Working Memory.

BACKGROUND: Working memory (WM) taps into multiple executive processes including encoding, maintenance, and retrieval of information, but the molecular and circuit modulation of these WM processes remains undefined due to the lack of methods to control G protein-coupled receptor signaling with temporal resolution of seconds. METHODS: By coupling optogenetic control of the adenosine A2A receptor (A2AR) signaling, the Cre-loxP-mediated focal A2AR knockdown with a delayed non-match-to-place (DNMTP) task, we investigated the effect of optogenetic activation and focal knockdown of A2ARs in the dorsomedial striatum (n = 8 to 14 per group) and medial prefrontal cortex (n = 16 to 22 per group) on distinct executive processes of spatial WM. We also evaluated the therapeutic effect of the A2AR antagonist KW6002 on delayed match-to-sample/place tasks in 6 normal and 6 MPTP-treated cynomolgus monkeys. RESULTS: Optogenetic activation of striatopallidal A2ARs in the dorsomedial striatum selectively at the delay and choice (not sample) phases impaired DNMTP performance. Optogenetic activation of A2ARs in the medial prefrontal cortex selectively at the delay (not sample or choice) phase improved DNMTP performance. The corticostriatal A2AR control of spatial WM was specific for a novel but not well-trained DNMTP task. Focal dorsomedial striatum A2AR knockdown or KW6002 improved DNMTP performance in mice. Last, KW6002 improved spatial WM in delayed match-to-sample and delayed match-to-place tasks of normal and dopamine-depleted cynomolgus monkeys. CONCLUSIONS: The A2ARs in striatopallidal and medial prefrontal cortex neurons exert distinctive control of WM maintenance and retrieval to achieve cognitive stability and flexibility. The procognitive effect of KW6002 in nonhuman primates provides the preclinical data to translate A2AR antagonists for improving cognitive impairments in Parkinson's disease.

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy.

Synucleinopathy is characterized by abnormal accumulation of misfolded α-synuclein (α-Syn)-positive cytoplasmic inclusions and by neurodegeneration and cognitive impairments, but the pathogenesis mechanism of synucleinopathy remains to be defined. Using a transmission model of synucleinopathy by intracerebral injection of preformed A53T α-Syn fibrils, we investigated whether aberrant adenosine A2A receptor (A2AR) signaling contributed to pathogenesis of synucleinopathy. We demonstrated that intra-hippocampal injection of preformed mutant α-Syn fibrils triggered a striking and selective induction of A2AR expression which was closely co-localized with pSer129 α-Syn-rich inclusions in neurons and glial cells of hippocampus. Importantly, by abolishing aberrant A2AR signaling triggered by mutant α-Syn, genetic deletion of A2ARs blunted a cascade of pathological events leading to synucleinopathy, including pSer129 α-Syn-rich and p62-positive aggregates, NF-κB activation and astrogliosis, apoptotic neuronal cell death and working memory deficits without affecting motor activity. These findings define α-Syn-triggered aberrant A2AR signaling as a critical pathogenesis mechanism of synucleinopathy with dual controls of cognition and neurodegeneration by modulating α-Syn aggregates. Thus, aberrant A2AR signaling represents a useful biomarker as well as a therapeutic target of synucleinopathy.

Proteomic analysis of purified Newcastle disease virus particles.

BACKGROUND: Newcastle disease virus (NDV) is an enveloped RNA virus, bearing severe economic losses to the poultry industry worldwide. Previous virion proteomic studies have shown that enveloped viruses carry multiple host cellular proteins both internally and externally during their life cycle. To address whether it also occurred during NDV infection, we performed a comprehensive proteomic analysis of highly purified NDV La Sota strain particles. RESULTS: In addition to five viral structural proteins, we detected thirty cellular proteins associated with purified NDV La Sota particles. The identified cellular proteins comprised several functional categories, including cytoskeleton proteins, annexins, molecular chaperones, chromatin modifying proteins, enzymes-binding proteins, calcium-binding proteins and signal transduction-associated proteins. Among these, three host proteins have not been previously reported in virions of other virus families, including two signal transduction-associated proteins (syntenin and Ras small GTPase) and one tumor-associated protein (tumor protein D52). The presence of five selected cellular proteins (i.e., ß-actin, tubulin, annexin A2, heat shock protein Hsp90 and ezrin) associated with the purified NDV particles was validated by Western blot or immunogold labeling assays. CONCLUSIONS: The current study presented the first standard proteomic profile of NDV. The results demonstrated the incorporation of cellular proteins in NDV particles, which provides valuable information for elucidating viral infection and pathogenesis.

Profiling of cellular proteins in porcine reproductive and respiratory syndrome virus virions by proteomics analysis.

BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is an enveloped virus, bearing severe economic consequences to the swine industry worldwide. Previous studies on enveloped viruses have shown that many incorporated cellular proteins associated with the virion's membranes that might play important roles in viral infectivity. In this study, we sought to proteomically profile the cellular proteins incorporated into or associated with the virions of a highly virulent PRRSV strain GDBY1, and to provide foundation for further investigations on the roles of incorporated/associated cellular proteins on PRRSV's infectivity. RESULTS: In our experiment, sixty one cellular proteins were identified in highly purified PRRSV virions by two-dimensional gel electrophoresis coupled with mass spectrometric approaches. The identified cellular proteins could be grouped into eight functional categories including cytoskeletal proteins, chaperones, macromolecular biosynthesis proteins, metabolism-associated proteins, calcium-dependent membrane-binding proteins and other functional proteins. Among the identified proteins, four have not yet been reported in other studied envelope viruses, namely, guanine nucleotide-binding proteins, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase, peroxiredoxin 1 and galectin-1 protein. The presence of five selected cellular proteins (i.e., ß-actin, Tubulin, Annexin A2, heat shock protein Hsp27, and calcium binding proteins S100) in the highly purified PRRSV virions was validated by Western blot and immunogold labeling assays. CONCLUSIONS: Taken together, the present study has demonstrated the incorporation of cellular proteins in PRRSV virions, which provides valuable information for the further investigations for the effects of individual cellular proteins on the viral replication, assembly, and pathogenesis.

Proteomic analysis of purified coronavirus infectious bronchitis virus particles.

BACKGROUND: Infectious bronchitis virus (IBV) is the coronavirus of domestic chickens causing major economic losses to the poultry industry. Because of the complexity of the IBV life cycle and the small number of viral structural proteins, important virus-host relationships likely remain to be discovered. Toward this goal, we performed two-dimensional gel electrophoresis fractionation coupled to mass spectrometry identification approaches to perform a comprehensive proteomic analysis of purified IBV particles. RESULTS: Apart from the virus-encoded structural proteins, we detected 60 host proteins in the purified virions which can be grouped into several functional categories including intracellular trafficking proteins (20%), molecular chaperone (18%), macromolcular biosynthesis proteins (17%), cytoskeletal proteins (15%), signal transport proteins (15%), protein degradation (8%), chromosome associated proteins (2%), ribosomal proteins (2%), and other function proteins (3%). Interestingly, 21 of the total host proteins have not been reported to be present in virions of other virus families, such as major vault protein, TENP protein, ovalbumin, and scavenger receptor protein. Following identification of the host proteins by proteomic methods, the presence of 4 proteins in the purified IBV preparation was verified by western blotting and immunogold labeling detection. CONCLUSIONS: The results present the first standard proteomic profile of IBV and may facilitate the understanding of the pathogenic mechanisms.

Genomic analysis of one Chinese strain YS07 of infectious bursal disease virus reveals unique genetic diversity.

The complete genome sequence of infectious bursal disease virus (IBDV) YS07 strain with low mortality isolated from Guangdong province of China in 2007 was reported in this study. The genome sequences and deduced amino acid (aa) sequences of YS07 were compared with that of previously reported IBDV strains. Phylogenetic analyses based on the deduced aa sequences of VP5, polyprotein, and VP1 protein revealed that YS07 bears its origin from European very virulent (vv) IBDV strains. Multiple aa sequences alignment revealed that YS07 contained a diversified genetic composition being characteristic to vv, variant, classical, and attenuated IBDV strains as well as its own unique ones. Our findings suggest that IBDV strains in China may gradually experience adaptive evolution due to immune pressure from intensive vaccination and demonstrate that the determination and analysis of full genome sequences is a valuable tool for studying the relationship between genetic composition and pathogenicity of IBDV strains.

Human leukocyte antigen class I polymorphism in Miao, Bouyei, and Shui ethnic minorities of Guizhou, China.

The majority of Miaos, Bouyeis, and Shuis are distributed in the Guizhou province of southwest China. They live within vast areas, while each ethnicity lives in individual concentrated communities in small areas. Their origin, migration, and relationship have long been interesting to anthropologists. In the present study, polymorphism of HLA-A, -B, and -C genes was investigated using the sequencing-based typing method in the Miao, Bouyei, and Shui from Guizhou, southwest China. Generally, Miao, Bouyei, and Shui share the most high-frequency alleles, suggesting that these three ethnic groups might be subject to intensive gene exchange because of their close location. However, it appears that some alleles distribute ethnic-specifically for each ethnicity. The dendrogram constructed according to the neighbor-joining method demonstrates that Miao, Bouyei, and Shui cluster together and form a branch with other southern Chinese ethnic groups, indicating that Miao, Bouyei, and Shui are three genetically close ethnic groups and inherit more characteristics of southern Chinese populations. The study will increase our understanding of the HLA polymorphism in Chinese populations.

HLA class II polymorphisms associated with the physiologic characteristics defined by Traditional Chinese Medicine: linking modern genetics with an ancient medicine.

OBJECTIVES: The aim of this study was to test whether human leukocyte antigen (HLA) polymorphism contributes to the physical constitutions classified in Traditional Chinese Medicine (TCM). DESIGN: Seven hundred six (706) individuals of the Han ethnic group inhabiting South China were classified into 7 TCM constitution groups, according to the criteria described in Theories of Physical Constitutions of Traditional Chinese Medicine, and the distributions of HLA-DRB1, DPB1, and DQB1 were investigated using the polymerase chain reaction-sequencing-based typing method. RESULTS: The allele frequencies of DPB1*0501 in the Yin-deficiency group, DRB1*09012 in the Phlegm-wetness group, and DQB1*03032 in the Qi-deficiency and Phlegm-wetness groups were significantly different from that of the corresponding alleles in the Normality constitution, suggesting those alleles might be group-specific alleles and thus related to a particular constitution. Based on our analysis of serological groups of HLA, the associations of DR*04 with the Blood-stasis group and DQ*09 with the Qi-deficiency and Phlegm-wetness groups were observed. CONCLUSIONS: This was the first study to systematically investigate the relationship between HLA and TCM constitution using a high-resolution typing technique. The results suggested a genetic basis for the classification of physical constitution in TCM. This study laid the foundation, for the first time ever, toward gaining insight into the theory of traditional medicine using modern biological approaches.