Association between serum copper levels and stroke in the general population: A nationally representative study.

OBJECTIVES: The objective was to explore the association between serum copper levels and the prevalence of stroke. METHODS: Data were obtained from 3 consecutive National Health and Nutrition Examination Survey (NHANES) cycles (2011-2016). Weighted multivariable logistic regression analysis was conducted to evaluate the association between serum copper levels and self-reported stroke. RESULTS: A total of 5,151 adults met the inclusion criteria. A total of 181 (3.51%) stroke patients were identified. In comparison to individuals with serum copper levels in the lowest tertile (<16.4 µmol/l), those with levels in the middle tertile (16.4-19.8 µmol/l) had an odds ratio (OR) of 0.99 (95% confidence interval [CI]: 0.44-2.25), while those with levels in the highest tertile (>19.8 µmol/l) had an OR of 2.36 (95% CI: 1.01-5.52). Furthermore, each standard deviation (SD) increase in serum copper was found to be positively associated with the prevalence of stroke, with an OR of 1.44 (95% CI: 1.11-1.86). Dose‒response analysis showed a positive linear association between serum copper levels and stroke (Pnonlinearity=0.554). CONCLUSIONS: This cross-sectional study suggested a positive association between serum copper levels and stroke among American adults.

Rewiring of 3D Chromatin Topology Orchestrates Transcriptional Reprogramming and the Development of Human Dilated Cardiomyopathy.

BACKGROUND: Transcriptional reconfiguration is central to heart failure, the most common cause of which is dilated cardiomyopathy (DCM). The effect of 3-dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive. METHODS: We generated a compendium of 3-dimensional epigenome and transcriptome maps from 101 biobanked human DCM and nonfailing heart tissues through highly integrative chromatin immunoprecipitation (H3K27ac [acetylation of lysine 27 on histone H3]), in situ high-throughput chromosome conformation capture, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and RNA sequencing. We used human induced pluripotent stem cell-derived cardiomyocytes and mouse models to interrogate the key transcription factor implicated in 3-dimensional chromatin organization and transcriptional regulation in DCM pathogenesis. RESULTS: We discovered that the active regulatory elements (H3K27ac peaks) and their connectome (H3K27ac loops) were extensively reprogrammed in DCM hearts and contributed to transcriptional dysregulation implicated in DCM development. For example, we identified that nontranscribing NPPA-AS1 (natriuretic peptide A antisense RNA 1) promoter functions as an enhancer and physically interacts with the NPPA (natriuretic peptide A) and NPPB (natriuretic peptide B) promoters, leading to the cotranscription of NPPA and NPPB in DCM hearts. We revealed that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (compartments, topologically associating domains) and their anchors unexpectedly had equivalent chromatin accessibility. We discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for HAND1 (heart and neural crest derivatives expressed 1), a key transcription factor involved in early cardiogenesis. In line with this, its protein expression was upregulated in human DCM and mouse failing hearts. To further validate whether HAND1 is a causal driver for the reprogramming of enhancer-promoter connectome in DCM hearts, we performed comprehensive 3-dimensional epigenome mappings in human induced pluripotent stem cell-derived cardiomyocytes. We found that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced a distinct gain of enhancer-promoter connectivity and correspondingly increased the expression of their connected genes implicated in DCM pathogenesis, thus recapitulating the transcriptional signature in human DCM hearts. Electrophysiology analysis demonstrated that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in dilated cardiac remodeling with impaired contractility/Ca2+ handling in cardiomyocytes, increased ratio of heart weight/body weight, and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM. CONCLUSIONS: This study provided novel chromatin topology insights into DCM pathogenesis and illustrated a model whereby a single transcription factor (HAND1) reprograms the genome-wide enhancer-promoter connectome to drive DCM pathogenesis.

Association between triglyceride glucose index and arterial stiffness and coronary artery calcification: a systematic review and exposure-effect meta-analysis.

BACKGROUND: The triglyceride and glucose (TyG) index has been linked to various cardiovascular diseases. However, it's still unclear whether the TyG index is associated with arterial stiffness and coronary artery calcification (CAC). METHODS: We conducted a systematic review and meta-analysis of relevant studies until September 2022 in the PubMed, Cochrane Library, and Embase databases. We used a random-effects model to calculate the pooled effect estimate and the robust error meta-regression method to summarize the exposure-effect relationship. RESULTS: Twenty-six observational studies involving 87,307 participants were included. In the category analysis, the TyG index was associated with the risk of arterial stiffness (odds ratio [OR]: 1.83; 95% CI 1.55-2.17, I2 = 68%) and CAC (OR: 1.66; 95% CI 1.51-1.82, I2 = 0). The per 1-unit increment in the TyG index was also associated with an increased risk of arterial stiffness (OR: 1.51, 95% CI 1.35-1.69, I2 = 82%) and CAC (OR: 1.73, 95% CI 1.36-2.20, I2 = 51%). Moreover, a higher TyG index was shown to be a risk factor for the progression of CAC (OR = 1.66, 95% CI 1.21-2.27, I2 = 0, in category analysis, OR = 1.47, 95% CI 1.29-1.68, I2 = 41% in continuity analysis). There was a positive nonlinear association between the TyG index and the risk of arterial stiffness (Pnonlinearity < 0.001). CONCLUSION: An elevated TyG index is associated with an increased risk of arterial stiffness and CAC. Prospective studies are needed to assess causality.

U-shaped association between the triglyceride-glucose index and atrial fibrillation incidence in a general population without known cardiovascular disease.

OBJECTIVE: The triglyceride-glucose (TyG) index has been shown to be a new alternative measure for insulin resistance. However, no study has attempted to investigate the association of the TyG index with incident atrial fibrillation (AF) in the general population without known cardiovascular diseases. METHODS: Individuals without known cardiovascular diseases (heart failure, coronary heart disease, or stroke) from the Atherosclerosis Risk in Communities (ARIC) cohort were recruited. The baseline TyG index was calculated as the Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The association between the baseline TyG index and incident AF was examined using Cox regression. RESULTS: Of 11,851 participants, the mean age was 54.0 years; 6586 (55.6%) were female. During a median follow-up of 24.26 years, 1925 incidents of AF cases (0.78/per 100 person-years) occurred. An increased AF incidence with a graded TyG index was found by Kaplan‒Meier curves (P < 0.001). In multivariable-adjusted analysis, both < 8.80 (adjusted hazard ratio [aHR] = 1.15, 95% confidence interval [CI] 1.02, 1.29) and > 9.20 levels (aHR 1.18, 95% CI 1.03, 1.37) of the TyG index were associated with an increased risk of AF compared with the middle TyG index category (8.80-9.20). The exposure-effect analysis confirmed the U-shaped association between the TyG index and AF incidence (P = 0.041). Further sex-specific analysis showed that a U-shaped association between the TyG index and incident AF still existed in females but not in males. CONCLUSIONS: A U-shaped association between the TyG index and AF incidence is observed in Americans without known cardiovascular diseases. Female sex may be a modifier in the association between the TyG index and AF incidence.

Prevalence estimates of the insulin resistance and associated prevalence of heart failure among United Status adults.

BACKGROUND: The triglyceride glucose (TyG) index, a metric for estimating insulin resistance (IR), is linked with cardiovascular disease (CVD) morbidity and mortality among the population regardless of diabetic status. However, IR prevalence and the association between the TyG index and heart failure (HF) in Americans is unclear. METHODS: The Nation Health and Nutrition Examination Survey (NHANES) (2009-2018) dataset was used. IR was defined by homeostatic model assessment of insulin resistance (HOMA-IR) > 2.0 and 1.5. The TyG index was calculated as Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. A weighted logistic regression was applied to evaluate the association between the TyG index and the prevalence of HF. RESULTS: This study comprised 12,388 people, including 322 (2.6%) individuals with HF. The average prevalence of IR was found to be 13.9% and 22.7% for cutoff values greater than 2.0 and 1.5, respectively. HOMA-IR and the TyG index showed a moderate correlation (r = 0.30). There is a significant positive association between the TyG index and HF prevalence (per 1-unit increment; adjusted OR [aOR]: 1.34; 95% confidence interval [CI]: 1.02-1.76). Patients with higher TyG values were associated with a prevalence of HF (OR:1.41; 95% CI: 1.01,1.95) (quartiles 4 vs 1-3). The TyG index is associated with a higher prevalence of dyslipidemia, coronary heart disease, and hypertension but not a stroke (cerebrovascular disease). CONCLUSIONS: Our results show that IR does not considerably increase from 2008 to 2018 in American adults. A moderate correlation is noted between HOMA-IR and the TyG index. TyG index is associated with the prevalence of HF, as were other cardiovascular diseases.

CRISPR activation of endogenous genes reprograms fibroblasts into cardiovascular progenitor cells for myocardial infarction therapy.

Fibroblasts can be reprogrammed into cardiovascular progenitor cells (CPCs) using transgenic approaches, although the underlying mechanism remains unclear. We determined whether activation of endogenous genes such as Gata4, Nkx2.5, and Tbx5 can rapidly establish autoregulatory loops and initiate CPC generation in adult extracardiac fibroblasts using a CRISPR activation system. The induced fibroblasts (>80%) showed phenotypic changes as indicated by an Nkx2.5 cardiac enhancer reporter. The progenitor characteristics were confirmed by colony formation and expression of cardiovascular genes. Cardiac sphere induction segregated the early and late reprogrammed cells that can generate functional cardiomyocytes and vascular cells in vitro. Therefore, they were termed CRISPR-induced CPCs (ciCPCs). Transcriptomic analysis showed that cell cycle and heart development pathways were important to accelerate CPC formation during the early reprogramming stage. The CRISPR system opened the silenced chromatin locus, thereby allowing transcriptional factors to access their own promoters and eventually forming a positive feedback loop. The regenerative potential of ciCPCs was assessed after implantation in mouse myocardial infarction models. The engrafted ciCPCs differentiated into cardiovascular cells in vivo but also significantly improved contractile function and scar formation. In conclusion, multiplex gene activation was sufficient to drive CPC reprogramming, providing a new cell source for regenerative therapeutics.

Toxicity of environmentally relevant concentration of PFAS chemicals in Lumbriculus variegatus (Oligochaeta, Lumbriculidae) - A multi-bioindicator study.

PFAS, or per- and polyfluoroalkyl substances, are a family of man-made chemicals found in a variety of products from non-stick cookware and food wrappers to firefighting foams. PFAS are persistent and widely distributed in the environment, including aquatic environments. In this study we examined the impact of PFAS chemicals on the physiological and behavioral endpoints of Lumbriculus variegatus (i.e., blackworms). Lumbriculus variegatus is a species of freshwater annelid worm that plays key roles in shallow freshwater ecosystems. At an environmentally relevant concentration of 1 µg/L, 12-day aqueous exposure to long chain PFAS, including PFOA, PFOS and PFDA, each markedly slowed the pulse rate of the dorsal blood vessel in L. variegatus, indicating a suppressive effect on blood circulation. The mean pulse rate was reduced from 9.6 beats/minute to 6.2 and 7.0 beats/min in PFOA and PFOS, respectively (P < 0.0001). Further, PFOA, PFOS and PFDA reduced the escape responsiveness of L. variegatus to physical stimulation. The percentage of worms showing normal escape behavior was reduced from 99.0% in control to 90.6% in the PFOS exposed group (P < 0.01). In a chronic (4 week) growth study, exposure to overlying water and sediment spiked with PFOA, PFOS or PFDA reduced the total biomass and the number of worms, indicating a suppressive effect on worm population growth. For instance, PFOA and PFDA reduced the total dry biomass by 26.3% and 28.5%, respectively, compared to the control (P < 0.05). The impact of PFAS on blackworm physiology is accompanied by an increase in lipid peroxidation. The level of malondialdehyde (MDA), an indicator of lipid peroxidation, and catalase, a major antioxidant enzyme, were markedly increased in PFOA, PFOS and PFDA exposed groups. Interestingly, exposure to PFHxA, a short chain PFAS, had no detectable effect on any of the measured endpoints. Our results demonstrate that L. variegatus is highly sensitive to the toxic impact of long chain PFAS chemicals as measured by multiple endpoints including blood circulation, behavior, and population growth. Such toxicity may have a detrimental impact on L. variegatus and the freshwater ecosystems where it resides.

The HVCN1 voltage-gated proton channel contributes to pH regulation in canine ventricular myocytes.

Regulation of intracellular pH (pHi ) in cardiomyocytes is crucial for cardiac function; however, currently known mechanisms for direct or indirect extrusion of acid from cardiomyocytes seem insufficient for energetically efficient extrusion of the massive H+ loads generated under in vivo conditions. In cardiomyocytes, voltage-sensitive H+ channel activity mediated by the HVCN1 proton channel would be a highly efficient means of disposing of H+ , while avoiding Na+ loading, as occurs during direct acid extrusion via Na+ /H+ exchange or indirect acid extrusion via Na+ -HCO3- cotransport. PCR and immunoblotting demonstrated expression of HVCN1 mRNA and protein in canine heart. Patch clamp analysis of canine ventricular myocytes revealed a voltage-gated H+ current that was highly H+ -selective. The current was blocked by external Zn2+ and the HVCN1 blocker 5-chloro-2-guanidinobenzimidazole. Both the gating and Zn2+ blockade of the current were strongly influenced by the pH gradient across the membrane. All characteristics of the observed current were consistent with the known hallmarks of HVCN1-mediated H+ current. Inhibition of HVCN1 and the NHE1 Na+ /H+ exchanger, singly and in combination, showed that either mechanism is largely sufficient to maintain pHi in beating cardiomyocytes, but that inhibition of both activities causes rapid acidification. These results show that HVCN1 is expressed in canine ventricular myocytes and provides a major H+ extrusion activity, with a capacity similar to that of NHE1. In the beating heart in vivo, this activity would allow Na+ -independent extrusion of H+ during each action potential and, when functionally coupled with anion transport mechanisms, could facilitate transport-mediated CO2 disposal. KEY POINTS: Intracellular pH (pHi ) regulation is crucial for cardiac function, as acidification depresses contractility and causes arrhythmias. H+ ions are generated in cardiomyocytes from metabolic processes and particularly from CO2 hydration, which has been shown to facilitate CO2 venting from mitochondria. Currently, the NHE1 Na+ /H+ exchanger is viewed as the dominant H+ extrusion mechanism in cardiac muscle. We show that the HVCN1 voltage-gated proton channel is present and functional in canine ventricular myocytes, and that HVCN1 and NHE1 both contribute to pHi regulation. HVCN1 provides an energetically efficient mechanism of H+ extrusion that would not cause Na+ loading, which can cause pathology, and that could contribute to transport-mediated CO2 disposal. These results provide a major advance in our understanding of pHi regulation in cardiac muscle.

Relationship between the triglyceride-glucose index and risk of cardiovascular diseases and mortality in the general population: a systematic review and meta-analysis.

BACKGROUND: The triglyceride-glucose (TyG) index is a new alternative measure for insulin resistance. This meta-analysis was conducted to assess the associations of the TyG index with the risks of cardiovascular diseases and mortality in the general population. METHODS: The PubMed, Cochrane Library and Embase databases were searched for randomized controlled trials or observational cohort studies reporting associations of the TyG index with cardiovascular diseases and mortality from inception to April 16, 2022. Effect sizes were pooled using random-effects models. Robust error meta-regression methods were applied to fit nonlinear dose-response associations. Evidence quality levels and recommendations were assessed using the Grading of Recommendations Assessment, Development and Evaluation system (GRADE). RESULTS: Twelve cohort studies (6 prospective and 6 retrospective cohorts) involving 6,354,990 participants were included in this meta-analysis. Compared with the lowest TyG index category, the highest TyG index was related to a higher incidence of coronary artery disease (CAD) (3 studies; hazard ratio [HR] = 2.01; 95% confidence interval [CI] 1.68-2.40; I2 = 0%), myocardial infarction (MI) (2 studies; HR = 1.36; 95% CI 1.18-1.56; I2 = 35%), and composite cardiovascular disease (CVD) (5 studies; HR = 1.46; 95% CI 1.23-1.74; I2 = 82%). However, there was no association between the TyG index and mortality (cardiovascular mortality [3 studies; HR = 1.10; 95% CI 0.82-1.47; I2 = 76%] or all-cause mortality [4 studies; HR = 1.08; 95% CI 0.92-1.27; I2 = 87%]). In the dose-response analysis, there was a linear association of the TyG index with the risk of CAD (Pnonlinear = 0.3807) or CVD (Pnonlinear = 0.0612). GRADE assessment indicated very low certainty for CVD, MI, cardiovascular mortality and all-cause mortality, and moderate certainty for CAD. CONCLUSIONS: Based on our current evidence, a higher TyG index may be associated with an increased incidence of CAD (moderate certainty), MI (very low certainty) and CVD (very low certainty) in the general population. There is a potential linear association of the TyG index with CAD and the composite CVD incidence. Further prospective studies (especially in non-Asians) are needed to confirm our findings.

Liver fibrosis scores and prognosis in patients with cardiovascular diseases: A systematic review and meta-analysis.

BACKGROUND: In patients with nonalcoholic fatty liver disease, liver fibrosis was associated with a higher risk of cardiovascular events. However, the relationship between liver fibrosis scores and clinical outcomes in patients with cardiovascular disease remains unclear. METHODS: Searching from PubMed, EMBASE and Cochrane Library databases yielded cohort studies that reported adjusted effect size between liver fibrosis scores (Fibrosis-4 score [FIB-4] or NAFLD fibrosis score [NFS]) and prognosis in patients with cardiovascular disease. The effect size was computed using a random-effects model. RESULTS: This meta-analysis included twelve cohort studies involving 25,252 patients with cardiovascular disease. Participants with the highest baseline level of FIB-4 or NFS had a significantly increased risk of cardiovascular events (FIB-4, HR: 1.75, 95% CI: 1.53-2.00, I 2  = 0%; NFS, HR: 1.92, 95% CI: 1.50-2.47, I 2  = 47%). This finding was consistent with the analysis of FIB-4 or NFS as a continuous variable (per 1-unit increment FIB-4, HR: 1.15, 95% CI: 1.06-1.24, I 2  = 72%; NFS, HR: 1.15, 95% CI: 1.07-1.24, I 2  = 71%). Furthermore, participants with the highest levels of FIB-4 or NFS had a greater risk of cardiovascular mortality (FIB-4, HR: 2.07, 95% CI: 1.19-3.61, I 2  = 89%; NFS, HR: 3.72, 95% CI: 2.62-5.29, I 2  = 60%) and all-cause mortality (FIB-4, HR: 1.81, 95% CI: 1.24-2.66, I 2  = 90%; NFS, HR: 3.49, 95% CI: 2.82-4.31, I 2  = 25%). This result was also consistent as a continuous variable. CONCLUSION: Higher levels of FIB-4 and NFS are related to an increased risk of cardiovascular events, cardiovascular mortality and all-cause mortality in patients with cardiovascular disease.

Prevalence of NSAID use among people with COVID-19 and the association with COVID-19-related outcomes: Systematic review and meta-analysis.

AIM: Recent reports of potential harmful effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in treating patients with coronavirus disease 2019 (COVID-19) have raised great concern. METHODS: We searched the PubMed, EMBASE, Cochrane Library and MedRxiv databases to examine the prevalence of NSAID use and associated COVID-19 risk, outcomes and safety. RESULTS: Twenty-five studies with a total of 101 215 COVID-19 patients were included. Prevalence of NSAID use among COVID-19 patients was 19% (95% confidence interval [CI] 14-23%, no. of studies [n] = 22) and NSAID use prior to admission or diagnosis of COVID-19 was not associated with an increased risk of COVID-19 (adjusted odds ratio [aOR] = 0.93, 95% CI 0.82-1.06, I2  = 34%, n = 3), hospitalization (aOR = 1.06, 95% CI 0.76-1.48, I2  = 81%, n = 5), mechanical ventilation (aOR = 0.71, 95% CI 0.47-1.06, I2  = 38%, n = 4) or length of hospital stay. Moreover, prior use of NSAIDs was associated with a decreased risk of severe COVID-19 (aOR = 0.79, 95% CI 0.71-0.89, I2  = 0%, n = 7) and death (aOR = 0.68, 95% CI 0.52-0.89, I2 = 85%, n = 10). Prior NSAID administration might also be associated with an increased risk of stroke (aOR = 2.32, 95% CI 1.04-5.2, I2  = 0%, n = 2), but not myocardial infarction (aOR = 1.49, 95% CI 0.25-8.92, I2  = 0, n = 2) and composite thrombotic events (aOR = 1.56, 95% CI 0.66-3.69, I2  = 52%, n = 2). CONCLUSION: Based on current evidence, NSAID use prior to admission or diagnosis of COVID-19 was not linked with increased odds or exacerbation of COVID-19. NSAIDs might provide a survival benefit, although they might potentially increase the risk of stroke. Controlled trials are still required to further assess the clinical benefit and safety (e.g., stroke and acute renal failure) of NSAIDs in treating patients with COVID-19.

Association of motor index scores with fall incidence among community-dwelling older people.

BACKGROUND: Several kinds of motor dysfunction have been studied for predicting future fall risk in community-dwelling older individuals. However, no study has tested the ability of the fine motor index (FINEA) and gross motor index (GROSSA) to predict the risk of falling, as well as the specific fall type. OBJECTIVE: We investigated the associations of FINEA/GROSSA scores with fall risk, explained falls, and unexplained falls. METHODS: A total of 6267 community-dwelling adults aged ≥ 50 years from the Irish Longitudinal Study on Aging (TILDA) cohort were included. First, the associations of FINEA and GROSSA scores with the history of total falls, explained falls and unexplained falls were assessed in a cross-sectional study and further verified in a prospective cohort after 2 years of follow-up by Poisson regression analysis. RESULTS: We found that high FINEA and GROSSA scores were positively associated with almost all fall histories (FINEA scores: total falls: adjusted prevalence ratio [aPR] = 1.28, P = 0.009; explained falls: aPR = 1.15, P = 0.231; unexplained falls: aPR = 1.88, P < 0.001; GROSSA scores: total falls: aPR = 1.39, P < 0.001; explained falls: aPR = 1.28, P = 0.012; unexplained falls: aPR = 2.18, P < 0.001) in a cross-sectional study. After 2 years of follow-up, high FINEA scores were associated with an increased incidence of total falls (adjusted rate ratio [aRR] = 1.42, P = 0.016) and explained falls (aRR = 1.51, P = 0.020) but not with unexplained falls (aRR = 1.41, P = 0.209). High GROSSA scores were associated with an increased incidence of unexplained falls (aRR = 1.57, P = 0.041) and were not associated with either total falls (aRR = 1.21, P = 0.129) or explained falls (aRR = 1.07, P = 0.656). Compared with individuals without limitations in either the FINEA or GROSSA, individuals with limitations in both indices had a higher risk of falls, including total falls (aRR = 1.35, P = 0.002), explained falls (aRR = 1.31, P = 0.033) and unexplained falls (aRR = 1.62, P = 0.004). CONCLUSION: FINEA scores were positively associated with accidental falls, while GROSSA scores were positively associated with unexplained falls. The group for whom both measures were impaired showed a significantly higher risk of both explained and unexplained falls. FINEA or GROSSA scores should be investigated further as possible tools to screen for and identify community-dwelling adults at high risk of falling.

Hydrogen sulfide restores sevoflurane postconditioning mediated cardioprotection in diabetic rats: Role of SIRT1/Nrf2 signaling-modulated mitochondrial dysfunction and oxidative stress.

Diabetic hearts are vulnerable to myocardial ischemia/reperfusion injury (IRI), but are insensitive to sevoflurane postconditioning (SPC), activating peroxiredoxins that confer cardioprotection. Previous studies have demonstrated that hydrogen sulfide (H2 S) can suppress oxidative stress of diabetic rats through increasing the expression of silent information regulator factor 2-related enzyme 1 (SIRT1), but whether cardioprotection by SPC can be restored afterward remains unclear. Diabetic rat was subjected to IRI (30 min of ischemia followed by 120 min reperfusion). Postconditioning treatment with sevoflurane was administered for 15 min upon the onset of reperfusion. The diabetic rats were treated with GYY4137 (H2 S donor) 5 days before the experiment. Myocardial infarct size, mitochondrial structure and function, ATP content, activities of complex I-IV, marker of oxidative stress, SIRT1, nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NADPH Oxidase-2 (Nox-2) protein expression were detected after reperfusion, and cardiac function was evaluated by echocardiography at 24 h after reperfusion. After H2 S activated SIRT1 in the impaired myocardium of diabetic rats, SPC significantly upregulated the expression of Nrf2 and its downstream mediator HO-1, thus reduced the expression of Nox-2. In addition, H2 S remarkably increased cytoplasmic and nuclear SIRT1 which was further enhanced by SPC. Furthermore, H2 S combined with SPC reduced the production of reactive oxygen species, increased the content of ATP, and maintained mitochondrial enzyme activity. Finally, myocardial infarct size and myocardium damage were decreased, and cardiac function was improved. Taken together, our study proved that H2 S could restore SPC-induced cardioprotection in diabetic rats by enhancing and promoting SIRT1/Nrf2 signaling pathway mediated mitochondrial dysfunction and oxidative stress.

Effect of non-vitamin K antagonist oral anticoagulants versus warfarin in heart failure patients with atrial fibrillation.

Several studies have investigated the efficacy and safety outcomes of non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin in patients with atrial fibrillation (AF) and heart failure (HF). Herein, this meta-analysis was aimed to compare the effect of NOACs with warfarin in this population. We systematically searched the PubMed database until December 2019 for studies that compared the effect of NOACs with warfarin in patients with AF and HF. Risk ratios (RRs) and 95% confidence intervals (CIs) were abstracted and then pooled using a random-effects model. A total of nine studies were included in this meta-analysis. Compared with warfarin use, the use of NOACs was significantly associated with reduced risks of stroke or systemic embolism (RR = 0.82 (95% CI, 0.73-0.92)), all-cause death (RR = 0.87 (95% CI, 0.80-0.94)), major bleeding (RR = 0.84; (95% CI, 0.74-0.97)), intracranial hemorrhage (RR = 0.50; 95% CI, 0.43-0.59), and hemorrhagic stroke (RR = 0.49 (95% CI, 0.38-0.63)). There were no differences in the risks of ischemic stroke (RR = 0.89 (95% CI, 0.75-1.04)) and gastrointestinal bleeding (RR = 1.11 (95% CI, 0.79-1.55)) in patients treated with NOACs versus warfarin. Compared with warfarin use, the use of NOACs had similar or lower risks of thromboembolic and bleeding events in patients with AF and HF.

The impact of chronic obstructive pulmonary disease on hospitalization and mortality in patients with heart failure.

BACKGROUND: Several studies have suggested that chronic obstructive pulmonary disease (COPD) could be predictive of the prognosis in patients with heart failure (HF), but yield conflicting findings. Therefore, we conducted a meta-analysis to examine the impact of COPD on adverse outcomes in patients with HF. METHODS: We systematically searched the databases of PubMed, EMBASE, Google Scholar, Cochrane library from inception to August 2020 for the relevant studies. Adjusted risk ratios (RRs) and confidence intervals (CIs) were collected and then pooled by the Review Manager version 5.30 software with a random-effects model. RESULTS: A total of 18 studies (6 post hoc analyses of trials and 12 observational studies) were included in this meta-analysis. COPD was associated with an increased risk of all-cause mortality (hospitalized HF: RR 1.43, 95% CI: 1.20-1.70; chronic HF: RR 1.24, 95% CI: 1.16-1.33), but not cardiovascular mortality, in patients with hospitalized HF or chronic HF. In addition, COPD was associated with increased risks of all-cause hospitalization (RR 1.31, 95% CI: 1.21-1.42) and HF hospitalization (RR 1.31, 95% CI: 1.21-1.42) in the chronic HF patients. CONCLUSIONS: COPD comorbidity could increase the risk of all-cause mortality of HF patients. Future research should confirm the findings on hospitalization because of the limited studies included for this outcome.

Effect of Rivaroxaban or Apixaban in Atrial Fibrillation Patients with Stage 4-5 Chronic Kidney Disease or on Dialysis.

BACKGROUND: Anticoagulant treatment in non-valvular atrial fibrillation (AF) patients with severe chronic kidney disease (CKD) or on dialysis remains a matter of debate. The object of this study was to quantify the benefit-risk profiles of rivaroxaban or apixaban versus warfarin in AF patients with stage 4-5 CKD or on dialysis. METHOD: A comprehensive search of the Cochrane Library, PubMed, Ovid, and Google Scholar databases was performed for eligible studies that comparing the effect and safety of rivaroxaban or apixaban versus warfarin in AF patients with stage 4-5 CKD or on dialysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were abstracted, and then pooled using a random-effects model. RESULTS: A total of seven studies, one post hoc analysis of RCT and six observational cohorts, were included in this meta-analysis. Compared with warfarin use, the use of rivaroxaban or apixaban was significantly associated with reduced risks of all-cause death (HR = 0.82, 95% CI 0.72-0.93) and gastrointestinal bleeding (HR = 0.87, 95% CI 0.80-0.95). There were no significant differences in the risks of stroke or systemic embolism (rivaroxaban, HR = 0.71, 95% CI 0.43-1.19; apixaban, HR = 0.86, 95%CI 0.68-1.09) and major bleeding (rivaroxaban, HR = 0.96, 95% CI 0.64-1.45; apixaban, HR = 0.56, 95%CI 0.28-1.12). CONCLUSIONS: Current evidence suggests that rivaroxaban or apixaban are safe and at least as effective as warfarin in patients with AF and stage 4-5 CKD or on dialysis.

Low vitamin D levels do not aggravate COVID-19 risk or death, and vitamin D supplementation does not improve outcomes in hospitalized patients with COVID-19: a meta-analysis and GRADE assessment of cohort studies and RCTs.

BACKGROUND: The associations between vitamin D and coronavirus disease 2019 (COVID-19) infection and clinical outcomes are controversial. The efficacy of vitamin D supplementation in COVID-19 is also not clear. METHODS: We identified relevant cohort studies that assessed the relationship between vitamin D, COVID-19 infection and associated death and randomized controlled trials (RCTs) that reported vitamin D supplementation on the outcomes in patients with COVID-19 by searching the PubMed, EMBASE, and medRxiv databases up to June 5th, 2021. Evidence quality levels and recommendations were assessed using the GRADE system. RESULTS: Eleven cohort studies with 536,105 patients and two RCTs were identified. Vitamin D deficiency (< 20 ng/ml) or insufficiency (< 30 ng/ml) was not associated with an significant increased risk of COVID-19 infection (OR for < 20 ng/ml: 1.61, 95% CI: 0.92-2.80, I2 = 92%) or in-hospital death (OR for < 20 ng/ml: 2.18, 95% CI: 0.91-5.26, I2 = 72%; OR for < 30 ng/ml: 3.07, 95% CI: 0.64-14.78, I2 = 66%). Each 10 ng/ml increase in serum vitamin D was not associated with a significant decreased risk of COVID-19 infection (OR: 0.92, 95% CI: 0.79-1.08, I2 = 98%) or death (OR: 0.65, 95% CI: 0.40-1.06, I2 = 79%). The overall quality of evidence (GRADE) for COVID-19 infection and associated death was very low. Vitamin D supplements did not significantly decrease death (OR: 0.57, I2 = 64%) or ICU admission (OR: 0.14, I2 = 90%) in patients with COVID-19. The level of evidence as qualified using GRADE was low. CONCLUSIONS: Current evidence suggested that vitamin D deficiency or insufficiency was not significantly linked to susceptibility to COVID-19 infection or its associated death. Vitamin D supplements did not significantly improve clinical outcomes in patients with COVID-19. The overall GRADE evidence quality was low, we suggest that vitamin D supplementation was not recommended for patients with COVID-19.

Effect of antidepressants on death in patients with heart failure: a systematic review and meta-analysis.

Depression is associated with an increased risk of death in patients with heart failure (HF); however, the association between the use of antidepressants and HF prognoses remains controversial. Therefore, this meta-analysis aimed to evaluate the effect of antidepressants on the risk of death in HF patients. We retrieved data from the PubMed and EMBASE databases until August 2019 for studies reporting the use of antidepressants in HF patients. Data were extracted from the eligible articles, and a random effects model was used to pool the effect estimates (risk ratios (RRs) and 95% confidence intervals (CIs)). A total of 8 studies were included in this meta-analysis. Overall, the use of antidepressants was associated with increased risks of all-cause death (RR = 1.27; 95% CI, 1.21-1.34) and cardiovascular death (RR = 1.14; 95% CI, 1.08-1.20) in HF patients with or without depression. Specifically, HF patients with depression taking antidepressants had increased risks of all-cause death (RR = 1.21; 95% CI, 1.16-1.27) and cardiovascular death (RR = 1.21; 95% CI, 1.13-1.30). Compared with nonusers, the use of selective serotonin reuptake inhibitors (SSRIs), tricyclics (TCAs), and selective serotonin reuptake inhibitors (SNRIs) significantly increased the rate of all-cause death (SSRIs (RR = 1.26; 95% CI, 1.19-1.32), TCAs (RR = 1.30; 95% CI, 1.16-1.46), and SNRIs (RR = 1.17; 95% CI, 1.08-1.26)) but not cardiovascular death (SSRIs (RR = 1.03; 95% CI, 0.84-1.26), TCAs (RR = 1.02; 95% CI, 0.86-1.21), and SNRIs (RR = 0.92; 95% CI, 0.48-1.78)). Based on current publications, the use of antidepressants could increase the risk of all-cause death in HF patients, regardless of whether they have depression or the type of antidepressants they use. Further study is needed to determine the relationship between antidepressant use and cardiovascular death.

Non-Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation and Peripheral Artery Disease: a Systematic Review and Meta-Analysis.

BACKGROUND: The efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) compared with warfarin in patients with atrial fibrillation (AF) and peripheral artery disease (PAD) remain largely unknown. Therefore, we conducted a meta-analysis to explore the effects of NOACs versus warfarin in this population. METHODS: We systematically searched the PubMed and Embase databases, with no linguistic restrictions, until December 2019 for relevant randomized controlled trials (RCTs) and observational studies. A random-effects model using an inverse variance method was selected to pool the risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: A total of six studies (three post hoc analyses of RCTs and three cohort studies) were included in this meta-analysis. Among AF patients treated with NOACs and warfarin, individuals with PAD had increased rates of all-cause death (RR = 1.26, 95% CI 1.07-1.48) and cardiovascular death (RR = 1.32, 95% CI 1.06-1.64) compared with those without PAD. In AF patients with PAD, we observed a similar risk of thromboembolic events, bleeding, and death with NOACs as with warfarin. In addition, there were no interactions between PAD and non-PAD subgroups regarding any of the reported outcomes of NOACs versus warfarin in AF patients (all Pinteraction > 0.05). CONCLUSIONS: Based on current evidence, AF patients with PAD are at a higher risk of death than those without PAD. Efficacy and safety outcomes with NOACs are comparable to those with warfarin, suggesting that the use of NOACs has effects similar to warfarin in AF patients with concomitant PAD.

Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation.

BACKGROUND: Human loss-of-function variants of ANK2 (ankyrin-B) are linked to arrhythmias and sudden cardiac death. However, their in vivo effects and specific arrhythmogenic pathways have not been fully elucidated. METHODS: We identified new ANK2 variants in 25 unrelated Han Chinese probands with ventricular tachycardia by whole-exome sequencing. The potential pathogenic variants were validated by Sanger sequencing. We performed functional and mechanistic experiments in ankyrin-B knockin (KI) mouse models and in single myocytes isolated from KI hearts. RESULTS: We detected a rare, heterozygous ANK2 variant (p.Q1283H) in a proband with recurrent ventricular tachycardia. This variant was localized to the ZU5C region of ANK2, where no variants have been previously reported. KI mice harboring the p.Q1283H variant exhibited an increased predisposition to ventricular arrhythmias after catecholaminergic stress in the absence of cardiac structural abnormalities. Functional studies illustrated an increased frequency of delayed afterdepolarizations and Ca2+ waves and sparks accompanied by decreased sarcoplasmic reticulum Ca2+ content in KI cardiomyocytes on isoproterenol stimulation. The immunoblotting results showed increased levels of phosphorylated ryanodine receptor Ser2814 in the KI hearts, which was further amplified on isoproterenol stimulation. Coimmunoprecipitation experiments demonstrated dissociation of protein phosphatase 2A from ryanodine receptor in the KI hearts, which was accompanied by a decreased binding of ankyrin-B to protein phosphatase 2A regulatory subunit B56α. Finally, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias in the KI mice. CONCLUSIONS: ANK2 p.Q1283H is a disease-associated variant that confers susceptibility to stress-induced arrhythmias, which may be prevented by the administration of metoprolol or flecainide. This variant is associated with the loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed afterdepolarization-mediated trigger activity, and arrhythmogenesis.