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Heart failure (HF) is a rising global cardiovascular epidemic driven by aging and chronic inflammation. As elderly populations continue to increase, precision treatments for age-related cardiac decline are urgently needed. Here we report that cardiac and blood expression of IGFBP7 is robustly increased in patients with chronic HF and in an HF mouse model. In a pressure overload mouse HF model, Igfbp7 deficiency attenuated cardiac dysfunction by reducing cardiac inflammatory injury, tissue fibrosis and cellular senescence. IGFBP7 promoted cardiac senescence by stimulating IGF-1R/IRS/AKT-dependent suppression of FOXO3a, preventing DNA repair and reactive oxygen species (ROS) detoxification, thereby accelerating the progression of HF. In vivo, AAV9-shRNA-mediated cardiac myocyte Igfbp7 knockdown indicated that myocardial IGFBP7 directly regulates pathological cardiac remodeling. Moreover, antibody-mediated IGFBP7 neutralization in vivo reversed IGFBP7-induced suppression of FOXO3a, restored DNA repair and ROS detoxification signals and attenuated pressure-overload-induced HF in mice. Consequently, selectively targeting IGFBP7-regulated senescence pathways may have broad therapeutic potential for HF.

Early identification of people with diabetes or prediabetes enables greater opportunities for glycemic control and management strategies to prevent related complications. To identify gaps in screening for these conditions, we examined population trends in receipt of timely glucose testing overall and in specific clinical subgroups.Using linked administrative databases, we conducted a retrospective cohort study of people aged 40 years and older without diabetes at baseline. Our primary outcome was up-to-date glucose testing, defined as having received testing at least once in the 3 years before each index year from 2010 to 2017, using linked administrative databases of people residing in Ontario, Canada. We calculated rates of up-to-date testing by age group, sex, ethnicity (South Asian, Chinese, general population) and comorbidities (hypertension, hyperlipidemia, cardiovascular disease).Over the 8-year study period, up-to-date glucose testing rates were stable at 67% for men and 77% for women (both relative risk 1.00 per year; 95% confidence interval 1.00-1.00). Testing rates were significantly lower in men than in women (all age groupsWe found lower glucose testing rates in younger men and people with hypertension. Our findings reinforce the need for initiatives to increase awareness of glycemic testing.

OBJECTIVE Heart failure (HF) often develops in patients with diabetes and is recognized for its role in increased cardiovascular morbidity and mortality in this population. Most existing models predict risk in patients with prevalent rather than incident diabetes and fail to account for sex differences in HF risk factors. We derived sex-specific models in Ontario, Canada to predict HF at diabetes onset and externally validated these models in the U.K. RESEARCH DESIGN AND METHODS Retrospective cohort study using international population-based data. Our derivation cohort comprised all Ontario residents aged ≥18 years who were diagnosed with diabetes between 2009 and 2018. Our validation cohort comprised U.K. patients aged ≥35 years who were diagnosed with diabetes between 2007 and 2017. Primary outcome was incident HF. Sex-stratified multivariable Fine and Gray subdistribution hazard models were constructed, with death as a competing event. RESULTS A total of 348,027 Ontarians (45% women) and 54,483 U.K. residents (45% women) were included. At 1, 5, and 9 years, respectively, in the external validation cohort, the C-statistics were 0.81 (95% CI 0.79–0.84), 0.79 (0.77–0.80), and 0.78 (0.76–0.79) for the female-specific model; and 0.78 (0.75–0.80), 0.77 (0.76–0.79), and 0.77 (0.75–0.79) for the male-specific model. The models were well-calibrated. Age, rurality, hypertension duration, hemoglobin, HbA1c, and cardiovascular diseases were common predictors in both sexes. Additionally, mood disorder and alcoholism (heavy drinker) were female-specific predictors, while income and liver disease were male-specific predictors. CONCLUSIONS Our findings highlight the importance of developing sex-specific models and represent an important step toward personalized lifestyle and pharmacologic prevention of future HF development.

Background: Cardiac hypertrophy is a key biological response to injurious stresses such as pressure overload and, when excessive, can lead to heart failure. Innate immune activation by danger signals, through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain 1 (Nod1) and its adaptor receptor-interacting protein 2 (RIP2), might play a major role in cardiac remodeling and progression to heart failure. We hypothesize that Nod1/RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone. Methods: To elucidate the contribution of Nod1/RIP2 signaling to cardiac hypertrophy, we randomized Nod1 –/– , RIP2 –/– , or wild-type mice to transverse aortic constriction or sham operations. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. Results: Nod1 and RIP2 proteins were upregulated in the heart after transverse aortic constriction, and this was paralleled by increased expression of mitochondrial proteins, including mitochondrial antiviral signaling protein (MAVS). Nod1 –/– and RIP2 –/– mice subjected to transverse aortic constriction exhibited better survival, improved cardiac function, and decreased cardiac hypertrophy. Downstream signal transduction pathways that regulate inflammation and fibrosis, including NF (nuclear factor) κB and MAPK (mitogen-activated protein kinase)-GATA4/p300, were reduced in both Nod1 –/– and RIP2 –/– mice after transverse aortic constriction compared with wild-type mice. Coimmunoprecipitation of extracted cardiac proteins and confocal immunofluorescence microscopy showed that Nod1/RIP2 interaction was robust and that this complex also included MAVS as an essential component. Suppression of MAVS expression attenuated the complex formation, NF κB signaling, and myocyte hypertrophy. Interrogation of mitochondrial function compared in the presence or ablation of MAVS revealed that MAVS serves to suppress mitochondrial energy output and mediate fission/fusion related dynamic changes. The latter is possibly linked to mitophagy during cardiomyocytes stress, which may provide an intriguing link between innate immune activation and mitochondrial energy balance under stress or injury conditions. Conclusions: We have identified that innate immune Nod1/RIP2 signaling is a major contributor to cardiac remodeling after stress. This process is critically joined by and regulated through the mitochondrial danger signal adapter MAVS. This novel complex coordinates remodeling, inflammatory response, and mitochondrial energy metabolism in stressed cardiomyocytes. Thus, Nod1/RIP2/MAVS signaling complex may represent an attractive new therapeutic approach toward heart failure.

Background: We previously found large variation among family physicians in adherence to the Canadian Cardiovascular Harmonization of National Guidelines Endeavour (C-CHANGE). We assessed the role of patient- and physician-level factors in the variation in adherence to recommendations for managing cardiovascular disease risk factors. Methods: We conducted a retrospective study using multilevel logistic regression analyses with the Electronic Medical Record Administrative data Linked Database (EMRALD) housed at ICES in Ontario. Five quality indicators based on C-CHANGE guidelines were modelled. Effects of clustering and between-group variation, patient-level (sociodemographics, comorbidities) and physician-level characteristics (demographic and practice information) were assessed to determine odds ratios of receiving C-CHANGE recommended care. Results: In all, 324 Ontario physicians practicing in 41 clinics who provided care to 227,999 adult patients were studied. We found significant variation in quality indicators, with 15% to 39% of the total variation attributable to nonpatient factors. The largest variation was in performing 2-hour plasma glucose testing in prediabetic patients. Patient-level factors most frequently associated with recommendation adherence included sex, age, and multi-comorbidities. Women were more likely than men to have their body mass index measured, and their blood pressure controlled, but less likely to receive antiplatelet medications and liver-enzyme testing if overweight or obese. Conclusions: The majority of variations in adherence were attributable to patient attributes, but a substantial proportion of unexplained variation was due to differences among physicians and clinics. This finding may signal suboptimal processes or structures and warrant further investigation to improve the quality of primary care management of cardiovascular disease in Ontario. Résumé: Contexte: Nous avions déjà constaté que l’observance des recommandations canadiennes en matière de prévention et de gestion des maladies cardiovasculaires de l’initiative C-CHANGE (Canadian Cardiovascular Harmonization of National Guidelines Endeavour) varie beaucoup d’un médecin de famille à l’autre. Nous avons évalué l’effet de caractéristiques des patients et des médecins sur l’observance de ces recommandations pour la gestion des facteurs de risque de maladies cardiovasculaires. Méthodologie: Nous avons mené une étude rétrospective reposant sur des analyses de régression logistique multiniveaux au sein de la base de données liée aux dossiers médicaux électroniques EMRALD (Electronic Medical Record Administrative data Linked Database) qui se trouve à l’ICES, en Ontario. Nous avons modélisé cinq indicateurs de la qualité en nous basant sur les recommandations de l’initiative C-CHANGE. Nous avons évalué les effets de regroupement, de la variation entre les groupes, des caractéristiques des patients (données sociodémographiques, maladies concomitantes), des caractéristiques des médecins (données démographiques et renseignements sur la pratique) afin de déterminer les risques relatifs approchés associés aux soins conformes aux recommandations de l’initiative C-CHANGE. Résultats: L’étude a porté sur un total de 324 médecins ontariens pratiquant dans 41 cliniques et ayant prodigué des soins à 227 999 adultes. Nous avons observé une variation significative entre les indicateurs de qualité, et de 15 % à 39 % de la variation totale était attribuable aux caractéristiques non reliées aux patients. La variation la plus importante concernait le test d’hyperglycémie provoquée (2 heures) chez les patients prédiabétiques. Les caractéristiques des patients qui étaient le plus souvent associées à l’observance des recommandations étaient le sexe, l’âge et la présence de multiples maladies concomitantes. L’indice de masse corporelle et la pression artérielle étaient plus souvent mesurés chez les femmes que chez les hommes, mais les femmes étaient moins susceptibles de recevoir un traitement antiplaquettaire ou de subir une analyse des enzymes hépatiques si elles étaient en surpoids ou obèses. Conclusions: La plus grande partie des variations dans l’observance des recommandations était liée aux caractéristiques des patients, mais une proportion importante de variations injustifiées était associée aux différences entre les médecins et entre les cliniques. Ces observations pourraient indiquer la présence de processus ou de structures sous-optimales et méritent une analyse approfondie qui permettra d’améliorer la qualité de la prise en charge des maladies cardiovasculaires par les médecins de soins primaires en Ontario.

The coronavirus disease 2019 (COVID-19) pandemic has affected health and economy worldwide on an unprecedented scale. Patients have diverse clinical outcomes, but those with preexisting cardiovascular disease, hypertension, and related conditions incur disproportionately worse outcome. The high infectivity of severe acute respiratory syndrome coronavirus 2 is in part related to new mutations in the receptor binding domain, and acquisition of a furin cleavage site in the S-spike protein. The continued viral shedding in the asymptomatic and presymptomatic individuals enhances its community transmission. The virus uses the angiotensin converting enzyme 2 receptor for internalization, aided by transmembrane protease serine 2 protease. The tissue localization of the receptors correlates with COVID-19 presenting symptoms and organ dysfunction. Virus-induced angiotensin converting enzyme 2 downregulation may attenuate its function, diminish its anti-inflammatory role, and heighten angiotensin II effects in the predisposed patients. Lymphopenia occurs early and is prognostic, potentially associated with reduction of the CD4+ and some CD8+ T cells. This leads to imbalance of the innate/acquired immune response, delayed viral clearance, and hyperstimulated macrophages and neutrophils. Appropriate type I interferon pathway activation is critical for virus attenuation and balanced immune response. Persistent immune activation in predisposed patients, such as elderly adults and those with cardiovascular risk, can lead to hemophagocytosis-like syndrome, with uncontrolled amplification of cytokine production, leading to multiorgan failure and death. In addition to the airways and lungs, the cardiovascular system is often involved in COVID-19 early, reflected in the release of highly sensitive troponin and natriuretic peptides, which are all extremely prognostic, in particular, in those showing continued rise, along with cytokines such as interleukin-6. Inflammation in the vascular system can result in diffuse microangiopathy with thrombosis. Inflammation in the myocardium can result in myocarditis, heart failure, cardiac arrhythmias, acute coronary syndrome, rapid deterioration, and sudden death. Aggressive support based on early prognostic indicators with expectant management can potentially improve recovery. Appropriate treatment for heart failure, arrhythmias, acute coronary syndrome, and thrombosis remain important. Specific evidence-based treatment strategies for COVID-19 will emerge with ongoing global collaboration on multiple approaches being evaluated. To protect the wider population, antibody testing and effective vaccine will be needed to make COVID-19 history.

Supplemental Digital Content is available in the text., Rationale: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. Objective: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. Methods and Results: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55–68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57–69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19–0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15–0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12–0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. Conclusions: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

Aims To evaluate the fracture risk among patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin. Methods and results We conducted a real-world nationwide retrospective cohort study using Taiwan’s National Health Insurance Research Database. All adult patients in Taiwan newly diagnosed with AF between 2012 and 2016 who received NOACs or warfarin were enrolled and followed up until 2017. Patients treated with NOACs were sub-grouped according to the NOAC used (dabigatran, rivaroxaban, and apixaban). Propensity score matching was performed for each head-to-head comparison. Cox regression analysis, with a shared frailty model, was used to calculate the adjusted hazard ratios (aHRs) for hip, vertebral, and humerus/forearm/wrist fractures. After matching, 19 414 patients were included (9707 in each NOAC and warfarin groups). The median follow-up time was 2.4 years. Compared with warfarin, NOACs were associated with a reduced fracture risk [aHR = 0.84, 95% confidence interval (CI) = 0.77–0.93; P Conclusion Compared with warfarin, NOAC was associated with a reduced fracture risk among AF patients. Therefore, if oral anticoagulants are indicated, NOACs rather than warfarin should be considered to lower the risk of fractures. However, further studies are needed to investigate the underlying mechanisms and elucidate causality.

Lipotoxicity is a recognized pathological trigger and accelerator of nonalcoholic steatohepatitis (NASH). However, the molecular basis of lipotoxicity-induced NASH remains elusive. Here, we systematically mapped the changes in hepatic transcriptomic landscapes in response to lipotoxic insults across multiple species. Conserved and robust activation of the arachidonic acid pathway, in particular the arachidonate 12-lipoxygenase (

IMA-1 targets the ALOX12-ACC1 interaction to both prevent and treat NASH without inducing hyperlipidemia.

Myocarditis and pericarditis may constitute adverse reactions of mRNA coronavirus disease 2019 (COVID-19) vaccines. This study aimed to document these reactions and to assess the association with patient sex and age. This is as an observational retrospective study using a case-non-case design (also called disproportionality study) on inflammatory heart reactions reported with mRNA COVID-19 vaccines within the World Health Organization (WHO) global safety database (VigiBase), up to June 30, 2021. Results are expressed using reporting odds ratios (RORs) and their 95% confidence interval (95% CI). Of 716,576 reports related to mRNA COVID-19 vaccines, 2,277 were cases of inflammatory heart reactions, including 1241 (55%) myocarditis and 851 (37%) pericarditis. The main age group was 18-29 years (704, 31%), and mostly male patients (1,555, 68%). Pericarditis onset was delayed compared with myocarditis with a median time to onset of 8 (3-21) vs. 3 (2-6) days, respectively (P = 0.001). Regarding myocarditis, an important disproportionate reporting was observed in adolescents (ROR, 22.3, 95% CI 19.2-25.9) and in 18-29 years old (ROR, 6.6, 95% CI 5.9-7.5) compared with older patients, as well as in male patients (ROR, 9.4, 95% CI 8.3-10.6). Reporting rate of myocarditis was increased in young adults and adolescents. Inflammatory heart reactions may rarely occur shortly following mRNA COVID-19 vaccination. Although an important disproportionate reporting of myocarditis was observed among adolescents and young adults, particularly in male patients, reporting rates support a very rare risk, that does not seem to compromise the largely positive benefit-risk balance of these vaccines. Furthermore, this study confirmed the value of disproportionality analyses for estimation of relative risks among subgroups of patients.

We aimed to determine whether hospital admissions during an extended holiday period (Chinese New Year) and weekends were associated with increased mortality risk from pulmonary embolism (PE), compared to admissions on weekdays. We conducted a nationwide retrospective cohort study using Taiwan’s National Health Insurance Research Database. Data of newly diagnosed PEs during the months of January and February from 2001 to 2017 were obtained from patient records and classified into three admission groups: Chinese New Year (≥ 4 consecutive holiday days), weekends, and weekdays. The adjusted odds ratios (aORs) (95% confidence intervals [CIs]) for 7-day and in-hospital mortality were calculated using multivariable logistic regression models. The 7-day and in-hospital mortality risks were higher for patients admitted during the Chinese New Year holiday (10.6% and 18.7%) compared to those admitted on weekends (8.4% and 16.1%) and weekdays (6.6% and 13.8%). These higher mortality risks for holiday admissions compared to weekday admissions were confirmed by multivariable analysis (7-day mortality: aOR = 1.68, 95% CI 1.15–2.44, P = 0.007; in-hospital mortality: aOR = 1.41, 95% CI 1.05–1.90, P = 0.022), with no subgroup effects by sex or age. Hospital admission for PE over an extended holiday period, namely Chinese New Year, was associated with an increased risk of mortality.

Background: A hallmark of heart failure pathologies is excessive and cumulative DNA damage, leading to an increased and accelerated cardiac cellular senescence. We aimed to investigate the role of DNA breaks in inducing inflammation leading to adverse remodeling, premature senescence, and cardiac dysfunction leading to onset of Heart Failure with preserved Ejection Fraction (HFpEF), a specific type of disease prevalent in the aging population. Results: We use heart-focused ionizing radiation, a novel in vivo technique to induce aging related DNA damage and onset of diastolic dysfunction and HFpEF (n= 4-5 per group & per species; animals used: Rattus norvegicus and Mus musculus). We performed functional analysis, histological tissue assessment and molecular investigations to evaluate and validate this novel animal model technique. DNA damage response is upregulated in aging-related Heart Failure, and here demonstrated in our novel heart-focused radiation technique. Using in vitro ionizing radiation exposure alters cardiomyocyte morphology and activates inflammation, leading to upregulation of fibrosis and senescence markers. Finally using experimental inhibitor compounds targeting the cGAS-STING axis of innate immunity, we show effective attenuation of this relevant pathway, leading to decreased systemic inflammation, cardiomyocyte remodeling, and senescence associated with DNA damage injury. Conclusions: We present a novel technique to induce genotoxic outcomes and inflammation of the heart, leading to HFpEF pathology. We elucidate novel connections from the onset and accumulation of unresolved DNA damage, to activation of specialized innate immune cellular responses, and ultimately upregulation of cardiac tissue specific inflammation, fibrosis and senescence. Finally we demonstrate that antagonizing the cGAS-STING pathway could allow a precision medicine approach to treating genotoxic and inflammatory HFpEF.

Fibrosis is the abnormal deposition of extracellular matrix, which can lead to organ dysfunction, morbidity, and death. The disease burden caused by fibrosis is substantial, and there are currently no therapies that can prevent or reverse fibrosis. Metabolic alterations are increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types. As a result, metabolically targeted therapies could become important strategies for fibrosis reduction. Indeed, some of the pathways targeted by antifibrotic drugs in development - such as the activation of transforming growth factor-β and the deposition of extracellular matrix - have metabolic implications. This Review summarizes the evidence to date and describes novel opportunities for the discovery and development of drugs for metabolic reprogramming, their associated challenges, and their utility in reducing fibrosis. Fibrotic therapies are potentially relevant to numerous common diseases such as cirrhosis, non-alcoholic steatohepatitis, chronic renal disease, heart failure, diabetes, idiopathic pulmonary fibrosis, and scleroderma.

Background Previous studies have identified ethnic differences in outcomes after episodes of acute heart failure in natives of Asia as compared to those of Europe. Whether these ethnic differences in outcomes would still exist, years after migration to a different geographical and cultural setting remain unclear. We investigated the one-year mortality after an episode of acute heart failure admission in Ontario residents of South Asian and Chinese descent as compared to the General Population. Methods We conducted a population-based, retrospective cohort study of adult Ontarions who were hospitalized for AHF between April 1, 2010 and March 31, 2016. Ethnicity was categorized using validated surname-based algorithms. The primary outcome was all-cause one-year mortality. Mortality rates were calculated using the Kaplan–Meier method. The relative hazard of death was assessed using a multivariable Cox proportional hazard model. Results Of 82,125 patients, 1287 (1.6%) were Chinese, 1662 (2.0%) were South Asians, and the remaining 79,176 (96.4%) were of the General Population. The risk of mortality was markedly lower amongst South Asians (adjusted HR 0.81, 95% CI [0.73–0.89]) relative to the General Population. There was no statistically significant difference in the risk of mortality between Chinese and the General Population (adjusted HR 1.00 [0.91–1.10]). In addition, guideline-directed medical therapies were associated with similar survival benefit in patients of all three ethnic origins. Conclusions We found a lower risk of one-year mortality after acute heart failure hospitalization amongst South Asians compared to Chinese and the General Population, and similar benefit of medical therapy in all three groups. Further studies are needed to explore the etiologies of these ethnic disparities to truly improve outcomes at the population level.

Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.

The innate immune system is an evolutionarily conserved system that senses and defends against infection and irritation. Innate immune signaling is a complex cascade that quickly recognizes infectious threats through multiple germline-encoded cell surface or cytoplasmic receptors and transmits signals for the deployment of proper countermeasures through adaptors, kinases, and transcription factors, resulting in the production of cytokines. As the first response of the innate immune system to pathogenic signals, inflammatory responses must be rapid and specific to establish a physical barrier against the spread of infection and must subsequently be terminated once the pathogens have been cleared. Long-lasting and low-grade chronic inflammation is a distinguishing feature of type 2 diabetes and cardiovascular diseases, which are currently major public health problems. Cardiometabolic stress-induced inflammatory responses activate innate immune signaling, which directly contributes to the development of cardiometabolic diseases. Additionally, although the innate immune elements are highly conserved in higher-order jawed vertebrates, lower-grade jawless vertebrates lack several transcription factors and inflammatory cytokine genes downstream of the Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) pathways, suggesting that innate immune signaling components may additionally function in an immune-independent way. Notably, recent studies from our group and others have revealed that innate immune signaling can function as a vital regulator of cardiometabolic homeostasis independent of its immune function. Therefore, further investigation of innate immune signaling in cardiometabolic systems may facilitate the discovery of new strategies to manage the initiation and progression of cardiometabolic disorders, leading to better treatments for these diseases. In this review, we summarize the current progress in innate immune signaling studies and the regulatory function of innate immunity in cardiometabolic diseases. Notably, we highlight the immune-independent effects of innate immune signaling components on the development of cardiometabolic disorders.

The Wnt/β-catenin signaling regulates ion channel gene expressions in cardiomyocytes. Because Wnt/β-catenin signaling is activated in myocardial infarction (MI), this study aims to investigate if β-catenin inhibition affects post-MI ion channel gene alterations and ventricular tachycardias (VT). MI was induced by permanent ligation of left anterior descending artery in wild-type (WT) and cardiomyocyte-specific β-catenin knockout (KO) mice. KO mice showed reduced susceptibility to VT (18% vs. 77% in WT) at week-8 after MI, associated with attenuated structural remodeling (reduced scar size and attenuated left ventricle dilation) as compared to WT. However, at the subacute phase (week-1) and chronic phase (week-8) after MI, Wnt/β-catenin signaling activation was found in non-cardiomyocytes, but not in cardiomyocytes. Downregulations of Scn5a (encoding Nav1.5) and Gja1 (encoding Cx43) were found at week-1 but not at week-8, while downregulations of K+ channel genes were present at both week-1 and -8. Consistent with no activation of Wnt/β-catenin pathway in cardiomyocytes at week-1 and -8, these alterations in ion channel/transporter genes were not different between KO and WT mice. This study demonstrated that mice with cardiomyocyte-specific β-catenin deletion have reduced VT susceptibility after MI which is caused by attenuated structural remodeling, instead of alterations in ion channel gene expressions.

Background Evidence on the differences in fracture risk associated with non‐vitamin K antagonist oral anticoagulants (NOAC) and warfarin is inconsistent and inconclusive. We conducted a systematic review and meta‐analysis to assess the fracture risk associated with NOACs and warfarin. Methods and Results We searched PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov from inception until May 19, 2020. We included studies presenting measurements (regardless of primary/secondary/tertiary/safety outcomes) for any fracture in both NOAC and warfarin users. Two or more reviewers independently screened relevant articles, extracted data, and performed quality assessments. Data were retrieved to synthesize the pooled relative risk (RR) of fractures associated with NOACs versus warfarin. Random‐effects models were used for data synthesis. We included 29 studies (5 cohort studies and 24 randomized controlled trials) with 388 209 patients. Patients treated with NOACs had lower risks of fracture than those treated with warfarin (pooled RR, 0.84; 95% CI, 0.77–0.91; P I 2 =38.9%). NOACs were also associated with significantly lower risks of hip fracture than warfarin (pooled RR, 0.89; 95% CI, 0.81–0.98; P =0.023). A nonsignificant trend of lower vertebral fracture risk in NOAC users was also observed (pooled RR, 0.74; 95% CI, 0.54–1.01; P =0.061). Subgroup analyses for individual NOACs demonstrated that dabigatran, rivaroxaban, and apixaban were significantly associated with lower fracture risks. Furthermore, the data synthesis results from randomized controlled trials and real‐world cohort studies were quite consistent, indicating the robustness of our findings. Conclusions Compared with warfarin, NOACs are associated with lower risks of bone fracture.

Supplemental Digital Content is available in the text., The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019, to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for high-sensitivity cardiac troponin I was 7.12 ([95% CI, 4.60–11.03] P