Molecular Choreography of Acute Exercise.

Acute physical activity leads to several changes in metabolic, cardiovascular, and immune pathways. Although studies have examined selected changes in these pathways, the system-wide molecular response to an acute bout of exercise has not been fully characterized. We performed longitudinal multi-omic profiling of plasma and peripheral blood mononuclear cells including metabolome, lipidome, immunome, proteome, and transcriptome from 36 well-characterized volunteers, before and after a controlled bout of symptom-limited exercise. Time-series analysis revealed thousands of molecular changes and an orchestrated choreography of biological processes involving energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor response, as well as regulatory pathways. Most of these processes were dampened and some were reversed in insulin-resistant participants. Finally, we discovered biological pathways involved in cardiopulmonary exercise response and developed prediction models revealing potential resting blood-based biomarkers of peak oxygen consumption.

Multi-ancestry GWAS analysis identifies two novel loci associated with diabetic eye disease and highlights APOL1 as a high risk locus in patients with diabetic macular edema.

Diabetic retinopathy (DR) is a common complication of diabetes. Approximately 20% of DR patients have diabetic macular edema (DME) characterized by fluid leakage into the retina. There is a genetic component to DR and DME risk, but few replicable loci. Because not all DR cases have DME, we focused on DME to increase power, and conducted a multi-ancestry GWAS to assess DME risk in a total of 1,502 DME patients and 5,603 non-DME controls in discovery and replication datasets. Two loci reached GWAS significance (p<5x10-8). The strongest association was rs2239785, (K150E) in APOL1. The second finding was rs10402468, which co-localized to PLVAP and ANKLE1 in vascular / endothelium tissues. We conducted multiple sensitivity analyses to establish that the associations were specific to DME status and did not reflect diabetes status or other diabetic complications. Here we report two novel loci for risk of DME which replicated in multiple clinical trial and biobank derived datasets. One of these loci, containing the gene APOL1, is a risk factor in African American DME and DKD patients, indicating that this locus plays a broader role in diabetic complications for multiple ancestries. Trial Registration: NCT00473330, NCT00473382, NCT03622580, NCT03622593, NCT04108156.

Metabolic Reprogramming: A Byproduct or a Driver of Cardiomyocyte Proliferation?

Defining mechanisms of cardiomyocyte proliferation should guide the understanding of endogenous cardiac regeneration and could lead to novel treatments for diseases such as myocardial infarction. In the neonatal heart, energy metabolic reprogramming (phenotypic alteration of glucose, fatty acid, and amino acid metabolism) parallels cell cycle arrest of cardiomyocytes. The metabolic reprogramming occurring shortly after birth is associated with alterations in blood oxygen levels, metabolic substrate availability, hemodynamic stress, and hormone release. In the adult heart, myocardial infarction causes metabolic reprogramming but these changes cannot stimulate sufficient cardiomyocyte proliferation to replace those lost by the ischemic injury. Some putative pro-proliferative interventions can induce the metabolic reprogramming. Recent data show that altering the metabolic enzymes PKM2 [pyruvate kinase 2], LDHA [lactate dehydrogenase A], PDK4 [pyruvate dehydrogenase kinase 4], SDH [succinate dehydrogenase], CPT1b [carnitine palmitoyl transferase 1b], or HMGCS2 [3-hydroxy-3-methylglutaryl-CoA synthase 2] is sufficient to partially reverse metabolic reprogramming and promotes adult cardiomyocyte proliferation. How metabolic reprogramming regulates cardiomyocyte proliferation is not clearly defined. The possible mechanisms involve biosynthetic pathways from the glycolysis shunts and the epigenetic regulation induced by metabolic intermediates. Metabolic manipulation could represent a new approach to stimulate cardiac regeneration; however, the efficacy of these manipulations requires optimization, and novel molecular targets need to be defined. In this review, we summarize the features, triggers, and molecular regulatory networks responsible for metabolic reprogramming and discuss the current understanding of metabolic reprogramming as a critical determinant of cardiomyocyte proliferation.

Longitudinal multi-omics of host-microbe dynamics in prediabetes.

Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2D better, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host-microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.

The novel antibody fusion protein rhNRG1-HER3i promotes heart regeneration by enhancing NRG1-ERBB4 signaling pathway.

Stimulating cardiomyocyte proliferation in the adult heart has emerged as a promising strategy for cardiac regeneration following myocardial infarction (MI). The NRG1-ERBB4 signaling pathway has been implicated in the regulation of cardiomyocyte proliferation. However, the therapeutic potential of recombinant human NRG1 (rhNRG1) has been limited due to the low expression of ERBB4 in adult cardiomyocytes. Here, we investigated whether a fusion protein of rhNRG1 and an ERBB3 inhibitor (rhNRG1-HER3i) could enhance the affinity of NRG1 for ERBB4 and promote adult cardiomyocyte proliferation. In vitro and in vivo experiments were conducted using postnatal day 1 (P1), P7, and adult cardiomyocytes. Western blot analysis was performed to assess the expression and activity of ERBB4. Cardiomyocyte proliferation was evaluated using Ki67 and pH 3 immunostaining, while fibrosis was assessed using Masson staining. Our results indicate that rhNRG1-HER3i, but not rhNRG1, promoted P7 and adult cardiomyocyte proliferation. Furthermore, rhNRG1-HER3i improved cardiac function and reduced cardiac fibrosis in post-MI hearts. Administration of rhNRG1-HER3i inhibited ERBB3 phosphorylation while increasing ERBB4 phosphorylation in adult mouse hearts. Additionally, rhNRG1-HER3i enhanced angiogenesis following MI compared to rhNRG1. In conclusion, our findings suggest that rhNRG1-HER3i is a viable therapeutic approach for promoting adult cardiomyocyte proliferation and treating MI by enhancing NRG1-ERBB4 signaling pathway.

Healthcare Utilization Among Adults With Vestibular Vertigo in the United States.

OBJECTIVES: Vestibular vertigo has been shown to have a high lifetime prevalence. Previous studies have described the increased morbidities associated with vestibular vertigo. DESIGN: In this cross-sectional study of the 2016 National Health Interview Study, we sought to explore whether individuals with vestibular vertigo were more likely to utilize healthcare resources compared with those without vestibular vertigo. We characterized utilization of specific healthcare resources including general doctors, specialist doctors, emergency departments, mental health professionals, and others among individuals with vestibular vertigo to better understand how individuals with vertigo interact with the US healthcare system. RESULTS: In multivariable analyses, participants with vestibular vertigo had an increased number of nights in the hospital in the last 12 months (mean difference = 0.67 days, 95% confidence interval [CI] = 0.37 to 0.97), increased odds of receiving healthcare 10 or more times in the last 12 months (odds ratio = 2.22, 95% CI = 1.99 to 2.48) and increased number of visits to a healthcare professional in the last 2 weeks (mean difference = 0.17 visits, 95% CI = 0.14 to 0.21). In addition, participants with vestibular vertigo had increased odds of visiting both general doctors, specialist doctors, and other healthcare professionals. CONCLUSIONS: These findings characterize how individuals with vestibular vertigo utilize and interact with healthcare resources compared with those without vestibular vertigo.

Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis.

Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 µg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 µM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 µM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.

Rhinoplasty Outcomes in Patients with Symptoms of Body Dysmorphia.

BACKGROUND: Patients with symptoms of body dysmorphia often seek consultation for aesthetic rhinoplasty. While body dysmorphic disorder is a formal psychiatric diagnosis, recent evidence indicates that patients with symptoms of this condition who seek rhinoplasty may experience increased satisfaction with their appearance following surgery. OBJECTIVES: To determine the psychological impact of rhinoplasty in patients screened pre-/postoperatively with a body dysmorphia screening questionnaire. METHODS: Retrospective chart review of patients who underwent aesthetic and/or functional rhinoplasty by a single surgeon (S.P.M.) from 6/2021- 4/2023. Adult patients with a complete pre- and postoperative body dysmorphic disorder-aesthetic surgery questionnaire (BDDQ-AS), Standardized Cosmesis and Health Nasal Outcomes Survey-Obstruction and Cosmesis (SCHNOS), and Visual Analog Scale (VAS) were included. Patient characteristics and outcomes were analyzed stratifying by BDDQ-AS screen. RESULTS: One-hundred fifteen patients (88% female) met criteria for inclusion. There was an 83% resolution rate in BDDQ-AS positive screening following rhinoplasty. Positive BDDQ-AS screening status pre- and postoperatively correlated with worse aesthetic satisfaction (all p<0.002). No patient reported outcome measures were indicative of which patients with a BDDQ-AS positive screen preoperatively would experience 'resolution' postoperatively. CONCLUSIONS: Body dysmorphia screening resolution following surgical intervention correlated with improved patient aesthetic satisfaction, pointing to a potential positive psychological impact of undergoing rhinoplasty.

The characteristics of proliferative cardiomyocytes in mammals.

Better understanding of the mechanisms regulating the proliferation of pre-existing cardiomyocyte (CM) should lead to better options for regenerating injured myocardium. The absence of a perfect research model to definitively identify newly formed mammalian CMs is lacking. However, methodologies are being developed to identify and enrich proliferative CMs. These methods take advantages of the different proliferative states of CMs during postnatal development, before and after injury in the neonatal heart. New approaches use CMs labeled in lineage tracing animals or single cell technique-based CM clusters. This review aims to provide a timely update on the characteristics of the proliferative CMs, including their structural, functional, genetic, epigenetic and metabolic characteristics versus non-proliferative CMs. A better understanding of the characteristics of proliferative CMs should lead to the mechanisms for inducing endogenous CMs to self-renew, which is a promising therapeutic strategy to treat cardiac diseases that cause CM death in humans.

Vestibular Vertigo and Disparities in Healthcare Access Among Adults in the United States.

OBJECTIVE: Vertigo and dizziness have a high lifetime prevalence with significant impacts on daily life. We sought to explore differences in access to and ability to afford care among adults with vestibular vertigo by race/ethnicity, income, and insurance type. DESIGN: This is a cross-sectional study using the 2016 National Health Interview Survey. A total of 32,047 adults who completed the 2016 National Health Interview Survey Balance Supplement were analyzed. We used a previously validated definition of vertigo defined as (1) positional vertigo, (2) rotational vertigo, or (3) recurrent dizziness with nausea and either oscillopsia or imbalance. We examined several self-reported measures of healthcare utilization and access. RESULTS: Among adults with vestibular vertigo, African Americans had significantly increased odds of delayed care due to lack of transportation; Hispanic ethnicity was associated with decreased odds of skipping medication doses and asking a doctor for a lower-cost medication. Adults with public insurance had significantly lower odds of reporting delayed care due to worry about cost, not receiving medical care due to cost, and delayed filling of a prescription, but had greater odds of reporting delayed care due to lack of transportation. Lack of insurance and lower income were associated with increased odds of delaying and not receiving care due to cost. CONCLUSION: These findings demonstrate significant differences in access to care among adults with vestibular vertigo in the United States based on race, income, and health insurance status.

Porcupine inhibitor CGX1321 alleviates heart failure with preserved ejection fraction in mice by blocking WNT signaling.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3 mg·kg-1·d-1) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of ß-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.

Gender Differences in Anxiety, Depression, Insomnia, and Quality of Life in Heart Failure With Preserved Ejection Fraction: A Multicenter, Cross-sectional Study.

BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) are more often female, but gender differences in psychological distress in patients with HFpEF have not been determined. OBJECTIVE: We aimed to compare anxiety, depression, insomnia, and quality of life (QoL) between women and men with HFpEF. METHODS: A total of 263 consecutive hospitalized patients with HFpEF were enrolled in a multicenter study. Demographic and clinical characteristics were recorded. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS), insomnia was assessed by the Insomnia Severity Index and Pittsburgh Sleep Quality Index, and QoL was assessed by the Kansas City Cardiomyopathy Questionnaire. RESULTS: Women accounted for 59% and men accounted for 41% of the patients with HFpEF. Women and men had similar New York Heart Association functional class and N-terminal pro-brain natriuretic peptide levels. Between women and men with HFpEF, similar depression prevalence (HADS-D: 4.9 ± 3.7 vs 4.1 ± 3.6, P = .222), insomnia severity (Insomnia Severity Index: 9.3 ± 6.4 vs 8.0 ± 6.5, P = .120), and QoL (Kansas City Cardiomyopathy Questionnaire: 46.6 ± 12.6 vs 47.6 ± 12.7, P = .738) were found when adjusting for potential confounders. Women had more severe anxiety (HADS-Anxiety: 2.4 ± 2.9 vs 1.6 ± 2.3, P = .025) and worse sleep quality (Pittsburgh Sleep Quality Index: 9.9 ± 4.6 vs 8.7 ± 4.5, P = .046) compared with men after adjustment. CONCLUSIONS: There were no gender differences in depression, insomnia, and QoL in patients with HFpEF when adjusting for confounders. Women with HFpEF suffered more severe anxiety and sleep quality than men after adjustment. Thus, it is recommended that psychological distress in patients with HFpEF be assessed in clinical practice, and gender differences taken into consideration.

Difference in Perception of Nasal Aesthetic Appearance Between Surgeons and Rhinoplasty Patients: A Single-Center Perspective.

BACKGROUND: Patient satisfaction is an essential outcome measure after a rhinoplasty. Yet it is not known whether the opinions of rhinoplasty patients and surgeons on nasal aesthetic appearance differ. OBJECTIVES: The aim of this study was to determine the differences between patients and surgeons in their perception of nasal aesthetic appearance. METHODS: A retrospective cohort of 300 patients seen in consultation for cosmetic, functional, or combined cosmetic and functional rhinoplasty at a single tertiary care center from June 2017 to June 2020 was studied. Based on preoperative patient images, 6 surgeons with varying levels of expertise assessed nasal aesthetics utilizing a modified Standardized Cosmesis and Health Nasal Outcomes Survey for nasal cosmesis (SCHNOS-C). These scores were then compared to the patient-reported SCHNOS-C scores. RESULTS: The cosmetic, functional, and combined subgroups consisted of 100 patients each. The mean [standard deviation] age was 35.4 [13.7] years and 64% were women. The modified SCHNOS-C scores were well-correlated among the 6 surgeons but showed only weak correlations of 0.07 to 0.20 between patient-reported scores and scores assessed by the surgeons. Compared with the surgeon's scores, patients in the cosmetic subgroup perceived their nasal aesthetic problems to be more severe whereas the those in the functional subgroup perceived their nasal aesthetic problems to be milder compared with the surgeons' assessment. CONCLUSIONS: Our findings suggest that patients and surgeons perceive nasal cosmesis differently. This difference should be considered carefully when planning rhinoplasty or assessing its outcome.

Loss of NPPA-AS1 promotes heart regeneration by stabilizing SFPQ-NONO heteromer-induced DNA repair.

The role of long non-coding RNA (lncRNA) in endogenous cardiac regeneration remains largely elusive. The mammalian cardiomyocyte is capable of regeneration for a brief period after birth. This fact allows the exploration of the roles of critical lncRNAs in the regulation of cardiac regeneration. Through a cardiac regeneration model by apical resection (AR) of the left ventricle in neonatal mice, we identified an lncRNA named natriuretic peptide A antisense RNA 1 (NPPA-AS1), which negatively regulated cardiomyocyte proliferation. In neonates, NPPA-AS1 deletion did not affect heart development, but was sufficient to prolong the postnatal window of regeneration after AR. In adult mice, NPPA-AS1 deletion improved cardiac function and reduced infarct size after myocardial infarction (MI), associated with a significant improvement in cardiomyocyte proliferation. Further analysis showed that NPPA-AS1 interacted with DNA repair-related molecule splicing factor, proline- and glutamine-rich (SFPQ). A heteromer of SFPQ and non-POU domain-containing octamer-binding protein (NONO) was required for double-strand DNA break repair, but NPPA-AS1 was competitively bound with SFPQ due to the overlapped binding sites of SFPQ and NONO. NPPA-AS1 deletion promoted the binding of SFPQ-NONO heteromer, decreased DNA damage, and activated cardiomyocyte cell cycle re-entry. Together, loss of NPPA-AS1 promoted cardiomyocyte proliferation by stabilizing SFPQ-NONO heteromer-induced DNA repair and exerted a therapeutic effect against MI in adult mice. Consequently, NPPA-AS1 may be a novel target for stimulating cardiac regeneration to treat MI.

The prognostic utility of GRACE risk score in predictive adverse cardiovascular outcomes in patients with NSTEMI and multivessel disease.

BACKGROUND: GRACE risk score models are capable of predicting all-cause mortality of non-ST elevation myocardial infarction (NSTEMI) patients. However, its utility for evaluating major adverse cardiovascular events (MACE) in NSTEMI patients with multivessel disease (MVD) remains unclear. METHODS AND RESULTS: This study was designed as a retrospective cohort study that recruited patients with NSTEMI and multivessel disease between September 2013 and December 2018 in Daping Hospital, Chongqing, China. The primary outcome was a composite outcome that included all-cause mortality, recurrent angina, non-fatal myocardial infarction, coronary re-vascularization, and non-fatal strokes. Of the 827 patients with NSTEMI, 32 did not complete follow-up and 430 were excluded because of single-vessel disease. The remaining 365 NSTEMI patients with MVD had a median follow-up of 3.0 (IQR 2.6-3.3) years, 78 patients experienced outcomes. The GRACE risk score predicted the MACE (hazard ratio 1.014, 95% CI 1.006-1.021, P < 0.001). The GRACE risk score performed well in predicting all-cause mortality (c-statistic 0.72, 95% CI 0.59-0.85, P = 0.001) in MVD but was less powerful in predicting MACE (c-statistic 0.69, 95% CI 0.62-0.75, P < 0.001). When combining the GRACE risk score with the SYNTAX score, and blood urea nitrogen for predicting all-cause mortality and MACE events, the c-statistic value increased to 0.82 and 0.81 (P < 0.001). CONCLUSION: In NSTEMI patients with MVD, the GRACE score showed an acceptable predictive value for all-cause mortality, but it was less powerful in predicting MACE. Blood urea nitrogen may be valuable in assessing long-term cardiovascular events in patients with MVD.

The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction.

AIMS: G protein-coupled receptor kinase 4 (GRK4) has been reported to play an important role in hypertension, but little is known about its role in cardiomyocytes and myocardial infarction (MI). The goal of present study is to explore the role of GRK4 in the pathogenesis and progression of MI. METHODS AND RESULTS: We studied the expression and distribution pattern of GRK4 in mouse heart after MI. GRK4 A486V transgenic mice, inducible cardiomyocyte-specific GRK4 knockout mice, were generated and subjected to MI with their control mice. Cardiac infarction, cardiac function, cardiomyocyte apoptosis, autophagic activity, and HDAC4 phosphorylation were assessed. The mRNA and protein levels of GRK4 in the heart were increased after MI. Transgenic mice with the overexpression of human GRK4 wild type (WT) or human GRK4 A486V variant had increased cardiac infarction, exaggerated cardiac dysfunction and remodelling. In contrast, the MI-induced cardiac dysfunction and remodelling were ameliorated in cardiomyocyte-specific GRK4 knockout mice. GRK4 overexpression in cardiomyocytes aggravated apoptosis, repressed autophagy, and decreased beclin-1 expression, which were partially rescued by the autophagy agonist rapamycin. MI also induced the nuclear translocation of GRK4, which inhibited autophagy by increasing HDAC4 phosphorylation and decreasing its binding to the beclin-1 promoter. HDAC4 S632A mutation partially restored the GRK4-induced inhibition of autophagy. MI caused greater impairment of cardiac function in patients carrying the GRK4 A486V variant than in WT carriers. CONCLUSION: GRK4 increases cardiomyocyte injury during MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These effects are mediated by the phosphorylation of HDAC4 and a decrease in beclin-1 expression.

Association of Nonalcoholic Fatty Liver Disease with Ventricular Tachycardia and Sinus Arrest in Patients with Non-ST-Segment Elevation Myocardial Infarction.

Nonalcoholic fatty liver disease (NAFLD) is an emerging driver of cardiac arrhythmias. However, the relationship between NAFLD and malignant arrhythmia in non-ST-segment elevation myocardial infarction (NSTEMI) patients is still unclear.In this study, 358 NSTEMI inpatients were enrolled. They all received 24-hour Holter monitoring after percutaneous coronary intervention. All inpatients were divided into two groups: the non-NAFLD group (236 cases, 65.9%) and the NAFLD group (122 cases, 34.1%). Compared with the non-NAFLD group, the NAFLD group had a significantly higher incidence of PVCs/hour > 5 (premature ventricular complexes, 32.0% versus 9.3%, P < 0.001), ventricular tachycardia (VT, 22.1% versus 5.9%, P < 0.001), and sinus arrest (SA, 7.4% versus 1.3%, P = 0.002). We found that NAFLD was closely associated with the occurrence of VT [unadjusted odds ratio (OR) 4.507, 95% confidence interval (CI) 2.263-8.974, P < 0.001] and SA (OR 6.186, 95%CI 1.643-23.291, P = 0.007). After adjusting for age, sex, body mass index, and other confounding factors, the above differences were still statistically significant (VT: OR 4.808, 95%CI 2.254-10.253, P < 0.001; SA: OR 9.589, 95%CI 2.027-45.367, P = 0.004).NAFLD is associated with the occurrence of VT and SA in NSTEMI patients. It indicates that NAFLD might be a risk factor for malignant arrhythmias in post-NSTEMI patients.

Microfluidic isoform sequencing shows widespread splicing coordination in the human transcriptome.

Understanding transcriptome complexity is crucial for understanding human biology and disease. Technologies such as Synthetic long-read RNA sequencing (SLR-RNA-seq) delivered 5 million isoforms and allowed assessing splicing coordination. Pacific Biosciences and Oxford Nanopore increase throughput also but require high input amounts or amplification. Our new droplet-based method, sparse isoform sequencing (spISO-seq), sequences 100k-200k partitions of 10-200 molecules at a time, enabling analysis of 10-100 million RNA molecules. SpISO-seq requires less than 1 ng of input cDNA, limiting or removing the need for prior amplification with its associated biases. Adjusting the number of reads devoted to each molecule reduces sequencing lanes and cost, with little loss in detection power. The increased number of molecules expands our understanding of isoform complexity. In addition to confirming our previously published cases of splicing coordination (e.g., BIN1), the greater depth reveals many new cases, such as MAPT Coordination of internal exons is found to be extensive among protein coding genes: 23.5%-59.3% (95% confidence interval) of highly expressed genes with distant alternative exons exhibit coordination, showcasing the need for long-read transcriptomics. However, coordination is less frequent for noncoding sequences, suggesting a larger role of splicing coordination in shaping proteins. Groups of genes with coordination are involved in protein-protein interactions with each other, raising the possibility that coordination facilitates complex formation and/or function. We also find new splicing coordination types, involving initial and terminal exons. Our results provide a more comprehensive understanding of the human transcriptome and a general, cost-effective method to analyze it.

Gastrin, via activation of PPARα, protects the kidney against hypertensive injury.

Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin. However, the relationship between gastrin and renal fibrosis in HN is still unknown. We, now, report that mice with angiotensin II (Ang II)-induced HN had increased renal cholecystokinin receptor B (CCKBR) expression. Knockout of CCKBR in mice aggravated, while long-term subcutaneous infusion of gastrin ameliorated the renal injury and interstitial fibrosis in HN and unilateral ureteral obstruction (UUO). The protective effects of gastrin on renal fibrosis can be independent of its regulation of blood pressure, because in UUO, gastrin decreased renal fibrosis without affecting blood pressure. Gastrin treatment decreased Ang II-induced renal tubule cell apoptosis, reversed Ang II-mediated inhibition of macrophage efferocytosis, and reduced renal inflammation. A screening of the regulatory factors of efferocytosis showed involvement of peroxisome proliferator-activated receptor α (PPAR-α). Knockdown of PPAR-α by shRNA blocked the anti-fibrotic effect of gastrin in vitro in mouse renal proximal tubule cells and macrophages. Immunofluorescence microscopy, Western blotting, luciferase reporter, and Cut&tag-qPCR analyses showed that CCKBR may be a transcription factor of PPAR-α, because gastrin treatment induced CCKBR translocation from cytosol to nucleus, binding to the PPAR-α promoter region, and increasing PPAR-α gene transcription. In conclusion, gastrin protects against HN by normalizing blood pressure, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis. Gastrin-mediated CCKBR nuclear translocation may make it act as a transcription factor of PPAR-α, which is a novel signaling pathway. Gastrin may be a new potential drug for HN therapy.

Cardiomyocyte PKA Ablation Enhances Basal Contractility While Eliminates Cardiac ß-Adrenergic Response Without Adverse Effects on the Heart.

RATIONALE: PKA (Protein Kinase A) is a major mediator of ß-AR (ß-adrenergic) regulation of cardiac function, but other mediators have also been suggested. Reduced PKA basal activity and activation are linked to cardiac diseases. However, how complete loss of PKA activity impacts on cardiac physiology and if it causes cardiac dysfunction have never been determined. OBJECTIVES: We set to determine how the heart adapts to the loss of cardiomyocyte PKA activity and if it elicits cardiac abnormalities. METHODS AND RESULTS: (1) Cardiac PKA activity was almost completely inhibited by expressing a PKA inhibitor peptide in cardiomyocytes (cPKAi) in mice; (2) cPKAi reduced basal phosphorylation of 2 myofilament proteins (TnI [troponin I] and cardiac myosin binding protein C), and one longitudinal SR (sarcoplasmic reticulum) protein (PLB [phospholamban]) but not of the sarcolemmal proteins (Cav1.2 α1c and PLM [phospholemman]), dyadic protein RyR2, and nuclear protein CREB (cAMP response element binding protein) at their PKA phosphorylation sites; (3) cPKAi increased the expression of CaMKII (Ca2+/calmodulin-dependent kinase II), the Cav1.2 ß subunits and current, but decreased CaMKII phosphorylation and CaMKII-mediated phosphorylation of PLB and RyR2; (4) These changes resulted in significantly enhanced myofilament Ca2+ sensitivity, prolonged contraction, slowed relaxation but increased myocyte Ca2+ transient and contraction amplitudes; (5) Isoproterenol-induced PKA and CaMKII activation and their phosphorylation of proteins were prevented by cPKAi; (6) cPKAi abolished the increases of heart rate, and cardiac and myocyte contractility by a ß-AR agonist (isoproterenol), showing an important role of PKA and a minimal role of PKA-independent ß-AR signaling in acute cardiac regulation; (7) cPKAi mice have partial exercise capability probably by enhancing vascular constriction and ventricular filling during ß-AR stimulation; and (8) cPKAi mice did not show any cardiac functional or structural abnormalities during the 1-year study period. CONCLUSIONS: PKA activity suppression induces a unique Ca2+ handling phenotype, eliminates ß-AR regulation of heart rates and cardiac contractility but does not cause cardiac abnormalities.