Xiaomei Yang

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by typical heart failure symptoms, left ventricular ejection fraction (LVEF) ≥50%, elevated natriuretic peptides, and impaired diastolic function. HFpEF constitutes a heterogeneous clinical syndrome with increasing prevalence worldwide and limited therapeutic options. Short-chain fatty acids (SCFAs), generated by gut microbial fermentation of dietary fibers, have recently been implicated as modulators of cardiovascular physiology and pathology. In this narrative review, we synthesize evidence linking SCFAs and SCFA-related signaling to HFpEF pathophysiology, with attention to the distinction between direct HFpEF evidence and findings extrapolated from broader cardiovascular and metabolic models. Although HFpEF-specific data remain limited, available evidence suggests that SCFAs may be relevant to several disease-associated processes, including systemic inflammation, adipokine dysregulation, endothelial dysfunction, myocardial stiffness, and metabolic derangement. We further discuss receptor-mediated and histone deacetylase-dependent mechanisms, consider differences among acetate, propionate, and butyrate, and evaluate the current limitations and therapeutic implications of SCFA-related pathways in HFpEF. At present, SCFA-directed interventions should be viewed as investigational rather than established therapeutic strategies for HFpEF.

Sepsis is a clinical syndrome caused by abnormal host response to infection. Thrombocytopenia and platelet dysfunction are common findings in sepsis and associated with worse outcomes. The innate immune single-stranded RNA sensor, Toll-like Receptor-7 (TLR7), plays a key role in thrombocytopenia in sepsis. This study investigated whether TLR7 signaling also contributes to platelet dysfunction in sepsis, and whether the bioactivity of downstream inflammatory mediators, specifically extracellular vesicles (EVs), is impacted by the TLR7 signaling pathway. Sepsis was induced in wild-type (WT) and TLR7-deficient (TLR7^−/−) mice by cecal ligation and puncture. Blood was collected at twenty-four hours for platelet and plasma isolation, and platelet function was assessed using aggregation, adhesion, and calcium flux assays. EVs were isolated from plasma and used in vitro to evaluate their impact on platelet–leukocyte aggregate (PLA) formation. We found that septic platelets are highly activated and more adhesive, yet show markedly impaired aggregation and reduced calcium signaling, indicating functional exhaustion despite activation. Notably, mice lacking TLR7 maintained stronger platelet aggregation, enhanced adhesion, and preserved calcium release in the septic state compared to wild-type controls, suggesting a protective effect of TLR7 deficiency. Plasma EVs increased in abundance and size during sepsis and promoted clot and PLA formation in vitro. Notably, EV-mediated platelet activation was reduced with EVs derived from TLR7-deficient mice. Our results demonstrate that while sepsis drives persistent platelet activation and dysfunction, TLR7 deficiency preserves platelet function and modulates the pathogenic activity of EV-mediated platelet activation, highlighting TLR7 as a key regulator and potential therapeutic target in sepsis-induced platelet dysfunction.

G‐protein‐coupled receptor 41 (GPR41) is a Gα _i ‐coupled receptor activated by short‐chain fatty acids (SCFAs). Here, we tested that GPR41 is also expressed in cardiomyocytes and exerts a direct negative inotropic effect when activated by SCFA butyrate. Primary cardiomyocytes were isolated from wild‐type (WT) and GPR41 knockout (GPR41 ^−/− ) adult mice and intracellular Ca ²⁺ concentration and cell shortening were measured using the IonOptix system. RNA localization (RNAScope), quantitative real‐time polymerase chain reaction (qRT‐PCR), immunofluorescence staining, and western blot were used to examine the expression of GPR41 in adult primary cardiomyocytes of WT and GPR41 ^−/− mice. The effect of butyrate on shortening and intracellular Ca ²⁺ transient via GPR41 was also tested in cardiomyocytes. We demonstrated for the first time the presence of GPR41s on cardiomyocytes. Butyrate dose‐dependently decreased cell shortening and the amplitude of intracellular Ca ²⁺ transients in cardiomyocytes from WT but not GPR41 ^−/− mice. In WT cardiomyocytes, butyrate decreased caffeine‐mediated amplitudes of intracellular Ca ²⁺ transients from the sarcoplasmic reticulum (SR). Moreover, the inhibitory effects of butyrate on cell shortening and intracellular Ca ²⁺ were pertussis toxin (PTX)‐sensitive. Finally, butyrate decreased the activity of sarcoendoplasmic reticulum Ca ²⁺ ‐ATPase (SERCA) and cellular 3′‐5′‐cyclic adenosine monophosphate (cAMP) content. In conclusion, GPR41 is expressed on cardiomyocytes. Butyrate, a known GPR41 agonist, reduces cardiomyocyte shortening and intracellular Ca ²⁺ transient via decreasing Ca ²⁺ content in the SR by inhibiting SERCA activity in a PTX‐dependent manner. These findings establish that GPR41 is directly activated by SCFAs to decrease contraction and intracellular Ca ²⁺ transient, highlighting the potential inhibitory role of GPR41 in cardiomyocytes.

Background: A significant reduction in regional cerebral oxygen saturation (rSO₂) is commonly observed during one-lung ventilation (OLV), while positive end-expiratory pressure (PEEP) can improve oxygenation. We compared the effects of three different PEEP levels on rSO₂, pulmonary oxygenation, and hemodynamics during OLV. Methods: Forty-three elderly patients who underwent thoracoscopic lobectomy were randomly assigned to one of six PEEP combinations which used a crossover design of 3 levels of PEEP—0 cmH₂O, 5 cmH₂O, and 10 cmH₂O. The primary endpoint was rSO₂ in patients receiving OLV 20 min after adjusting the PEEP. The secondary outcomes included hemodynamic and respiratory variables. Results: After exclusion, thirty-six patients (36.11% female; age range: 60–76 year) were assigned to six groups (n = 6 in each group). The rSO₂ was highest at OLV(0) than at OLV(10) (difference, 2.889%; [95% CI, 0.573 to 5.204%]; p = 0.008). Arterial oxygen partial pressure (PaO₂) was lowest at OLV(0) compared with OLV(5) (difference, -62.639 mmHg; [95% CI, -106.170 to -19.108 mmHg]; p = 0.005) or OLV(10) (difference, -73.389 mmHg; [95% CI, -117.852 to -28.925 mmHg]; p = 0.001), while peak airway pressure (Ppeak) was lower at OLV(0) (difference, -4.222 mmHg; [95% CI, -5.140 to -3.304 mmHg]; p < 0.001) and OLV(5) (difference, -3.139 mmHg; [95% CI, -4.110 to -2.167 mmHg]; p < 0.001) than at OLV(10). Conclusions: PEEP with 10 cmH₂O makes rSO₂ decrease compared with 0 cmH₂O. Applying PEEP with 5 cmH₂O during OLV in elderly patients can improve oxygenation and maintain high rSO₂ levels, without significantly increasing peak airway pressure compared to not using PEEP. Trial registration: Chinese Clinical Trial Registry ChiCTR2200060112 on 19 May 2022.

Background: By continually monitoring end-tidal carbon dioxide concentrations, capnography can detect abnormal ventilation or apnoea early. This randomized, controlled study explored the effect of early intervention with capnography on the incidence of hypoxia in mildly obese patients undergoing sedation for esophagogastroduodenoscopy (EGD) and colonoscopy. Methods: This is a single-center, randomized, single-blind, parallel-assignment, controlled trial. Mildly obese patients (28 kg/m² ≤ BMI < 40 kg/m²) undergoing sedation for EGD and colonoscopy were randomly assigned to either the standard or capnography group. Standard cardiopulmonary monitoring equipment was used in both groups, and additional capnography was performed in the capnography group. In the event of inadequate alveolar ventilation during sedation, five interventions were administered in sequence (a-e) : a: increasing oxygen flow (5 L/min); b: a chin lift or jaw thrust maneuver; c: placement of the nasopharyngeal airway and chin lift; d: mask positive-pressure ventilation, and e: ventilator-assisted ventilation with tube insertion. The primary outcome was the incidence of hypoxia (SpO₂ < 90%, ≥ 10 s) in each group. The secondary outcomes included the incidence of severe hypoxia (SpO₂ ≤ 85%), subclinical respiratory depression (90% ≤ SpO₂ < 95%), interventions, minimum SpO₂ during operation, patient satisfaction, endoscopist satisfaction, and other adverse events of anesthesia sedation. Results: 228 patients were included (capnography group = 112; standard group = 113; three patients were excluded) in this study. The incidence of hypoxia was significantly lower in the capnography group than in the standard group (13.4% vs. 30.1%, P = 0.002). Subclinical respiratory depression in the capnography group was higher than that of the standard group (30.4% vs. 17.7%, P = 0.026). There was only a 5.4% incidence of severe hypoxia in the capnography group compared with 14.2% in the standard group (P = 0.026). During sedation, 96 and 34 individuals in the capnography and standard groups, respectively, underwent the intervention. There was a statistically significant difference (P < 0.0001) in the number of the last intraoperative intervention between the two groups ( a:47 vs. 1, b:46 vs. 26, c:2 vs. 5, d:1 vs. 2, e:0 vs. 0 ). No significant differences were found between the two groups in terms of minimum SpO₂ during operation, patient satisfaction, or endoscopist satisfaction rating. There was no statistically significant difference in adverse events of anesthesia sedation between the two groups. Conclusion: Capnography during sedation for EGD and colonoscopy allows for the detection of apnea and altered breathing patterns in mildly obese patients before SpO₂ is reduced. Effective intervention measures are given to patients within this time frame, which reduces the incidence of hypoxia and severe hypoxia in patients. Trial registration: Ethical approval was granted by the Medical Ethics Committee (Chairperson Professor Tian Hui) of Qilu Hospital, Shandong University ((Ke) Lun Audit 2021 (186)) on 15/07/2021. The study was registered (https://www.chictr.org.cn) on 23/10/2021(ChiCTR2100052234). Designed and reported using CONSORT statements.

Background: Remimazolam tosilate is a new ultra-short-acting benzodiazepine sedative medicine. In this study, we evaluated the effect of remimazolam tosilate on the incidence of hypoxemia during sedation in elderly patients undergoing gastrointestinal endoscopy.Methods: Patients in the remimazolam group received an initial dose of 0.1 mg/kg and a bolus dose of 2.5 mg of remimazolam tosilate, whereas patients in the propofol group received an initial dose of 1.5 mg/kg and a bolus dose of 0.5 mg/kg of propofol. Patients received ASA standard monitoring (heart-rate, non-invasive blood pressure, and pulse oxygen saturation) during the entire examination process. The primary outcome was the incidence of moderate hypoxemia (defined as 85%≤ SpO₂< 90%, >15s) during the gastrointestinal endoscopy. The secondary outcomes included the incidence of mild hypoxemia (defined as SpO₂ 90%–94%) and severe hypoxemia (defined as SpO₂< 85%, >15s), the lowest pulse oxygen saturation, airway maneuvers used to correct hypoxemia, patient’s hemodynamic as well as other adverse events.Results: 107 elderly patients (67.6 ± 5.7 years old) in the remimazolam group and 109 elderly patients (67.5 ± 4.9 years old) in the propofol group were analyzed. The incidence of moderate hypoxemia was 2.8% in the remimazolam group and 17.4% in the propofol group (relative risk [RR] = 0.161; 95% confidence interval [CI], 0.049 to 0.528; p < 0.001). The frequency of mild hypoxemia was less in the remimazolam group, but not statistically significant (9.3% vs. 14.7%; RR = 0.637; 95% CI, 0.303 to 1.339; p = 0.228). There was no significant difference in the incidence of severe hypoxemia between the two groups (4.7% vs. 5.5%; RR = 0.849; 95% CI, 0.267 to 2.698; p = 0.781). The median lowest SpO₂ during the examination was 98% (IQR, 96.0%–99.0%) in patients in the remimazolam group, which was significantly higher than in patients in the propofol group (96%, IQR, 92.0%–99.0%, p < 0.001). Patients in the remimazolam group received more drug supplementation during endoscopy than patients in the propofol group (p = 0.014). There was a statistically significant difference in the incidence of hypotension between the two groups (2.8% vs. 12.8%; RR = 0.218; 95% CI, 0.065 to 0.738; p = 0.006). No significant differences were found in the incidence of adverse events such as nausea and vomiting, dizziness, and prolonged sedation.Conclusion: This study explored the safety of remimazolam compared with propofol during gastrointestinal endoscopy in elderly patients. Despite the increased supplemental doses during sedation, remimazolam improved risk of moderate hypoxemia (i.e., 85%≤ SpO₂ < 90%) and hypotension in elderly patients.

Background: Cardiac failure is the primary cause of death in most patients with pulmonary arterial hypertension (PH). As pleiotropic cytokines, human resistin (Hresistin) and its rodent homolog, resistin‐like molecule α, are mechanistically critical to pulmonary vascular remodeling in PH. However, it is still unclear whether activation of these resistin‐like molecules can directly cause PH‐associated cardiac dysfunction and remodeling. Methods and Results: In this study, we detected Hresistin protein in right ventricular (RV) tissue of patients with PH and elevated resistin‐like molecule expression in RV tissues of rodents with RV hypertrophy and failure. In a humanized mouse model, cardiac‐specific Hresistin overexpression was sufficient to cause cardiac dysfunction and remodeling. Dilated hearts exhibited reduced force development and decreased intracellular Ca ²⁺ transients. In the RV tissues overexpressing Hresistin, the impaired contractility was associated with the suppression of protein kinase A and AMP‐activated protein kinase. Mechanistically, Hresistin activation triggered the inflammation mediated by signaling of the key damage‐associated molecular pattern molecule high‐mobility group box 1, and subsequently induced pro‐proliferative Ki67 in RV tissues of the transgenic mice. Intriguingly, an anti‐Hresistin human antibody that we generated protected the myocardium from hypertrophy and failure in the rodent PH models. Conclusions: Our data indicate that Hresistin is expressed in heart tissues and plays a role in the development of RV dysfunction and maladaptive remodeling through its immunoregulatory activities. Targeting this signaling to modulate cardiac inflammation may offer a promising strategy to treat PH‐associated RV hypertrophy and failure in humans.

Background: Blood urea nitrogen to albumin ratio (BAR) has been implicated in predicting outcomes of various inflammatory-related diseases. However, the predictive value of BAR in long-term mortality in patients with acute myocardial infarction (AMI) has not yet been evaluated. Methods: In this retrospective cohort study, the patients were recruited from the Medical Information Mart for Intensive Care III (MIMIC III) database and categorized into two groups by a cutoff value of BAR. Kaplan–Meier (K-M) analysis and Cox proportional hazard model were performed to determine the predictive value of BAR in long-term mortality following AMI. In order to adjust the baseline differences, a 1:1 propensity score matching (PSM) was carried out and the results were further validated. Results: A total of 1827 eligible patients were enrolled. The optimal cutoff value of BAR for four-year mortality was 7.83 mg/g. Patients in the high BAR group tended to have a longer intensive care unit (ICU) stay and a higher rate of one-, two-, three- and four-year mortality (all p< 0.001) compared with those in the low BAR group. K-M curves indicated a significant difference in four-year survival (p< 0.001) between low and high BAR groups. The Cox proportional hazards model showed that higher BAR (> 7.83) was independently associated with increased four-year mortality in the entire cohort, with a hazard ratio (HR) of 1.478 [95% CI (1.254– 1.740), p< 0.001]. After PSM, the baseline characteristics of 312 pairs of patients in the high and low BAR groups were well balanced, and similar results were observed in K-M curve (p=0.003). Conclusion: A higher BAR (> 7.83) was associated with four-year mortality in patients with AMI. As an easily available biomarker, BAR can predict the long-term mortality in AMI patients independently.