Substances released by cardiomyocytes after myocardial infarction (MI) lead to inflammasome assembly. Heart failure (HF) is associated with skeletal muscle inflammation. Methotrexate (MTX) reduces cardiovascular outcomes in chronic inflammation patients. Lipid core nanoparticle-associated MTX (MTX-LDE) attenuated cardiac remodeling in MI rats. We investigated the effects of early MTX-LDE administration on cardiac remodeling and inflammasomes in soleus muscle of MI rats. Wistar rats were separated into Sham, MI, and MI-MTX groups. MTX was initiated 24 h after MI at 1 mg/kg/week intraperitoneally for 10 weeks. Soleus protein expression of NLRP1, NLRP3, NLRC4, ASC, procaspase-1, Caspase-1, pro-IL-1β, and IL-1β was quantified by Western blotting; Nlrp1a, Nlrp3, Nlrc4, Pycard (Asc), Casp1, and Il1b gene expression was assessed by qPCR; and statistical analysis used Student’s t test and ANOVA. Rats with infarction size > 35% total left ventricle (LV) area were included in the study; infarction size did not differ between groups. Echocardiogram showed infarcted groups with LV dilation and dysfunction. Diastolic function was worse in MI-MTX than MI. NLRP1 and NLRC4 protein expression was lower in MI-MTX than Sham. Expression of other proteins and gene expression did not differ between groups. Early MTX-LDE administration reduces NLRP1 and NLRC4 protein expression in soleus muscle without improving cardiac remodeling in rats.

BACKGROUND The coexistence of cardiac myxoma and hypertrophic cardiomyopathy is exceedingly rare and poses diagnostic and therapeutic challenges. While atrial myxomas may cause acute hemodynamic compromise, concomitant left ventricular outflow tract obstruction (LVOTO) due to hypertrophic cardiomyopathy can remain clinically underestimated, raising uncertainty regarding the optimal timing of septal reduction therapy. CASE REPORT A 38-year-old man was admitted with acute dyspnea and hypoxemia. Imaging revealed pulmonary congestion and a large left atrial mass causing functional mitral stenosis. Transthoracic echocardiography demonstrated asymmetric septal hypertrophy (maximum thickness 25 mm) with dynamic LVOTO and a mobile left atrial mass consistent with myxoma. The patient underwent surgical resection of the tumor with concomitant septal myectomy. Histopathology confirmed atrial myxoma and myocardial hyperplasia. Postoperatively, complete atrioventricular block required permanent dual-chamber pacemaker implantation. At short-term follow-up, the patient was asymptomatic with mild residual LVOTO. CONCLUSIONS This case underscores the importance of comprehensive structural and functional assessment in patients with intracardiac tumors. In young patients with favorable prognostic features and significant left atrial dilatation, early septal myectomy performed concomitantly with tumor resection may be justified, even when resting LVOT gradients are below conventional thresholds. This strategy aligns with the latest American and European guidelines on cardiomyopathies and may prevent delayed intervention and disease progression. The case also highlights atrioventricular block as a relevant complication of surgical myectomy, reinforcing the need for careful perioperative planning. Overall, this report provides an instructive example of individualized surgical decision-making in complex cardiomyopathy presentations.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial outcomes on the renal and cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, the effects of SGLT2 inhibition in Type 1 DM are not completely clarified. OBJECTIVE:To evaluate the effects of long-standing SGLT2 inhibitor dapagliflozin on the protein profile in rats with a Type 1 DM model. METHODS:Male Wistar rats were divided into Control (C), DM, and DM treated with dapagliflozin (DM+DAPA) for 30 weeks. DM was induced by a single injection of streptozotocin (40 mg/kg); dapagliflozin was added to chow (5 mg/kg/day). Label-free mass spectrometry was used to assess left ventricular proteome. The bioinformatic tools used were STRING, Cytoscape, Cluster Marker, and ClueGO. STATISTICAL ANALYSIS:ANOVA and Tukey or Kruskal-Wallis and Dunn. RESULTS:Dapagliflozin attenuated body weight loss (C 574 ± 43; DM 339 ± 31*; DM+DAPA 413 ± 30*# g; p < 0.05 * vs C; # vs DM) and reduced glycemia [C 108 (101-111); DM 554 (529-562)*; DM + DAPA 343 (237-416)*# mg/dL; p < 0.05 * vs C; # vs DM]. Most proteins identified in the networks downregulated in DM vs C were upregulated in DM + DAPA vs DM. Proteins related to energy metabolism (CKm, Ak1, Atp5pf, Mdh1, Idh2), excitation-contraction coupling (Actc1, Casq2, Serca1, Serca2a), and oxidative stress (Sod1, Sod2) were upregulated in DM + DAPA. KEGG pathways enriched in DM vs Control included gap junction, necroptosis, and fatty acid degradation (upregulated), and Alzheimer's disease, cardiac contraction, and glycolysis/gluconeogenesis (downregulated). In DM + DAPA vs DM, upregulated pathways included Parkinson's disease, cardiac contraction, citrate cycle, necroptosis, and cyclic guanosine monophosphate-dependent protein kinase (PKG) signaling pathway; downregulated proteins were linked to ketone body metabolism. CONCLUSION:Dapagliflozin modulates cardiac protein abundance by attenuating DM-induced changes in Type 1 DM rats.

Septic cardiomyopathy is recognized as an acute, transient, and reversible condition. However, septic insult may induce latent changes characteristic of cardiac remodeling, with future consequences. Therefore, the present study aimed to evaluate the morphological and functional cardiac changes in the acute and subacute phases (with 7-day follow-up) in male Wistar rats subjected to experimental sepsis using a cecal ligation and puncture (CLP) model. In the acute phase, the animals underwent echocardiographic assessment at baseline and 48 h after the induction of sepsis. In the subacute 7 days follow-up, animals were allocated in control and sepsis groups. After this period, the animals underwent echocardiographic assessment, followed by euthanasia, papillary muscle testing, and subsequent morphometric and biochemical analyses. Fecal samples from six animals per group were collected at baseline and after 7 days for microbiota analysis. In the acute phase, echocardiographic assessment revealed that, following sepsis, animals exhibited reduced systolic function. In the subacute 7 days follow-up, both echocardiogram and papillary muscles revealed cardiac dysfunction in the sepsis group. Cardiomyocyte cross-sectional area and collagen content were significantly greater in the sepsis group compared with that in the control group. Analysis of maximal enzymatic activities involved in cardiac energy metabolism and oxidative stress biomarkers revealed no significant differences between groups. Considering microbiota assessment, beta diversity analysis revealed significant differences between septic animals and controls. In conclusion, sepsis was associated with persistent systolic/diastolic dysfunction, cardiomyocyte hypertrophy, and fibrosis after 7 days. These data suggest that septic cardiomyopathy should not be considered merely an acute, transient, and reversible condition in this experimental context.

Skeletal muscle changes occur in heart failure (HF). Despite the cardioprotective effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors in HF, their impact on skeletal muscle remains poorly understood. We investigated the effects of the SGLT2 inhibitor empagliflozin (EMPA) on cardiac remodeling and the soleus muscle of rats with myocardial infarction (MI)-induced HF. METHODS:One week after MI induction, rats were assigned to Sham, Sham + EMPA, MI, and MI + EMPA groups. EMPA was administered (5 mg/kg/day) for 12 weeks. RESULTS:MI + EMPA and MI had dilated left cardiac chambers; the left atrium diameter and left ventricle end-diastolic area were smaller in MI + EMPA than MI. The ejection fraction did not differ between infarcted groups. MI + EMPA had a larger soleus cross-sectional area and higher Type II myosin heavy chain expression than MI. Carbonylated protein and malondialdehyde levels were lower and superoxide dismutase activity higher in MI + EMPA than MI. Respiratory Complex I expression was higher in MI + EMPA than MI. Metabolic enzyme activities, altered in MI, were normalized in MI + EMPA. EMPA up-regulated anabolic proteins and down-regulated catabolic proteins. CONCLUSION:Empagliflozin attenuates infarction-induced cardiac remodeling in rats. In soleus muscle, empagliflozin preserves cell trophism, reduces oxidative stress, normalizes muscle and mitochondrial metabolism, and positively modulates proteins involved in synthesis and degradation-related pathways.

Despite the introduction of new drugs, cardiac remodeling (CR) following myocardial infarction (MI) is still associated with increased mortality. Therefore, the search for new therapeutic strategies and bioactive compounds capable of attenuating CR is highly relevant. Although the underlying mechanisms are not fully understood, growing evidence suggests that oxidative stress regulation and modulation of the intestinal microbiota may contribute to the cardioprotective effects of bean consumption in cardiovascular diseases. We investigated the influence of bean flour on CR and intestinal microbiota after MI. Male Wistar rats underwent experimental infarction or sham surgery and were allocated into (1) Sham fed a standard diet (C = 18); (2) MI fed a standard diet (I = 22); and (3) MI fed a diet with bean flour (IB = 28) 15%. After 3 months were submitted to functional, morphometric, and biochemical study. The average infarct size was 38% for the I group and 40% for the IB group, there being no difference between the groups. The MI groups presented morphological changes and functional variables compared with C. Beans did not attenuate these changes, however, microbiota, the S24-7 Bacteroides, and the Halobacteriaceae firmicutes had reduced abundance after the MI in IB group. The supplementation of bean flour modulates the intestinal microbiota after MI. However, it does not attenuate the CR process following MI.

Acute myocardial necrosis activates the immune response and inflammatory processes. Although the initial response is helpful in restoring tissue injury, dysregulated and exacerbated inflammation contributes to the progression of cardiac remodeling. Inflammasomes play important roles in post-infarction inflammation. NALP1/NLRP1, NLRP 3, and NLRC4 are the best-known inflammasomes. NLRP3, which has received the most study in cardiovascular disease, has been linked to increased IL-1β (IL1B) production and caspase-1 activity, as well as impaired cardiac function. The role of NLRP1 and NLRC4 inflammasomes after acute myocardial infarction (MI) is poorly understood. We evaluated the expression of myocardial inflammasomes and inflammatory markers 72 h after MI in rats. Male Wistar rats were divided into Sham (n = 15) and MI (n = 16) groups. MI was induced by ligating the left anterior descending coronary artery. Infarct size was assessed by histology. Myocardial protein and gene expression was analyzed by Western blot and RT-qPCR, respectively. IL-1β (Il1b) concentrations in serum and heart macerate supernatant were evaluated by ELISA. Statistical analysis was performed using Student’s t test. Rats with an MI size less than 30% of the total left ventricle (LV) area were excluded; infarct size was 46 ± 11% of the total LV area in MI. The interstitial collagen fraction was higher in MI. Nlrc4, caspase-1 (Casp1), and IL-1β (Il1b) protein expressions were higher in MI. Nlrp3, Nlrp1, ASC (Pycard), pro-caspase-1, and pro-IL-1β (Il1b) expressions did not differ between groups. Expression of the Nlrp3 and ASC (Pycard) genes, as well as myocardial and serum IL-1β (Il1b) concentrations, was higher in MI. Acute post-myocardial infarction inflammation is characterized by increased protein expression of Nlrc4, caspase-1, and interleukin-1β; increased gene expression of Nlrp3 and ASC (Pycard); and elevated serum and myocardial concentrations of interleukin-1β in combination with an increased myocardial collagen interstitial fraction.

This study evaluated the effects of concurrent isolated training (T) or training combined with the antioxidant N-acetylcysteine (NAC) on cardiac remodeling and oxidative stress in spontaneously hypertensive rats (SHR). Six-month-old male SHR were divided into sedentary (S, n = 12), concurrent training (T, n = 13), sedentary supplemented with NAC (SNAC, n = 13), and concurrent training with NAC supplementation (TNAC, n = 14) groups. T and TNAC rats were trained three times a week on a treadmill and ladder; NAC supplemented groups received 120 mg/kg/day NAC in rat chow for eight weeks. Myocardial antioxidant enzyme activity and lipid hydroperoxide concentration were assessed by spectrophotometry. Gene expression of NADPH oxidase subunits Nox2, Nox4, p22 phox, and p47 phox was evaluated by real time RT-PCR. Statistical analysis was performed using ANOVA and Bonferroni or Kruskal–Wallis and Dunn. Echocardiogram showed concentric remodeling in TNAC, characterized by increased relative wall thickness (S 0.40 ± 0.04; T 0.39 ± 0.03; SNAC 0.40 ± 0.04; TNAC 0.43 ± 0.04 *; * p < 0.05 vs T and SNAC) and diastolic posterior wall thickness (S 1.50 ± 0.12; T 1.52 ± 0.10; SNAC 1.56 ± 0.12; TNAC 1.62 ± 0.14 * mm; * p < 0.05 vs T), with improved contractile function (posterior wall shortening velocity: S 39.4 ± 5.01; T 36.4 ± 2.96; SNAC 39.7 ± 3.44; TNAC 41.6 ± 3.57 * mm/s; * p < 0.05 vs T). Myocardial lipid hydroperoxide concentration was lower in NAC treated groups (S 210 ± 48; T 182 ± 43; SNAC 159 ± 33 *; TNAC 110 ± 23 *# nmol/g tissue; * p < 0.05 vs S, # p < 0.05 vs T and SNAC). Nox 2 and p22 phox expression was higher and p47 phox lower in T than S [S 1.37 (0.66–1.66); T 0.78 (0.61–1.04) *; SNAC 1.07 (1.01–1.38); TNAC 1.06 (1.01–1.15) arbitrary units; * p < 0.05 vs S]. NADPH oxidase subunits did not differ between TNAC, SNAC, and S groups. N-acetylcysteine supplementation alone reduces oxidative stress in untreated spontaneously hypertensive rats. The combination of N-acetylcysteine and concurrent exercise further decreases oxidative stress. However, the lower oxidative stress does not translate into improved cardiac remodeling and function in untreated spontaneously hypertensive rats.

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. However, as most trials have focused on Type 2 DM, the impact of SGLT2 inhibitors on Type 1 DM remains unclear. Objective To investigate the effects of long-term treatment with SGLT2 inhibitor dapagliflozin on the left ventricular (LV) proteome in Type 1 DM rats. Methods Male Wistar rats were divided into three groups: Control (C, n=7); Diabetes (DM, n=6); and Diabetes treated with Dapagliflozin (DM+DAPA, n=8) for 30 weeks. Diabetes was induced by streptozotocin (40 mg/kg). Dapagliflozin was added to chow at 5 mg/kg/day. Label-free mass spectrometry was used to assess LV proteome using a nanoAcquity UPLC-Xevo QTof MS system and ProteinLynx Global Server (PLGS) software. Cytoscape software, Cluster Marker, and Cluego plugins were used for bioinformatic analysis. Statistical analysis: ANOVA and Tukey or Kruskal-Wallis and Dunn. Results Dapagliflozin increased body weight (C 574±43; DM 339±31*; DM+DAPA 413±30*# g; p<0.05: * vs C; # vs DM) and reduced glycemia [C 108 (101–111); DM 554 (529–562)*; DM+DAPA 343 (237–416)*# mg/dL; p<0.05: * vs C; # vs DM]. One rat died in C and two in DM+DAPA. A total of 252 differentially expressed proteins were identified. Most proteins identified in the networks were downregulated in DM vs C and upregulated in DM+DAPA vs DM. Six proteins related to energy metabolism (Atp5j, P21571; CKm, P00564; Ak1, P39069; Atp5h, P31399; Mdh1, O88989; and Idh2, P56574), four involved in myocyte excitation-contraction (Act1, P68065; Casq2, P51868; SERCA1, Q64578; and SERCA2a, P11507), and two associated with oxidative stress (Sod1, P07632; and Sod2, P07895) were upregulated in DM+DAPA x DM. Comparing DM with C, the KEEG Pathway with the highest percentage of gene associations for upregulated proteins was related to gap junction (25.6%), necroptosis (25.6%), and fatty acid degradation (25.6%), and for downregulated proteins was related to Alzheimer disease (27.3%), cardiac muscle contraction (25%) and glycolysis/gluconeogenesis (13.6%). Comparing DM+DAPA with DM, the KEEG Pathway with the highest percentage of gene associations for upregulated proteins was related to Parkinson disease (18.3%), cardiac muscle contraction (14.2%), citrate acid cycle (9.47%), necroptosis (8.88%), and cGMP-PKG signaling (7.10 %), and for downregulated proteins was related to ketone bodies synthesis and degradation (100%). Conclusion Dapagliflozin is safe and prevents changes in the expression of proteins related to energy metabolism, cardiac muscle contraction, and oxidative stress in Type 1 diabetes mellitus rats. These results offer new insights into the cardioprotective mechanisms of dapagliflozin in Type 1 diabetes mellitus.

This study aimed to evaluate the influence of combined intermittent fasting (IF) and high‐intensity interval training (HIIT) on morphology, caspase‐independent apoptosis signaling pathway, and myostatin expression in soleus and gastrocnemius (white portion) muscles from healthy rats. Sixty‐day‐old male Wistar rats (n = 60) were divided into four groups: control (C), IF, high‐intensity‐interval training (T), and high‐intensity‐interval training and intermittent fasting (T‐IF). The C and T groups received ad libitum chow daily; IF and T‐IF received the same standard chow every other day. Animals from T and T‐IF underwent a HIIT protocol five times a week for 12 weeks. IF reduced gastrocnemius mass and increased pro‐apoptotic proteins apoptosis‐inducing factor (AIF) and endonuclease G (EndoG) in soleus and cleaved‐to‐non‐cleaved PARP‐1 ratio and myostatin expression in gastrocnemius white portion. HIIT increased AIF and apoptosis repressor with caspase recruitment domain expression in soleus and cleaved‐to‐total PARP‐1 ratio in gastrocnemius muscle white portion. The combination of IF and HIIT reduced fiber cross‐sectional area in both muscles, increased EndoG and AIF expression, and decreased cleaved‐to‐non‐cleaved PARP‐1 ratio in gastrocnemius muscle white portion. Muscle responses to IF and HIIT are directly impacted by the muscle fiber type composition and are modulated, at least in part, by myostatin and caspase‐independent apoptosis signaling.

Abstract Introduction Metabolic, morphological, and biochemical changes in skeletal muscle are common in chronic heart failure patients. Despite the cardioprotective effects of sodium-glucose co-transporter 2 (SGLT2) inhibition in heart failure, the impact of this drug on skeletal muscle remains poorly understood. This study investigated the effects of SGLT2 inhibitor empagliflozin (EMPA) on the soleus muscle of rats with myocardial infarction (MI)-induced heart failure. Methods One week after MI induction, male Wistar rats were divided into Sham (n=10), Sham+EMPA (n=12), MI (n=10) and MI+EMPA (n=09) groups. EMPA was added to rat chow (5 mg/kg/day) for 12 weeks. Cardiac remodeling was evaluated by echocardiogram. Enzymatic activity and oxidative stress marker concentrations were assessed by spectrophotometry; protein expression was evaluated by Western blotting. After histological analysis of the left ventricle (LV), only rats with MI greater than 35% of total LV area were included in the study. Statistical analysis: ANOVA and Tukey or Kruskal–Wallis and Dunn and t test; p<0.05. Results Infarction size did not differ between groups. Infarcted groups had larger LV systolic and diastolic diameters, LV diastolic area (Sham 47±7.1; Sham+EMPA 48±4.5; MI 100±16.1*; MI+EMPA 85±10.1#† mm2; p<0.05: * vs Sham; # vs Sham+EMPA; † vs MI), and left atrial diameter (Sham 5.62±0.2; Sham+EMPA 5.65±0.3; MI 7.69±1.3*; MI+EMPA 6.85±0.9#† mm; p<0.05: * vs Sham; # vs Sham+EMPA; † vs MI); and lower LV posterior wall shortening velocity and ejection fraction than control groups. Echocardiographic changes were attenuated in MI+EMPA compared to MI. Other results are shown in Picture 1. Conclusion SGLT2 inhibitor empagliflozin attenuates infarction-induced cardiac remodeling in rats. Empagliflozin prevents increase in oxidative stress, modulates protein turnover by IGF-1 pathway, and attenuates morphological and biochemical changes in the soleus muscle of infarcted rats.

Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have been shown to reduce oxidative stress and inflammation. In this study, we evaluated the effect of pretreatment with liraglutide on doxorubicin-induced acute cardiotoxicity. A total of 60 male Wistar rats were allocated into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received subcutaneous injection of liraglutide 0.6 mg/kg daily, while C and D received saline for 2 weeks. Afterwards, D and DL received a single intraperitoneal injection of doxorubicin 20 mg/kg; C and L received an injection of saline. Forty-eight hours after doxorubicin administration, the rats were subjected to echocardiogram, isolated heart functional study, and euthanasia. Liraglutide-treated rats ingested significantly less food and gained less body weight than animals that did not receive the drug. Rats lost weight after doxorubicin injection. At echocardiogram and isolated heart study, doxorubicin-treated rats had systolic and diastolic function impairment. Myocardial catalase activity was statistically higher in doxorubicin-treated rats. Myocardial protein expression of tumor necrosis factor alpha (TNF-α), phosphorylated nuclear factor-κB (p-NFκB), troponin T, and B-cell lymphoma 2 (Bcl-2) was significantly lower, and the total NFκB/p-NFκB ratio and TLR-4 higher in doxorubicin-treated rats. Myocardial expression of OPA-1, MFN-2, DRP-1, and topoisomerase 2β did not differ between groups (p > 0.05). In conclusion, doxorubicin-induced cardiotoxicity is accompanied by decreased Bcl-2 and phosphorylated NFκB and increased catalase activity and TLR-4 expression. Liraglutide failed to improve acute doxorubicin-induced cardiotoxicity in rats.

Objective: Hypertension and the aging process result in changes to the endothelial-related muscular system that may negatively impact exercise capacity. Research has shown that high-intensity interval training(HIIT) may be beneficial for individuals with hypertension.However, there are currently no studies that compare the effects of this type of exercise on endothelial markers in the skeletal muscles of aging rats.In order to examine the effects of HIIT on muscular microcirculation markers in hypertension, we assessed the genes encoding proteins related to vasomotor function (NOS3 and ET-1) and angiogenesis (VEGF and PIK3R2) in the soleus and diaphragm muscles of old spontaneously hypertensive rats. To corroborate our results, we analyzed the expression of these genes in samples from individuals who participated in HIIT for 6 weeks (GSE 109657). Design and method: Male 12-month-old spontaneously hypertensive rats were randomly assigned to either a sedentary group (n=10) or a high-intensity interval training (HIIT) group (n=10). The HIIT group underwent training on a rodent treadmill for 50 minutes per day, five times per week, for a period of eight weeks. Systolic blood pressure (SBP), functional capacity, and expression of endothelial gene-encoding proteins associated with NOS3, ET-1, VEGF, and PIK3R2 were analyzed. We retrieved a transcriptomic dataset (GSE109657) of human muscle biopsies collected from the vastus lateralis pre- and post-HIIT (a total of 22 samples, 11 pre-HIIT and 11 post-HIIT) for differential expression analysis. The relative expressions of NOS3, PIK3R2, VEGF were displayed through a heatmap using the MORPHEUS tool. In this dataset, ET-1 expression was not detected thus, we only represented the ET-2 transcriptional variant in the heatmap Results: Our findings indicated that that 8-week of HIIT led to a statistically significant reduction in SBP (p=0.001) and improvement in functional capacity (p<0.001) without affecting the expression of NOS3, PIK3R2, VEGF, or ET-1 in the soleus and diaphragm muscles. Additionally, our reanalysis of vastus lateralis muscle biopsy revealed no differences in the genes of interest, corroborating our results. Conclusions: These findings suggest that 8-week of HIIT may promote decreased arterial pressure and enhanced physical condition without interfering with the expression of mRNA-encoding vasomotor and angiogenic factors in different skeletal muscles.

Abstract Introduction Aortic stenosis (AS) represents one of the most prevalent valvular heart diseases and an important cause of heart failure. Currently, no medical therapies influence the natural history of aortic stenosis. Although sodium glucose co-transporter 2 inhibitors (SGLT2i) have improved cardiovascular outcomes in heart failure patients with both reduced and preserved ejection fraction, their action mechanisms are not clear. Transcriptome analysis present great potential to identify biomarkers of disease and to gain insight into disease pathophysiology. In this study, we analyzed myocardial mRNA profile in aortic stenosis rats treated with empagliflozin. Methods Eighteen weeks after supra-aortic banding surgery, male Wistar rats were divided into 3 groups: Sham (n=15); aortic stenosis (AS, n=27); AS+empagliflozin (AS-EMP, n=27). Empagliflozin (10 mg/kg/day) was added to rat chow for 8 weeks. Transcriptome of left ventricle (LV) myocardium was studied by RNA-sequencing (sample size: 5 per group). Differential gene expression was analyzed in R environment using the DESeq2 package. Genes were considered differentially expressed (DEG) when they exhibited a log2 fold change (log2FC) higher than 1 (upregulated) or lower than -1 (downregulated), coupled with an adjusted p-value below 0.05. Functional enrichment analysis using gene ontology was performed by the online tool Enrich. Statistical analysis: ANOVA and Tukey. Results AS-EMP had lower LV diastolic diameter (Sham 8.39±0.57; AS 9.80±0.53*; AS-EMP 9.08±0.87# mm; p<0.05: * vs Sham; # vs AS), left atrium diameter (Sham 5.68±0.40; AS 9.67±1.00*; AS-EMP 8.97±1.36*# mm; p<0.05: * vs Sham; # vs AS), and LV mass (Sham 0.85±0.11; AS 2.19±0.27*; AS-EMP 1.76±0.34*# g; p<0.05: * vs Sham; # vs AS) than AS. A total of 1246 differentially expressed genes were identified, comprising 663 upregulated genes (70 genes in AS vs SHAM; 593 in AS-EMP vs AS) and 583 downregulated genes (35 genes in AS vs SHAM; 548 in AS-EMP vs AS). Most of the differentially expressed genes were enriched in processes such as extracellular matrix and structure organization, signal transduction regulation, and substrate-dependent cell migration (AS vs SHAM), as well as myocardial contraction, negative regulation of programmed cell death, and mitochondrial membrane organization (AS-EMP vs AS). The main upregulated genes were Loxl1, Mfap4, Postn, Col8a1, Pi16, and Nppa in AS vs SHAM; and Mxra8, Zfta, Pnisr, Thoc1, and Ralbp1 in AS-EMP vs AS comparison. The main downregulated genes were Mxra8, Ralbp1, and Tubgcp6 in AS vs SHAM; and Itgb5, Ltbp2, Tmem109, Plec, and Rorc in AS-EMP vs AS comparison. Conclusion We identified myocardial genes and biological processes that are potentially involved in aortic stenosis-induced heart failure. Empagliflozin attenuates cardiac remodeling and modulates myocardial genes involved with myocyte contraction, apoptosis, and mitochondrial organization in aortic stenosis rats.

Abstract Background Cancer is one of the main causes of morbidity and mortality worldwide. Despite doxorubicin (DOX) being an effective chemotherapy drug, DOX-induced cardiotoxicity is the most severe side effect, limiting its use. There is no effective treatment for preventing DOX-induced cardiotoxicity. Gut microbiota seems to have a role in cardiovascular disease. Glucagon like peptide-1 (GLP-1) analogs such as liraglutide have shown benefits in cardiovascular diseases and seem to affect gut microbiota. Purpose To evaluate the role of liraglutide in modulating acute DOX-induced cardiotoxicity and gut microbiota. Methods Sixty male Wistar rats were allocated into four groups: Control (C), DOX (D), Liraglutide (L), and DOX + Liraglutide (DL). Animals in L and DL groups received a subcutaneous injection of 0.6 mg/kg liraglutide daily for 2 weeks. After 12 days, D and DL groups received an intraperitoneal injection of DOX (20 mg/kg). Rats were subjected to echocardiogram and isolated heart functional study 48 hours after DOX injection. At the end of the experiment, feces were collected to evaluate microbiota and short chain fatty acid concentration. Statistical analyses: Generalized linear model (GLM), ANCOVA and PERMANOVA (p<0.05). Results DOX-treated rats had worse cardiac function than rats that did not receive DOX in both echocardiography and isolated heart study; liraglutide did not change any functional parameters (Table). In feces, the phylum Bacteroidota was reduced in D and L groups compared to C and the phylum Pseudomonadota was increased in D and DL compared to C and L. Alpha-diversity did not differ between groups. Beta-diversity differed between C, D and L groups, and was similar between D and DL (Figure). Feces short chain fatty acid concentration was reduced in DOX-treated rats, with no effect from liraglutide (Figure). Conclusion DOX altered the function and composition of gut microbiota and caused acute cardiotoxicity; liraglutide changed gut microbiota and did not improve cardiac function.Table.Left ventricular functional dataFigure.Microbiota

Introduction: Spaced fiber bundles, less evident cell striations, deposition of collagen fiber bundles, and increased presence of fibroblasts in the cardiac tissue of rats that voluntarily and chronically ingested ethanol were observed by our research group. In addition, we observed increased proliferation and cell death of cardiomyocytes. To find out whether these changes lead to impaired heart functionality, some clinical tests were performed. Aim: to investigate whether chronic ethanol decreases the left ventricular performance assessed by exercise testing, electrocardiogram, and echocardiogram of male and female UChB strain rats. Material and methods: ten adult males and ten adult females, Wistar strain rats, named UChB (University of Chile), spontaneous high ethanol drinkers (consumption greater than 2 g ethanol / Kg body weight/day), and ten male UChB rats and ten adults female UChB rats, not exposed to ethanol, UChBC rats (controls) were used. Cardiac performance was evaluated by the stress test, electrocardiogram, and echocardiogram. Results: Exposed females showed ventricular morphological changes in the heart. The exposed females and males had the highest heart relative weight with females being larger than males. The exposed females showed altered electrocardiogram and echocardiogram. Conclusion: Chronic ethanol decreases the left ventricular cardiac performance in rats. Females are more sensitive to changes in cardiac electrical conduction.

Cardiotoxicity is the serious side effect of doxorubicin treatment. Ceramides are formed from the degradation of sphingolipids in cell membranes and play an important role in signaling and modulating biological processes. There is evidence that omega-3 fatty acid administration can act on this pathway. To evaluate the role of the ceramide pathway in the pathophysiology of doxorubicin-induced cardiotoxicity and the effect of omega-3 fatty acid supplementation in the attenuation of chronic doxorubicin-induced cardiotoxicity in rats. Sixty male Wistar rats were divided into four groups: Control (C), Doxorubicin (D), Omega-3 fatty acids (W), and Doxorubicin + Omega-3 fatty acids (DW). The groups received omega-3 fatty acids (400 mg/kg/day, via gavage) or water for 6 weeks and doxorubicin (3.5 mg/kg, intraperitoneal) or saline once a week for 4 weeks. Doxorubicin-treated animals showed increases in left atrium and left ventricle diameters, serum triglycerides and cholesterol, malondialdehyde, and protein carbonylation. We also observed a decrease in left ventricular shortening fraction and nSMase1 expression in the heart. Omega-3 fatty acid supplementation attenuated the structural and functional alterations caused by doxorubicin and decreased protein carbonylation. In contrast to doxorubicin, omega-3 fatty acids increased neutral nSMase activity in animals that both received and did not receive doxorubicin but with no effect on nSMase1 protein expression. Omega-3 fatty acid supplementation attenuated the cardiotoxicity caused by doxorubicin. The ceramide pathway may be involved in the pathophysiology of cardiotoxicity, but it is not the mechanism by which omega-3 fatty acids attenuated cardiac dysfunction.

Introduction: Exercise is an important therapeutic strategy for preventing and treating myocardial infarction (MI)-induced cardiac remodeling and heart failure. However, the myocardial effects of resistance exercise on infarcted hearts are not completely established. In this study, we investigated the effects of resistance exercise on structural, functional, and molecular cardiac alterations in infarcted rats. Methods: Three months after MI induction or simulated surgery, Wistar rats were assigned into three groups: Sham (n = 14); MI (n = 9); and exercised MI (MI-Ex, n = 13). Exercised rats performed, 3 times a week for 12 weeks, four climbs on a ladder with progressive loads. Cardiac structure and left ventricle (LV) function were analyzed by echocardiogram. Myocyte diameters were evaluated in hematoxylin- and eosin-stained histological sections as the smallest distance between borders drawn across the nucleus. Myocardial energy metabolism, lipid hydroperoxide, malondialdehyde, protein carbonylation, and antioxidant enzyme activities were evaluated by spectrophotometry. Gene expressions of NADPH oxidase subunits were evaluated by RT-PCR. Statistical analyses were performed using ANOVA and Tukey or Kruskal–Wallis and Dunn’s test. Results: Mortality did not differ between the MI-Ex and MI groups. MI had dilated left atrium and LV, with LV systolic dysfunction. Exercise increased the maximum load-carrying capacity, with no changes in cardiac structure or LV function. Myocyte diameters were lower in MI than in Sham and MI-Ex. Lactate dehydrogenase and creatine kinase activity were lower in MI than in Sham. Citrate synthase and catalase activity were lower in MI and MI-Ex than in Sham. Lipid hydroperoxide concentration was lower in MI-Ex than in MI. Nox2 and p22phox gene expressions were higher in MI-Ex than in Sham. Gene expression of Nox4 was higher in MI and MI-Ex than in Sham, and p47phox was lower in MI than in Sham. Conclusion: Late resistance exercise was safe in infarcted rats. Resistance exercise improved maximum load-carrying capacity, reduced myocardial oxidative stress, and preserved myocardial metabolism, with no changes in cardiac structure or left ventricle function in infarcted rats.