TNNT2 Gene Polymorphisms are Associated with Susceptibility to Idiopathic Dilated Cardiomyopathy in Kazak and Han Chinese.

BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement, systolic dysfunction, and heart failure. Both genetic and non-genetic factors have been linked to DCM pathogenesis. Familial DCM (FDCM) accounts for 20%-50% of all DCM cases, highlighting the importance of genetics in pathogenesis. Indeed, more than 40 DCM-associated genes have been identified, including the gene encoding cardiac troponin T type-2 (TNNT2). We examined polymorphisms of the TNNT2 gene in idiopathic DCM (IDCM) patients of Kazak and Han ethnicity compared with healthy Kazak and Han controls. MATERIAL AND METHODS: Peripheral blood samples were collected from 180 patients with IDCM (90 Kazak and 90 Han), and 180 healthy controls (90 Kazak and 90 Han). PCR was used to amplify 15 exons and nearby introns of the TNNT2 gene. The amplified products were sequenced and compared to the standard sequence in PubMed by BLAST and CHROMAS software, to identify mutation sites. RESULTS: Results from Kazak and Han IDCM patients were complied for Hardy-Weinberg equilibrium analysis. There was a significant difference in the genotype distribution (χ2=6.67, P=0.015) and allele frequency (χ2=5.71, P=0.017) between Kazaks with IDCM and Kazak controls of SNP rs3729547. There was also a difference in the genotype distribution (χ2=6.62, P=0.036) and allele frequency (χ2=4.91, P=0.018) between Han with IDCM and Han controls. The TNNT2 gene polymorphism loci rs3729547 may be associated with the IDCM onset in Kazak and Han patients (OR=2.5, 95% CI: 1.233~5.068). CONCLUSIONS: The TNNT2 polymorphisms might play an important role in susceptibility to DCM in Xinjiang Kazak and Han patients.

Effects of ivabradine on cardiac electrophysiology in dogs with age-related atrial fibrillation.

BACKGROUND: Ivabradine is an inhibitor of mixed Na+-K+ current that could combine with HCN channels to reduce the transmembrane velocity of funny current (If), heart rate, and cardiac efficiency, and thus be used for the treatment of cardiovascular diseases such as chronic heart failure. As an ion channel blocker, Ivabradine is also a potential antiarrhythmic agent. MATERIAL/METHODS: Twelve aging dogs (8-10 years old) underwent rapid atrial pacing for 2 months to induce age-related AF in this study. The dogs were randomly divided into the Ivabradine group and aging-AF group. The effects of Ivabradine on the electrophysiological parameters, including the effective refractory period (ERP) of the pulmonary veins and atrium, duration of AF, and inducing rate of AF, were investigated. RESULTS: As compared to the aging-AF group, the ERPs of the left superior pulmonary vein (139.00±4.18 ms vs. 129.00±4.08 ms, P=0.005) and left auricle (135.00±3.53 ms vs. 122.00±4.47 ms, P=0.001) were significantly increased, while the duration of AF (46.60±5.07 s vs. 205.40±1.14 s, P=0.001) and inducing rate of AF (25% vs. 60%, P=0.001) were significantly decreased. CONCLUSIONS: Ivabradine could effectively reduce the inducing rate of AF, and thus be used as an upstream drug for the prevention of age-related AF.

Association between reversal in the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel and age-related atrial fibrillation.

BACKGROUND: We compared cardiac electrophysiological indicators and regional expression levels of cardiac hyperpolarization-activated cyclic nucleotide-gated (HCN) channels between adult and aged dogs to identify possible mechanisms of age-related atrial fibrillation. MATERIAL/METHODS: Corrected sinus node recovery time (SNRTc) and effective refractory period (ERP) of the atrium and pulmonary veins were measured in 10 adult (3-6 years old) and 10 aged dogs (>9 years old). Expression levels of HCN2 and HCN4 channel mRNAs and proteins were measured in the sinoatrial node, atrium, and pulmonary veins by real-time PCR and Western blotting. RESULTS: Aged dogs exhibited a higher induction rate of atrial fibrillation (AF) in response to electrical stimulation, longer AF duration after induction, longer SNRTc, longer right atrial effective refractory period (AERP), shorter left AERP, and increased AERP dispersion compared to adults. Expression levels of HCN2 and HCN4 channel mRNAs and proteins were lower in the sinoatrial node but higher in the atrium and pulmonary veins of aged dogs. CONCLUSIONS: Changes in atrial electrophysiological indicators in aged dogs revealed sinoatrial node dysfunction. There was a reversal in the local tissue distribution of HCN2 and HCN4 channel mRNA and protein, a decrease in sinoatrial node expression, and increase in atrial and pulmonary vein expression with age. Changes in atrial electrophysiological characteristics and regional HCN channel expression patterns were associated with the onset and maintenance of age-related atrial fibrillation.

Aspiration Thrombectomy Versus Stent-Retriever Thrombectomy for the First-Pass Therapy of Intracranial Atherosclerosis-Related Large Vessel Occlusion: A Post Hoc Analysis of The Endovascular Treatment With Versus Without Tirofiban for Patients with Large Vessel Occlusion Stroke Trial.

BACKGROUND: This study sought to scrutinize the clinical outcomes associated with first-pass mechanical thrombectomy strategies in the management of intracranial atherosclerosis (ICAS)-related large vessel occlusion (LVO). METHODS: Within this post-hoc analysis of the The Endovascular Treatment With vs Without Tirofiban for Patients with Large Vessel Occlusion Stroke (RESCUE BT) trial, we compared data pertaining to patients with ICAS-LVO situated in the anterior circulation who underwent initial therapeutic interventions utilizing either aspiration thrombectomy or stent-retriever thrombectomy. The analysis encompassed the assessment of intraprocedural recanalization, rescue procedures involving balloon angioplasty or stenting, 48-hour reocclusion rates, occurrences of cerebral hemorrhagic complications, and 90-day Modified Rankin Scale scores. RESULTS: Among the 948 patients encompassed in the RESCUE BT trial, a total of 230 patients with ICAS-LVO in the anterior circulation were enrolled in the study. Of these, 111 underwent aspiration thrombectomy as the first-pass therapy, while 119 patients underwent stent-retriever thrombectomy as the initial intervention. The difference in first pass recanalization rates between aspiration thrombectomy and stent-retriever thrombectomy was not statistically significant (17.1% vs. 14.3%, P = 0.555), and mechanical thrombectomy success rates (90.1% vs. 90.8%, P = 0.864), the use of balloon angioplasty or stenting for rescue therapy (54.6% vs. 45.9%, P = 0.189; 23.4% vs. 25.2%, P = 0.752), and favorable 90-day Modified Rankin Scale outcomes (53.2% vs. 40.3%, P = 0.051) showed no statistically significant differences. CONCLUSIONS: Both aspiration thrombectomy and stent-retriever thrombectomy can be considered as primary therapeutic options for patients presenting with ICAS-LVO in the anterior circulation.

Effects of Pacemaker Implantation on Sudden Cardiac Death Rate and Quality of Life in Atrial Fibrillation Patients With Ventricular Pauses.

Ventricular arrest is a rare arrhythmic disease in the clinic; 35% to 55% of cases are associated with atrial fibrillation (AF). It is well known that ventricular arrest for ≥3 seconds can lead to brain symptoms such as dizziness and even syncope, but it is not clear whether ventricular pauses (≥3 seconds) with AF will lead to sudden cardiac death. If the implantation of a pacemaker can improve the quality of life of patients with permanent AF with ventricular arrest and whether it has a long-term protective effect on sudden cardiac death. To this end, we conducted a prospective follow-up observation study, which was conducted through telephone interviews and clinical hospital observation to obtain information on the quality of life, survival rate, and other details. The results show that for patients with permanent AF with ventricular arrest, pacemaker implantation cannot reduce sudden cardiac death, cardiovascular events, and stroke nor can it improve the cumulative survival rate. Fortunately, the implantation of pacemakers can improve the quality of life of patients.

Long-term follow-up results of testicular torsion in children.

A retrospective cohort study was conducted at the Children's Hospital of Chongqing Medical University from November 2004 to December 2020 to investigate the long-term follow-up results after testicular torsion (TT) in children. Boys with TT were divided into the salvage orchiopexy group and the orchiectomy group, and the baseline characteristics, ultrasonographic indications, intraoperative findings, testicular volumes, and adverse events during follow-up were compared. A total of 145 cases were included in this study. Approximately 56.6% of patients who underwent salvage orchiopexy had testicular atrophy (TA), and the median testicular volume loss of the testes was 57.4%. Age less than 6 years, delayed surgery, and intraoperative poor blood supply were associated with TA in pediatric TT after orchiopexy. Most atrophied testes appeared within 3-6 months after surgery. Compared with the corresponding age-matched healthy controls, the contralateral testicular volumes were larger in the orchiopexy (P = 0.001 without TA, and P = 0.042 with TA) and orchiectomy groups (P = 0.033). The adverse events were comparable in patients with orchiectomy or orchiopexy. In summary, follow-up before 3 months after surgery may not offer sufficient clinical value, while that 3 months after surgery should be regarded as the first follow-up time for testicular monitoring. The contralateral testes of patients with TT showed compensatory hypertrophy. We suggest performing orchiectomy when torsed testes are surgically assessed as Arda grade III or inviable.

Thirty-Day Outcomes of the Enterprise Stent in Treating Hypoperfusion of Symptomatic Intracranial Stenosis.

OBJECTIVE: To evaluate the 30-day outcomes of using the Enterprise stent to treat patients with hypoperfusion of symptomatic severe intracranial stenosis. METHODS: Patients with symptomatic severe intracranial stenosis (70%-99%) who underwent Enterprise stent intervention between August 2014 and November 2018 were retrospectively analyzed. The 30-day primary outcomes included the success rate of stenting and the incidence of complications, including ischemic stroke, cerebral hemorrhage, and death. The 30-day complication rates of patients with different lesion locations and classifications of Mori morphology were compared. RESULTS: Sixty-eight patients were treated using 70 Enterprise stents. The success rate was 100%. The 30-day complication rate was 4.4%. The rates of ischemic stroke, cerebral hemorrhage, and death were 1.5%, 2.9%, and 0%, respectively. No significant difference was found in the 30-day complication rate between patients with different lesion locations and classifications of Mori morphology (P > 0.05). CONCLUSION: Enterprise stents were relatively safe in treating patients with hypoperfusion of symptomatic severe intracranial stenosis.

Lactobacillus acidophilus K301 Inhibits Atherogenesis via Induction of 24 (S), 25-Epoxycholesterol-Mediated ABCA1 and ABCG1 Production and Cholesterol Efflux in Macrophages.

Lactobacillus acidophilus species are well-known probiotics with the beneficial activity of regulating cholesterol levels. In this study, we showed that L. acidophilus K301 reduced the level of cholesterol through reverse transport in macrophages. L. acidophilus K301 upregulated the mRNA and protein levels of genes such as ATP-binding cassette A1 (ABCA1) and ATP-binding cassette G1 (ABCG1) under the control of liver X receptor (LXR), resulting in increased apoA-I-dependent cholesterol efflux in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells. L. acidophilus K301 induced both ABCA1 and ABCG1 through the endogenous LXR agonist 24(S), 25-epoxcycholesterol, which is synthesized by intracellular cholesterol synthetic pathways. In vivo studies using L. acidophilus K301-treated ApoE-/- mice showed reduced accumulation of lipoproteins in the arterial lumen. The inhibitory effects of L. acidophilus K301 on accumulation of lipoprotein in atherosclerotic plaques were mediated by the induction of squalene reductase (SQLE) and oxidosqualene cyclase (OSC) and resulted in ABCA1-mediated cholesterol efflux. Taken together, our findings revealed that Lactobacillus acidophilus K301 regulates the expression of genes related to cholesterol reverse transport via the induction of endogenous LXR agonist, suggesting the therapeutic potential of Lactobacillus acidophilus K301 as an anti-atherosclerotic agent.

Differential Cytokine Regulatory Effect of Three Lactobacillus Strains Isolated from Fermented Foods.

Lactic acid bacteria (LAB) isolated from fermented foods have potential as a treatment for immune-related disorders and the use of LAB has been increasing worldwide. In this study, the differential cytokine regulatory effect was examined with three isolates of lactobacilli strains; namely, Lactobacillus plantarum K55-5 isolated from dairy product, and L. sakei K101 and L. plantarum K8 previously isolated from kimchi (a Korean traditional fermented vegetable). Production of cytokines such as IL-10, IL-12, IFN-γ, and TNF-α was significantly increased in L. sakei K101- and L. plantarum K55-5-treated splenocytes as compared with controls. The oral administration of L. sakei K101 and L. plantarum K55-5 increased cytokine production in the immunosuppressed mouse splenocytes and blood. NK cell cytotoxic activity was also increased in L. sakei K101- and L. plantarum K55-5-fed mice. On the other hand, L. plantarum K8 did not affect cytokine induction in all the experiments performed in this study. The cytokine-inducing effect of L. plantarum K55-5 was significantly increased by lysates of heat-killed bacteria as compared with live, heat-killed, or supernatant of cell lysates. TNF-α production by lipoteichoic acids (LTAs) isolated from the three isolates of lactobacilli was compared, and it was found that K55-5 LTA had a highest cytokine-inducing ability, which was mediated by TLR2-mediated NF-κB and ERK activation. Taken together, our study suggests that L. plantarum K55-5 and L. sakei K101 can be used for the treatment of immunosuppressed disorders.

Lipoteichoic Acid Isolated from Weissella cibaria Increases Cytokine Production in Human Monocyte-Like THP-1 Cells and Mouse Splenocytes.

Lactic acid bacteria (LAB) have beneficial effects on intestinal health and skin diseases. Lipoteichoic acid (LTA), a cell wall component of gram-positive bacteria, is known to induce the production of several cytokines such as TNF-α, IL-1ß, and IL-8 and affect the intestinal microflora, anti-aging, sepsis, and cholesterol level. In this study, Weissella cibaria was isolated from Indian dairy products, and we examined its immune-enhancing effects. Live and heatkilled W. cibaria did not induce the secretion of immune-related cytokines, whereas LTA isolated from W. cibaria (cLTA) significantly increased the secretion of TNF-α, IL-1ß, and IL-6 in a dose-dependent manner. cLTA increased the phosphorylation of nuclear factor kappalight-chain-enhancer of activated B cells, p38 mitogen-activated protein kinases, and c-Jun N-terminal kinases in THP-1 cells. The secretion of TNF-α and IL-6 was also increased in the cLTA-treated mouse splenocytes. These results suggest that cLTA, but not W. cibaria whole cells, has immune-boosting potential and can be used to treat immunosuppression diseases.

Lipoteichoic acid isolated from Lactobacillus plantarum down-regulates UV-induced MMP-1 expression and up-regulates type I procollagen through the inhibition of reactive oxygen species generation.

BACKGROUND: Ultraviolet (UV) irradiation from the sun is the primary environmental factor that causes human skin aging. UV irradiation induces the expressions of matrix metalloproteinases (MMPs) and extracellular matrix degrading enzymes. Among the members of MMP family, MMP-1 is an interstitial collagenase that degrades the collagen triple helix. We investigated the effect of Lactobacillus plantarum, well known as useful microorganism, on UV-induced-MMP-1 expression in human dermal fibroblasts. METHODS: Human dermal fibroblasts (HDF) was pre-stimulated with lipoteichoic acid isolated from L. plantarum followed by UV irradiation. Secreted protein level of MMP-1 was evaluated by Western blot analysis. The phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) from the cell lysates was also examined by western blotting. Electrophoretic mobility-shift assay (EMSA) was used to detect the activated transcription factor, AP-1 and NF-κB. The detection of type 1 procollagen was carried with Procollagen type 1 C-peptide (PIP) EIA kit. The generation of reactive oxygen species (ROS) by LTA and UV irradiation was examined by Griess reagent assay and fluorescence microscope. RESULTS: We found that lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, isolated from L. plantarum, inhibited MMP-1 expression. Pretreatment with LTA from L. plantarum (pLTA) reduced MMP-1 expression in a dose-dependent manner and inhibited activation of extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK). It also led to the inhibition of DNA binding activity of activator protein-1 (AP-1) and of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB). Furthermore, LTA promoted type 1 procollagen synthesis and reduced the generation of ROS induced by UV irradiation. CONCLUSION: Our study demonstrates that pLTA inhibits degradation of collagen and promotes its synthesis and that pLTA contributes to a decrease in ROS production. Therefore, pLTA from L. plantarum has potential abilities to prevent and treat skin photo-aging.

Immune Regulatory Effect of Newly Isolated Lactobacillus delbrueckii from Indian Traditional Yogurt.

Lactic acid bacteria (LAB) are microorganisms that are believed to provide health benefits. Here, we isolated LAB from Indian fermented foods, such as traditional Yogurt and Dosa. LAB from Yogurt most significantly induced TNF-α and IL-1ß production, whereas LAB from Dosa induced mild cytokine production. After 16S rRNA gene sequencing and phylogenetic analysis, a Yogurt-borne lactic acid bacterium was identified and classified as Lactobacillus delbrueckii subsp. bulgaricus, and it was renamed L. delbrueckii K552 for the further studies. Our data suggest that the newly isolated L. delbrueckii can be used for the treatment of immune deficiency disorders.

Altered expression of hyperpolarization-activated cyclic nucleotide-gated channels and microRNA-1 and -133 in patients with age-associated atrial fibrillation.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels mediate pacemaker currents in the atrium. The microRNA (miR) families miR-1 and miR-133 regulate the expression of multiple genes involved in myocardial function, including HCN channels. It was hypothesized that age­dependent changes in HCN2, HCN4, miR­1 and miR­133 expression may contribute to age­associated atrial fibrillation, and therefore the correlation between expression levels, among adult (≤65 years) and aged patients (≥65 years), and sinus rhythm was determined. Right atrial appendage samples were collected from 60 patients undergoing coronary artery bypass grafting. Reverse transcription-quantitative polymerase chain reaction (PCR) and western blot analyses were performed in order to determine target RNA and protein expression levels. Compared with aged patients with sinus rhythm, aged patients with atrial fibrillation exhibited significantly higher HCN2 and HCN4 channel mRNA and protein expression levels (P<0.05), but significantly lower expression levels of miR­1 and miR­133 (P<0.05). In addition, aged patients with sinus rhythm exhibited significantly higher expression levels of HCN2 and HCN4 channel mRNA and protein (P<0.05), but significantly lower expression levels of miR­1 and ­133 (P<0.05), compared with those of adult patients with sinus rhythm. Expression levels of HCN2 and HCN4 increased with age, and a greater increase was identified in patients with age­associated atrial fibrillation compared with that in those with aged sinus rhythm. These electrophysiological changes may contribute to the induction of ectopic premature beats that trigger atrial fibrillation.

Different immune regulatory potential of Lactobacillus plantarum and Lactobacillus sakei isolated from Kimchi.

It is known that lactic acid bacteria (LAB) have many beneficial health effects, including antioxidative activity and immune regulation. In this study, the immune regulatory effects of Lactobacillus sakei and Lactobacillus plantarum, which are found in different types of kimchi, were evaluated. L. sakei and its lipoteichoic acid (LTA) have greater immune stimulating potential in IL-12, IFN-γ, and TNF-α production as compared with L. plantarum in an in vitro condition. On the other hand, L. plantarum is assumed to repress the Th1 immune response in murine experiments. After being injected with LPS, L. plantarum-fed mice maintained a healthier state, and the level of TNF-α in their blood was lower than in other bacterial strainfed mice and in the LPS-only control mice. Additionally, IL-12 production was significantly decreased and the production of IL-4 was greatly increased in the splenocytes from L. plantarum-fed mice. Further experiments revealed that the pre-injection of purified LTA from L. plantarum (pLTA), L. sakei (sLTA), and S. aureus (aLTA) decreased TNF-α and IL-4 production in LPS-injected mice. Mouse IL-12, however, was significantly increased by aLTA pre-injection. In conclusion, the L. sakei and L. plantarum strains have immune regulation effects, but the effects differ in cytokine production and the regulatory effects of the Th1/Th2 immune response.