Dapagliflozin attenuates LPS-induced myocardial injury by reducing ferroptosis.

Septic cardiomyopathy is a severe cardiovascular disease with a poor prognosis. Previous studies have reported the involvement of ferroptosis in the pathogenesis of septic cardiomyopathy. SGLT2 inhibitors such as dapagliflozin have been demonstrated to improve ischemia-reperfusion injury by alleviating ferroptosis in cardiomyocyte. However, the role of dapagliflozin in sepsis remains unclear. Therefore, our study aims to investigate the therapeutic effects of dapagliflozin on LPS-induced septic cardiomyopathy. Our results indicate that dapagliflozin improved cardiac function in septic cardiomyopathy experimental mice. Mechanistically, dapagliflozin works by inhibiting the translation of key proteins involved in ferroptosis, such as GPX4, FTH1, and SLC7A11. It also reduces the transcription of lipid peroxidation-related mRNAs, including PTGS2 and ACSL4, as well as iron metabolism genes TFRC and HMOX1.

Research on a Visual/Ultra-Wideband Tightly Coupled Fusion Localization Algorithm.

In the autonomous navigation of mobile robots, precise positioning is crucial. In forest environments with weak satellite signals or in sites disturbed by complex environments, satellite positioning accuracy has difficulty in meeting the requirements of autonomous navigation positioning accuracy for robots. This article proposes a vision SLAM/UWB tightly coupled localization method and designs a UWB non-line-of-sight error identification method using the displacement increment of the visual odometer. It utilizes the displacement increment of visual output and UWB ranging information as measurement values and applies the extended Kalman filtering algorithm for data fusion. This study utilized the constructed experimental platform to collect images and ultra-wideband ranging data in outdoor environments and experimentally validated the combined positioning method. The experimental results show that the algorithm outperforms individual UWB or loosely coupled combination positioning methods in terms of positioning accuracy. It effectively eliminates non-line-of-sight errors in UWB, improving the accuracy and stability of the combined positioning system.

Prediction of Drug-Drug Interactions with Ensartinib as a Time-Dependent CYP3A Inhibitor Using Physiologically Based Pharmacokinetic Model.

Ensartinib (X-396) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of ALK-positive patients with locally advanced or metastatic non-small cell lung cancer. Although in vitro experiments and molecular docking suggested its potential as a cytochrome P450 inhibitor, no further investigation or clinical trials have been conducted to assess its drug-drug interaction (DDI) risk. In this study, we conducted a series of in vitro experiments to elucidate the inhibition mechanism of ensartinib. Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed based on in vitro, in silico, and in vivo parameters, verified using clinical data, and applied to predict the clinical DDI mediated by ensartinib. The in vitro incubation experiments suggested that ensartinib exhibited strong time-dependent inhibition. Simulation results from the PBPK model indicated a significant increase in the exposure of CYP3A substrates in the presence of ensartinib, with the maximal plasma concentration and area under the plasma concentration-time curve increasing up to 12-fold and 29-fold for sensitive substrates. Based on these findings, it is evident that co-administration of ensartinib and CYP3A substrates requires careful regulatory consideration. SIGNIFICANCE STATEMENT: Ensartinib was found to be a strong time-dependent inhibitor of CYP3A for the first time based on in vitro experiments, but there was no research conducted to estimate the risk of drug-drug interaction (DDI) of ensartinib in clinic. Therefore, the first ensartinib physiologically based pharmacokinetic model was developed and applied to predict various untested scenarios. The simulation result indicated that the exposure of CYP3A substrate increased significantly and urged the further clinical DDI study.

Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity.

BACKGROUND: Galectin-3 (Gal-3), the only chimeric ß-galactosides-binding lectin, consists of Gal-3N (N-terminal regulatory peptide) and Gal-3C (C-terminal carbohydrate-recognition domain). Interestingly, Gal-3C could specifically inhibit endogenous full-length Gal-3 to exhibit anti-tumor activity. Here, we aimed to further improve the anti-tumor activity of Gal-3C via developing novel fusion proteins. METHODS: PK5 (the fifth kringle domain of plasminogen) was introduced to the N-terminus of Gal-3C via rigid linker (RL) to generate novel fusion protein PK5-RL-Gal-3C. Then, we investigated the anti-tumor activity of PK5-RL-Gal-3C in vivo and in vitro by using several experiments, and figured out their molecular mechanisms in anti-angiogenesis and cytotoxicity to hepatocellular carcinoma (HCC). RESULTS: Our results show that PK5-RL-Gal-3C can inhibit HCC both in vivo and in vitro without obvious toxicity, and also significantly prolong the survival time of tumor-bearing mice. Mechanically, we find that PK5-RL-Gal-3C inhibits angiogenesis and show cytotoxicity to HCC. In detail, HUVEC-related and matrigel plug assays indicate that PK5-RL-Gal-3C plays an important role in inhibiting angiogenesis by regulating HIF1α/VEGF and Ang-2 both in vivo and in vitro. Moreover, PK5-RL-Gal-3C induces cell cycle arrest at G1 phase and apoptosis with inhibition of Cyclin D1, Cyclin D3, CDK4, and Bcl-2, but activation of p27, p21, caspase-3, -8 and -9. CONCLUSION: Novel fusion protein PK5-RL-Gal-3C is potent therapeutic agent by inhibiting tumor angiogenesis in HCC and potential antagonist of Gal-3, which provides new strategy for exploring novel antagonist of Gal-3 and promotes their application in clinical treatment.

A Membrane-Permeable and Immobilized Metal Affinity Chromatography (IMAC) Enrichable Cross-Linking Reagent to Advance In†Vivo Cross-Linking Mass Spectrometry.

Cross-linking mass spectrometry (XL-MS) is an attractive method for the proteome-wide characterization of protein structures and interactions. Currently, the depth of in vivo XL-MS studies is lagging behind the established applications to cell lysates, because cross-linking reagents that can penetrate intact cells and strategies to enrich cross-linked peptides lack efficiency. To tackle these limitations, we have developed a phosphonate-containing cross-linker, tBu-PhoX, that efficiently permeates various biological membranes and can be robustly enriched using routine immobilized metal ion affinity chromatography. We have established a tBu-PhoX-based in vivo XL-MS approach that enables cross-links in intact human cells to be identified in high numbers with substantially reduced analysis time. Collectively, the developed cross-linker and XL-MS approach pave the way for the comprehensive XL-MS characterization of living systems.

Alopecines A-E, five chloro-containing matrine-type alkaloids with immunosuppressive activities from the seeds of Sophora alopecuroides.

Alopecines A-E (1-5), five unusual matrine-type alkaloids featuring with an additional dichlorocyclopropane (1-3) or a di/tri-chloromethyl (4/5) attached on the D ring, were isolated from the seeds of Sophora alopecuroides. Their structures and absolute configurations were elucidated by extensive spectroscopic techniques, and X-ray diffraction analyses or time-dependent density functional theory-based electronic circular dichroism (TDDFT-ECD) calculations. Alkaloid 4 exhibited potent inhibitory effects on the proliferation of ConA-induced T lymphocytes or LPS-induced B cells with IC50 value of 3.98 or 3.74 µM, respectively.

Qualitative and quantitative analysis of multiple components for quality control of Deng-Zhan-Sheng-Mai capsules by ultra high performance liquid chromatography tandem mass spectrometry method coupled with chemometrics.

Deng-Zhan-Sheng-Mai capsules are a well-known traditional Chinese patent medicine that was developed in China for the treatment of ischemic stroke. Its quality control focuses on Erigerontis Herba but ignores the contributions of Ginseng Radix et Rhizoma, Schisandrae Chinensis Fructus, and Ophiopogonis Radix. To improve the quality standards for this medicine, this work reports the application of a systematic ultra high performance liquid chromatography tandem mass spectrometric method coupled with chemometrics. Three qualitative and quantitative parameters are established for the evaluation of quality: chemical profiling, the relationship between the contents of 18 compounds and the antioxidant activity, and chemometric analysis. A total of 55 compounds, including 20 phenolic acids, 10 flavonoids, 15 saponins, and 10 lignans, were identified. The method for the quantitative determination of the aforementioned 18 compounds was validated. The limit of quantification ranged from 0.13 to 9.60 ng/mL. The overall recoveries ranged from 95.31 to 103.54%. Hierarchical cluster analysis and principal component analysis were applied to the data of 18 components in ten batches of samples. Nine compounds, including scutellarin, 3,5-O-dicaffeoylquinic acid, 4,5-O-dicaffeoylquinic acid, ginsenoside Rb1, ginsenoside Re, ginsenoside Rg1, ophiopogonin D, schisandrin, and schisandrol B, are suggested as chemical markers for evaluating the quality.

RNF125­mediated ubiquitination of MCM6 regulates the proliferation of human liver hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality worldwide. Minichromosome maintenance proteins (MCMs), particularly MCM2-7, are upregulated in various cancers, including HCC. The aim of the present study was to investigate the role of MCM2-7 in human liver HCC (LIHC) and the regulation of the protein homeostasis of MCM6 by a specific E3 ligase. Bioinformatics analyses demonstrated that MCM2-7 were highly expressed in LIHC compared with corresponding normal tissues at the mRNA and protein levels, and patients with LIHC and high mRNA expression levels of MCM2, MCM3, MCM6 and MCM7 had poor overall survival rates. Cell Counting Kit-8 and colony formation assays revealed that the knockdown of MCM2, MCM3, MCM6 or MCM7 in Huh7 and Hep3B HCC cells inhibited cell proliferation and colony formation. In addition, pull-down, co-immunoprecipitation and ubiquitination assays demonstrated that RNF125 interacts with MCM6 and mediates its ubiquitination. Furthermore, co-transfection experiments indicated that RNF125 promoted the proliferation of HCC cells mainly through MCM6. In summary, the present study suggests that the RNF125-MCM6 axis plays an important role in the regulation of HCC cell proliferation and is a promising therapeutic target for the treatment of LIHC.

[Meta-analysis of the role of fibular fixation in tibiofibular fractures].

OBJECTIVE: To compare the role and importance of fibular fixation in tibiofibular fractures by Meta-analysis. METHODS: The literature related to the comparison of the efficacy of fixation of the fibula with or without fixation on the treatment of tibiofibular fractures was searched through the databases of China Knowledge Network, Wipu, Wanfang, The Cochrane Library, Web of science and Pubmed, and statistical analysis was performed using RevMan 5.3 software. The rates of malrotation, rotational deformity, internal/external deformity, anterior/posterior deformity, non-union, infection, secondary surgery and operative time were compared between the fibula fixation and non-fixation groups. RESULTS: A total of 11 publications were included, six randomised controlled trials and five case-control trials, eight of which were of high quality. A total of 813 cases were included, of which 383 were treated with fibula fixation and 430 with unfixed fibulae.Meta-analysis results showed that fixation of the fibulae in the treatment of tibiofibular fractures reduced the rates of postoperative rotational deformity[RR=0.22, 95%CI(0.10, 0.45), P<0.000 1] and internal/external deformity[RR=0.34, 95%CI(0.14, 0.84), P=0.02] and promoted fracture healing [RR=0.76, 95%CI(0.58, 0.99), P=0.04]. In contrast, the rates of poor reduction [RR=0.48, 95% CI(0.10, 2.33), P=0.36], anterior/posterior deformity[RR=1.50, 95%CI(0.76, 2.96), P=0.24], infection[RR=1.43, 95%CI(0.76, 2.72), P=0.27], secondary surgery[RR=1.32, 95%CI(0.82, 2.11), P=0.25], and operative time[MD=10.21, 95%CI(-17.79, 38.21), P=0.47] were not statistically significant (P>0.05) for comparison. CONCLUSION: Simultaneous fixation of the tibia and fibula is clinically more effective in the treatment of tibiofibular fractures.

Physiologically Based Pharmacokinetic Modeling and Clinical Extrapolation for Topical Application of Pilocarpine on Eyelids: A Comprehensive Study.

Exploiting a convenient and highly bioavailable ocular drug delivery approach is currently one of the hotspots in the pharmaceutical industry. Eyelid topical application is seen to be a valuable strategy in the treatment of chronic ocular diseases. To further elucidate the feasibility of eyelid topical administration as an alternative route for ocular drug delivery, pharmacokinetic and pharmacodynamic studies of pilocarpine were conducted in rabbits. Besides, a novel physiologically based pharmacokinetic (PBPK) model describing eyelid transdermal absorption and ocular disposition was developed in rabbits. The PBPK model of rabbits was extrapolated to human by integrating the drug-specific permeability parameters and human physiological parameters to predict ocular pharmacokinetic in human. After eyelid topical application of pilocarpine, the concentration of pilocarpine in iris peaked at 2 h with the value of 18,724 ng/g and the concentration in aqueous humor peaked at 1 h with the value of 1,363 ng/mL. Significant miotic effect were observed from 0.5 h to 4.5 h after eyelid topical application of pilocarpine in rabbits, while that were observed from 0.5 h to 3.5 h after eyedrop instillation. The proposed eyelid PBPK model was capable of reasonably predicting ocular exposure of pilocarpine after application on the eyelid skin and based on the PBPK model, the human ocular concentration was predicted to be 10-fold lower than that in rabbits. And it was suggested that drugs applied on the eyelid skin could transfer into the eyeball through corneal pathway and scleral pathway. This work could provide pharmacokinetic and pharmacodynamic data for the development of eyelid drug delivery, as well as the reference for clinical applications.

Controlling the interaction between CaMKII and Calmodulin with a photocrosslinking unnatural amino acid.

Using unnatural amino acid mutagenesis, we made a mutant of CaMKII that forms a covalent linkage to Calmodulin upon illumination by UV light. Like wild-type CaMKII, the L308BzF mutant stoichiometrically binds to Calmodulin, in a calcium-dependent manner. Using this construct, we demonstrate that Calmodulin binding to CaMKII, even under these stochiometric conditions, does not perturb the CaMKII oligomeric state. Furthermore, we were able to achieve activation of CaMKII L308BzF by UV-induced binding of Calmodulin, which, once established, is further insensitive to calcium depletion. In addition to the canonical auto-inhibitory role of the regulatory segment, inter-subunit crosslinking in the absence of CaM indicates that kinase domains and regulatory segments are substantially mobile in basal conditions. Characterization of CaMKIIL308BzF in vitro, and its expression in mammalian cells, suggests it could be a promising candidate for control of CaMKII activity in mammalian cells with light.

Camrelizumab and apatinib combined with chemotherapy in perioperative effective therapy for advanced gastric carcinoma with peritoneal metastasis: a case report.

Background: Peritoneal metastases (PMs) are the most frequent metastatic pattern with a very poor prognosis in stage IV gastric cancer (GC). An effective therapeutic option has yet to be established. Combination therapy of anti-angiogenesis therapy, immunotherapy and chemotherapy was first used in advanced GC for perioperative treatment in this case. Case Description: A 39-year-old man was diagnosed with stage IV GC with PM (CY1, P1) and the patient had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 and adequate organ function. After disease progression on the first-line chemotherapy of paclitaxel plus S-1, the patient received a transformational therapy of camrelizumab (immune checkpoint inhibitors) plus apatinib (anti-angiogenic agent) combined with chemotherapy leading to macroscopic disappearance of the peritoneal lesions, negative peritoneal cytology, and the absence of other distant metastases, rendering him suitable to accept a radical gastrectomy with D2 lymph node dissection. The postoperative histopathology showed a tumor regression rate of more than 90%. Later, the patient was admitted for adjuvant therapy of camrelizumab plus apatinib combined with chemotherapy and relapsed at around 8 months after surgery. Treatment was well tolerated with no significant adverse effects. Conclusions: Camrelizumab plus apatinib combined with chemotherapy as second-line treatment demonstrated feasible anti-tumor activity and manageable safety in this advanced GC patient with PM and provided an opportunity for radical resection, improving the objective response rate (ORR) and prolonging patient survival. The incorporation may overcome resistance to treatment with therapy alone and produce synergistic effects, indicating a promising treatment option in the clinic to GC with PM.

CaMKII autophosphorylation can occur between holoenzymes without subunit exchange.

The dodecameric protein kinase CaMKII is expressed throughout the body. The alpha isoform is responsible for synaptic plasticity and participates in memory through its phosphorylation of synaptic proteins. Its elaborate subunit organization and propensity for autophosphorylation allow it to preserve neuronal plasticity across space and time. The prevailing hypothesis for the spread of CaMKII activity, involving shuffling of subunits between activated and naive holoenzymes, is broadly termed subunit exchange. In contrast to the expectations of previous work, we found little evidence for subunit exchange upon activation, and no effect of restraining subunits to their parent holoenzymes. Rather, mass photometry, crosslinking mass spectrometry, single molecule TIRF microscopy and biochemical assays identify inter-holoenzyme phosphorylation (IHP) as the mechanism for spreading phosphorylation. The transient, activity-dependent formation of groups of holoenzymes is well suited to the speed of neuronal activity. Our results place fundamental limits on the activation mechanism of this kinase.

Enhancing drug-drug Interaction Prediction by Integrating Physiologically-Based Pharmacokinetic Model with Fraction Metabolized by CYP3A4.

BACKGROUND: Enhancing the precision of drug-drug interaction (DDI) prediction is essential for improving drug safety and efficacy. The aim is to identify the most effective fraction metabolized by CY3A4 (fm) for improving DDI prediction using physiologically based pharmacokinetic (PBPK) models. RESEARCH DESIGN AND METHODS: The fm values were determined for 33 approved drugs using a human liver microsome for in vitro measurements and the ADMET Predictor software for in silico predictions. Subsequently, these fm values were integrated into PBPK models using the GastroPlus platform. The PBPK models, combined with a ketoconazole model, were utilized to predict AUCR (AUCcombo with ketoconazole/AUCdosing alone), and the accuracy of these predictions was evaluated by comparison with observed AUCR. RESULTS: The integration of in vitro fm method demonstrates superior performance compared to the in silico fm method and fm of 100% method. Under the Guest-limits criteria, the integration of in vitro fm achieves an accuracy of 76%, while the in silico fm and fm of 100% methods achieve accuracies of 67% and 58%, respectively. CONCLUSIONS: Our study highlights the importance of in vitro fm data to improve the accuracy of predicting DDIs and demonstrates the promising potential of in silico fm in predicting DDIs.

[Treatment of severe medial tibial bone defect in primary total knee arthroplasty with autogenous bone graft and plate fixation].

OBJECTIVE: To explore the technique of autogenous bone graft combined with plate fixation in total knee arthroplasty(TKA) with severe proximal medial tibial bone defect. METHODS: From March 2012 to October 2018, 21 patients (9 males and 12 females) with severe bone defects in the proximal medial tibia during primary total knee arthroplasty were treated with autogenous structural bone grafting and steel plate fixation, with an age of 61 to 77 years old with an average of (69.6±9.1) years and a course of 64 to 257 months with an average of (73.6±170.7) months. According to Rand classification, there were 13 cases of type Ⅲb and 8 cases of type Ⅳb. Postoperative complications were observed, and knee joint function was evaluated by the Hospital for Special Surgery (HSS) score and SF-36 quality of life score. RESULTS: All 21 patients were followed up for 37 to 64 months with an average of (49.5±13.7) months. The incisions of all patients healed smoothly, and 2 patients developed lower limb intermuscular venous plexus thrombosis after operation. There were no periprosthetic infection, loosening of prosthesis and other complications. The autogenous bone grafts of all patients achieved bony healing during postoperative X-ray follow-up, and the healing time was 8 to 13 months with an average of (10.1±2.3) months. The HSS score of patients increased significantly from 30 to 48 with an average of (53.4±4.2) before operation to 75 to 92 with an average of (81.2±8.4) at the final follow-up (P<0.05). The SF-36 quality of life score of patients after operation was significantly different from that before operation (P<0.05). CONCLUSION: The technique of autogenous bone graft combined with steel plate fixation can achieve satisfactory osseointegration effect in the treatment of severe proximal tibial bone defects in primary knee arthroplasty, with less complications and obvious improvement in knee function.

Collaboration between Law Enforcement Agencies in Combating Cybercrime: Implications of a Taiwanese Case Study about ATM Hacking.

An increasing number of cybercrimes has presented new global challenges to law enforcement agencies that traditionally operate within designated geographical jurisdictions and patrol territories. The borderless nature of cyberspace has brought substantial opportunities-both legal and illegal-to its users, and many local law enforcement agencies have encountered motivated offenders taking advantage of the globally connected Internet and causing damage locally and transnationally. This study examines a high-profile case of European criminals who hacked into a Taiwanese financial institution-First Commercial Bank (FCB)-and programmed its ATMs to "spit out" cash netting the thieves $2.6 million US dollars in 2016 summer. Before the incident of FCB, this European criminal group committed more than a hundred similar ATMs hackings, victimizing dozens of financial institutions across several European countries, and profiting over one billion Euros. FCB is the only case revealing specific details about the modus operandi of ATM hacking thus far, in addition to disclosing reactions from law enforcement. By analyzing qualitative data collected from different branches of law enforcement involved in the investigations, this unique case study underscores the importance of national-local law enforcement collaboration in fighting transnational cybercrime. Empirical implications are particularly valuable in the law enforcement context of "turf jealousies" when defending homeland security.

Peglated-H1/pHGFK1 nanoparticles enhance anti-tumor effects of sorafenib by inhibition of drug-induced autophagy and stemness in renal cell carcinoma.

BACKGROUND: Tumor targeting small molecular inhibitors are the most popular treatments for many malignant diseases, including cancer. However, the lower clinical response and drug resistance still limit their clinical efficacies. HGFK1, the first kringle domain of hepatocyte growth factor, has been defined as a potent anti-angiogenic factor. Here, we aimed to develop and identify novel nanoparticles-PH1/pHGFK1 as potential therapeutic agents for the treatment of renal cell carcinoma (RCC). METHODS: We produced a novel cationic polymer-PH1 and investigated the anti-tumor activity of PH1/pHGFK1 nanoparticle alone and its combination therapy with sorafenib in RCC cell line xenografted mice model. Then, we figured out its molecular mechanisms in human RCC cell lines in vitro. RESULTS: We firstly demonstrated that intravenous injection of PH1/pHGFK1 nanoparticles significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice, as well as synergistically enhanced anti-tumor activities of sorafenib. Furthermore, we elucidated that recombinant HGFK1 improved sorafenib-induced cell apoptosis and arrested cell cycle. In addition, HGFK1 could also decrease sorafenib-induced autophagy and stemness via blockading NF-κB signaling pathway in RCC both in vitro and in vivo. CONCLUSIONS: HGFK1 could inhibit tumor growth, synergistically enhance anti-tumor activities of sorafenib and reverse its drug resistance evolution in RCC. Our results provide rational basis for clinical application of sorafenib and HGFK1 combination therapy in RCC patients.

Cardiac rehabilitation in acute myocardial infarction patients after percutaneous coronary intervention: A community-based study.

BACKGROUND: Acute myocardial infarction (AMI) is one of the leading causes of death and physical disability worldwide. However, the development of community- based cardiac rehabilitation (CR) in AMI patients is hysteretic. Here, we aimed to evaluate the safety and efficacy of CR applied in the community in AMI patients who underwent percutaneous coronary intervention (PCI). METHODS: A total of 130 ST-segment elevated myocardial infarction (STEMI) patients after PCI were randomly divided into 2 groups in the community, rehabilitation group (n = 65) and control group (n = 65). Cardiac function, a 6-minute walk distance, exercise time and steps, cardiovascular risk factors were monitored respectively and compared before and after the intervention of 2 groups. The software of EpiData 3.1 was used to input research data and SPSS16.0 was used for statistical analysis. RESULTS: After a planned rehabilitation intervention, the rehabilitation group showed better results than the control group. The rehabilitation group had a significant improvement in recurrence angina and readmission (P < .01). Left ventricular ejection fraction (LVEF) of rehabilitation group showed improvement in phase II (t = 4.963, P < .01) and phase III (t = 11.802, P < .01), and the New York Heart Association (NYHA) classification was recovered within class II. There was a significant difference compared with before (Z = 7.238, P < .01). Six minutes walking distance, aerobic exercise time, and steps all achieved rehabilitation requirements in rehabilitation group in phase II and III, there existed distinct variation between 2 phases. Rehabilitation group had a better result in cardiovascular risk factors than control group (P < .05). CONCLUSION: Community-based CR after PCI through simple but safe exercise methods can improve the AMI patient's living quality, which includes increasing cardiac ejection fraction, exercise tolerance, and physical status. It must be emphasized that the good result should be established by the foundation of close cooperation between cardiologists and general practitioners, also the importance of cooperation of patients and their families should not be ignored. The rehabilitation program we used is feasible, safe, and effective.