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Identification of galectin-3 as a novel potential prognostic/predictive biomarker and therapeutic target for cerebral cavernous malformation disease

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Genes & Diseases 2024年第1期11卷 67-71页

作者： Souvik Kar Andrea Perrelli Kiran Kumar Bali Raffaella Mastrocola Arpita Kar Bushra Khan Luis Gand Arnab Nayak Christian Hartmann Wolfram SKunz Amir Samii Helmut Bertalanffy Saverio Francesco Retta International Neuroscience Institute Rudolf-PichlmayrStrasse 4Hannover 30625Germany Department of Clinical and Biological Sciences University of TorinoOrbassano(TO)10043Italy CCM Italia Research Network National Coordination Center at the Department of Clinical and Biological SciencesUniversity of TorinoOrbassano(TO)10043Italy Department of Experimental Pain Research Mannheim Center for Translational Neuroscience(MCTN)Medical Faculty MannheimHeidelberg UniversityMannheim 68167Germany Department of Kidney Liver and Metabolic DiseasesChildren’s HospitalHannover Medical SchoolHannover 30625Germany Ricarda-Huch-Street-10B Hannover 30880Germany Institute of Molecular and Cell Physiology Hannover Medical SchoolHannover 30625Germany Department of Neuropathology Institute of PathologyHannover Medical SchoolHannover 30625Germany Institute of Experimental Epileptology and Cognition Research and Department of Epileptology University Hospital BonnVenusberg-Campus 1Bonn 53127Germany epartment of Pharmacology and Physiology University of Rochester Medical CenterRochesterNY 14642USA

cerebrovascular disease of genetic origin characterized by abnormally dilated capillaries and a wide spectrum of symptoms,including headaches,seizures,neurological deficits,and intracerebral hemorrhage.Its unpredictable clinical course and the current lack of therapies make the identification of prognostic and predictive biomarkers an imperative research challenge.1 Herein,we provide evidence that galectin-3(Gal-3),a major tissue and circulating biomarker of oxidative stress and inflammation,is significantly up-regulated both in CCM patients and experimentalmodels.Specifically,wholetranscriptome sequencing,qRT-PCR,and Western blotting studies demonstrated a significant up-regulation of Gal-3 expression levels both in surgical CCM specimens and in blood samples of CCM patients.

关键词： inflammation cerebral dilated

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RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy

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Protein & Cell 2019年第6期10卷 405-416页

作者： Jing Liu Xu Kong Mengkai Zhang Xiao Yang Xiuqin Xu The Institute of Stem Cell and Regenerative Medicine Medical College Xiamen University Xiamen 361100 China State Key Laboratory of Proteomics Genetic Laboratory of Development and Disease Institute of Biotechnology Beijing 100071 China

RNA splicing contributes to a broad spectrum of posttranscriptional gene regulation during normal development, as well as pathological manifestation of heart diseases. However, the functional role and regulation of splicing in heart failure remain poorly understood. RNA binding protein (RBP), a major component of the splicing machinery, is a critical factor in this process. RNA binding motif protein 24 (RBM24) is a tissue-specific RBP which is highly expressed in human and mouse heart. Previous studies demonstrated the functional role of RBM24 in the embryonic heart development. However, the role of RBM24 in postnatal heart development and heart disease has not been investigated. In this paper, using conditional RBM24 knockout mice, we demonstrated that ablation of RBM24 in postnatal heart led to rapidly progressive dilated cardiomyopathy (DCM), heart failure, and postnatal lethality. Global splicing profiling revealed that RBM24 regulated a network of genes related to cardiac function and diseases. Knockout of RBM24 resulted in misregulation of these splicing transitions which contributed to the subsequent development of cardiomyopathy. Notably, our analysis identified RBM24 as a splice factor that determined the splicing switch of a subset of genes in the sacomeric Z-disc complex, including Titin, the major disease gene of DCM and heart failure. Together, this study identifies regulation of RNA splicing by RBM24 as a potent player in remodeling of heart during postnatal development, and provides novel mechanistic insights to the pathogenesis of DCM.

关键词： RNA binding protein RBM24 dilated cardiomyopathy alternative splicing heart failure

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D-dimer level and long-term outcome in patients with end-stage heart failure secondary to idiopathic dilated cardiomyopathy

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Journal of Geriatric Cardiology 2019年第8期16卷 621-629页

作者： Bi HUANG Yuan-Jing LI Jian SHEN Yuan YANG Gang LIU Su-Xin LUO Department of Cardiology the First Affiliated Hospital of Chongqing Medical University

Background Previous studies had demonstrated hemostatic abnormalities in patients with heart failure (HF) and several studies have shown that abnormal coagulation indices, represented by elevated D-dimer, had prognostic significance in patients with compatible or acute decompensated HF. However, the impact of D-dimer on the outcome in patients with end-stage HF remains unclear. Methods A total of 244 consecutive patients with end-stage HF due to idiopathic dilated cardiomyopathy (DCM) were prospectively enrolled from February 2011 to September 2014. D-dimer levels were measured and its prognostic value was assessed. Primary endpoint was all-cause mortality during the follow-up period. Secondary endpoints were stroke, bleeding, occurrence of sustained ventricular tachycardia or ventricular fibrillation, and major adverse cardiovascular events (MACE). Results D-dimer was significantly elevated in the non-survivors (median: 0.8 vs. 1.1 mg/L, P < 0.001). Traditional markers including B-type natriuretic peptide, troponin I, left ventricular ejection fraction, and left ventricular end-diastolic dimension provided limited prognostic value;but the addition of D-dimer refined the risk stratification. The optimal cut-off value of D-dimer to predict all-cause mortality was 0.84 mg/L by receiver operator characteristic analysis. Elevated D-dimer level was independently associated with increased risk of long-term all-cause mortality (HR = 2.315, 95% CI: 1.570–3.414, P < 0.001) and MACE (HR = 1.256, 95% CI: 1.058–1.490, P = 0.009), and the predictive value was independent of age, sex, atrial fibrillation and anticoagulation status. Conclusions Elevated D-dimer level was independently associated with poor long-term outcome in patients with end-stage HF secondary to idiopathic DCM, and the predictive value was superior to that of traditional prognostic markers.

关键词： D-dimer End-stage heart failure Idiopathic dilated cardiomyopathy Long-term outcome

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Clinical characteristics, treatment and prognosis of patients with idiopathic dilated cardiomyopathy: a tertiary center experience

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Journal of Geriatric Cardiology 2019年第4期16卷 320-328页

作者： Abdullah Hagar Xiao-Bo PU Shi-Jian CHEN Jageshwar-Prasad Shah Mao CHEN Department of Cardiology West China HospitalSichuan UniversitySichuanChina Department of Cardiology Affiliated Minda Hospital of Hubei Institute for NationalitiesHubeiChina

Background Contemporary heart failure medications have led to considerable improvement in the survival of patients with heart failure. However,limited evidence is available regarding the effect of those medications in patients with idiopathic dilated cardiomyopathy (IDCM),particularly in China. We sought to analyze the trends in clinical characteristics and the prescription rate of recommended therapies and its prognostic impact in patients with IDCM. Methods From 2009 to 2016,1441 consecutive patients (age: 55±14 years,68% men,LVEF: 33%± 12%) fulfilling World Health Organization criteria for IDCM were enrolled in the current retrospective cohort study. Temporal trends of baseline clinical characteristics,treatment and prognosis were analyzed,and potential influential factors were explored. Results Rates of patients receiving angiotensin-converting enzyme inhibitors/angiotensin II receptors blockers,β-blockers,aldosterone receptor antagonists and diuretics increased from 55%,45%,58%,51% in 2009 to 67%,69%,71%,64% in 2016,respectively (P < 0.05);whereas,the proportion of patients receiving digoxin decreased from 39% in 2009 to 28% in 2016 (P < 0.05). The overall proportion of patients with optimal guideline-directed medical therapy (GDMT) was 44.6%;however,that rate increased from 33% in 2009 to 41%,49% and 56% in 2012,2014 and 2016 respectively (P < 0.05). Patients with optimal GDMT had a better outcome than those without,but there was no temporal trend toward improvement in the overall long-term prognosis of IDCM patients with the years. There was a trend towards admission of patients with milder disease and toward increased admission to a cardiology ward with the years. Conclusions An improvement in prescription rates of guideline-recommended medications in IDCM patients was observed. However,it remains suboptimal,and there is still some room for improvement. The prognosis of patients with optimal GDMT was better than those without. Moreover,the following patient category also had an improved prognosis: patient

关键词： dilated cardiomyopathy Heart failure Medications Prognosis

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Miraculous Recovery of a dilated Heart after Usage of Supramaximal Titrated Valsartan for 8 Months

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Chinese Medical Journal 2016年第22期129卷 2771-2772页

作者： Lan-Yan Guo Bing Liu Zhono-Chan Sun Yun Sun Jing-Xia Li Zheng He Department of Cardiology Xijing Hospital Fourth Military Medical University Xi'an Shaanxi 710032 China Department of Ultrasound Medicine Xijing Hospital Fourth Military Medical University Xi'an Shaanxi 710032 China

To the Editor：dilated cardiomyopathy （DCM） is characterized by ventricular chamber enlargement and systolic dysfunction.DCM is identified when complicated by severe clinical symptoms and disability and ultimately leads to progressive heart failure （HF） and a decline in left ventricular （LV） contractile function,ventricular and supraventricular arrhythmias,conduction system abnormalities,thromboembolism,and sudden heart failure-related death.

关键词： dilated cardiomyopathy characterized

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Dhcr24 activates the PI3K/Akt/HKII pathway and protects against dilated cardiomyopathy in mice

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Animal Models and Experimental Medicine 2018年第1期1卷 40-52页

作者： Wei Dong Fei-fei Guan Xu Zhang Shan Gao Ning Liu Wei Chen Lian-feng Zhang Dan Lu Key Laboratory of Human Disease Comparative Medicine NHFPC Institute of Laboratory Animal Science Chinese Academy of Medical Sciences & Comparative Medical Center Peking Union Medical College

Background: 24-dehydrocholesterol reductase(Dhcr24) catalyzes the last step of cholesterol biosynthesis, which is required for normal development and antiapoptotic activities of tissues. We found that Dhcr24 expression decreased in the cTnTR141 Wdilated cardiomyopathy(DCM) transgenic mice. Therefore, we tested whether rescued expression of Dhcr24 could prevent the development of DCM and its possible mechanism.Methods: Heart tissue specific transgenic overexpression mice of Dhcr24 was generated, then was crossed to c TnTR141 Wmouse to obtain the double transgenic mouse(DTG). The phenotypes were demonstrated by the survival, cardiac geometry and function analysis, as well as microstructural and ultrastructural observations based on echocardiography and histology examination. The pathway and apoptosis were analysed by western blotting and TUNEL assay in vivo and in vitro.Results: We find that Dhcr24 decreased in hearts tissues of cTnTR141 Wand LMNAE82 KDCM mice. The transgenic overexpression of Dhcr24 significantly improves DCM phenotypes in cTnTR141 Wmice, and activates PI3K/Akt/HKII pathway, followed by a reduction of the translocation of Bax and release of cytochrome c, caspase-9 and caspase-3 activation and myocyte apoptosis. Knockdown the expression of Dhcr24 reduces the activation of PI3K/Akt/HKII pathway and inhibition of the mitochondrial-dependent apoptosis. The anti-apoptotic effect of Dhcr24 could be completely removed by the inhibition of PI3K pathway and partly removed by the HKII inhibitor in H9c2 cell line.Conclusion: Compensatory expression of Dhcr24 protect against DCM through activated PI3K/Akt/HKII pathway and reduce Bax translocation. This is the first investigation for the molecular mechanism of Dhcr24 participate in development of DCM.

关键词： apoptosis Dhcr24 dilated cardiomyopathy gene expression and regulation

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Radionuclide techniques for evaluating dilated cardiomyopathy and ischemic cardiomyopathy

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Chinese Medical Journal 2000年第5期113卷 8-11页

作者：田月琴刘秀杰史蓉芳刘蕴忠吴清文张晓丽 Department of Nuclear Medicine Cardiovasc. Inst. and Fu Wai Hosp. CAMS and PUMC Beijing 100037 China

To assess the clinical significance of radionuclide techniques in evaluating dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (CAD CM) Methods 28 patients with DCM and 55 patients with CAD CM were studied All patients underwent 99m Tc MIBI myocardial perfusion SPECT and 18 F FDG myocardial metabolic PET 78 patients had 99m Tc RBC radionuclide ventriculography and 68 patients had coronary angiography Results The results of 23 patients (82%) with DCM showed mild and non segmental distribution perfusion abnormalities 52 patients with CAD CM (95%) showed perfusion abnormalities that distributed along the coronary vessel territories Significant perfusion defects were found in 4 patients with DCM (14%) and 45 patients with CAD CM (82%) ( P <0 01) The average perfusion score was 4 5±2 6 in DCM and 9 6±2 5 in CAD CM and the area of diminished perfusion was significantly smaller in DCM than in CAD CM ( P <0 001) Two patients with DCM and 18 patients with CAD CM had metabolic defects The patterns of perfusion/metabolic imaging showed mismatch in most patients with CAD CM but match in most patients with DCM The LVEF in patients with DCM and CAD CM was both decreased but the decreases were not statistically different between DCM and CAD CM The RVEF in patients with DCM was significantly lower than that in patients with CAD CM (32 4%±13 9% vs 40 9%±15 4%, P<0 05) Conclusion The radionuclide techniques are helpful for distinguishing DCM from CAD CM The segmental perfusion abnormality and RVEF are the most important factors for differentiation of DCM from CAD CM

关键词： cardiomyopathy dilated ischemic radionuclide imaging

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Effect of arotinolol on right ventricular function in patients with dilated cardiomyopathy

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Journal of Geriatric Cardiology 2007年第3期4卷 170-173页

作者： Hong Yang Li Xu Yongkang Tao Zhimin Xu Xiuqing Du Naqiang Lu Kefei Dou Jinglin Zhao Xianqi Yuan Yanfen Zhao Rongfang Shi Chaomei Fan Key Laboratory of Clinical Trials Research in Cardiovascular Drugs Ministry of HealthClinical Pharmacology CenterCardiovascular Institute and Fuwai Hospital CAMS and PUMCBeijing 100037China Key Laboratory of Clinical Trials Research in Cardiovascular DrugsMinistry of HealthClinical Pharmacology CenterCardiovascular Institute and Fuwai Hospital CAMS and PUMCBeijing 100037China Key Laboratory of Clinical Trials Research in Cardiovascular DrugsMinistry of HealthClinical Pharmacology CenterCardiovascular Institute and Fuwai Hospital CAMS and PUMCBeijing 100037China Key Laboratory of Clinical Trials Research in Cardiovascular DrugsMinistry of HealthClinical Pharmacology CenterCardiovascular Institute and Fuwai Hospital CAMS and PUMCBeijing 100037China Beijing Nuclear Industry Hospital Beijing 100042China. Beijing Nuclear Industry Hospital Beijing 100042China. Key Laboratory of Clinical Trials Research in Cardiovascular DrugsMinistry of HealthClinical Pharmacology CenterCardiovascular Institute and Fuwai Hospital CAMS and PUMCBeijing 100037China Key Laboratory of Clinical Trials Research in Cardiovascular DrugsMinistry of HealthClinical Pharmacology CenterCardiovascular Institute and Fuwai Hospital CAMS and PUMCBeijing 100037China Key Laboratory of Clinical Trials Research in Cardiovascular DrugsMinistry of HealthClinical Pharmacology CenterCardiovascular Institute and Fuwai Hospital CAMS and PUMCBeijing 100037China Key Laboratory of Clinical Trials Research in Cardiovascular DrugsMinistry of HealthClinical Pharmacology CenterCardiovascular Institute and Fuwai Hospital CAMS and PUMCBeijing 100037China Key Laboratory of Clinical Trials Research in Cardiovascular DrugsMinistry of HealthClinical Pharmacology CenterCardiovascular Institute and Fuwai Hospital CAMS and PUMCBeijing 100037China Key Laboratory of Clinical Trials Research in Cardiovascular DrugsMinistry of HealthClinical Pharmacology CenterCardiovascular Institute and Fuwai Hospital CAMS and PUMCBeijing 100037Ch

Objective dilated cardiomyopathy(DCM) is generally considered to be accompanied by both left and right ventricular dysfunction,but most studies only analyze the left ventricular function. In this study,we evaluated the effect of arotinolol on right ventricular function in patients with DCM. Methods Right ventricular ejection fraction(RVEF) and right ventricular diameter(RVD) were measured by two-dimensional echocardiography(2-DE) in 33 DCM patients;RVEF measured by first-pass radionuclide angiography(FPRA) was compared with that by 2-DE. Results The treatment with arotinolol for one year resulted in a reduction in the right ventricular diameter(baseline,23.0 ± 8.3 mm vs after one-year treatment,20.7 ± 5.4 mm;P=0.004 ) and an associated increase in ejection fraction(baseline,36.9 ± 10.3% vs after one-year treatment,45.8 ± 9.6%;P < 0.001 ) ;there is a high correlation between the 2-DE method and radionuclide ventriculographic method. The correlation coefficient is 0.933(P<0.001) . Conclusion Arotinolol therapy could not only improve left ventricular function,but also improve right ventricular function in DCM patients.

关键词： dilated cardiomyopathy arotinolol right ventricular function

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A rare cause of pulmonary hypertension in an elderly woman

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Journal of Geriatric Cardiology 2023年第4期20卷 314-316页

作者： Shing Ching Chiu Sun Yue Division of Cardiology Department of Medicine and GeriatricsUnited Christian HospitalHong KongChina

Diastolic dysfunction is a common substrate of pulmonary hypertension(PH) in the elderly.A minority of them,however,has another etiology of PH with diastolic dysfunction as a confounder,the alarming echocardiographic features of which are important to recognize.For example,dilated coronary sinus is unusual,as is significantly dilated right atrium.

关键词： hypertension dilated coronary

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Contemporary characteristics and outcomes of adults with familial dilated cardiomyopathy listed for heart transplantation

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World Journal of Cardiology 2019年第1期11卷 38-46页

作者： Mohamed Khayata Sadeer G Al-Kindi Guilherme H Oliveira Cardiology Section Department of Internal Medicine University Hospitals Cleveland Medical Center Harrington Heart and Vascular Institute

BACKGROUND Familial dilated cardiomyopathy(FDCM) account for 20%-30% of non-ischemic cardiomyopathies(NICM). Previous published data showed that some patients with FDCM tend to have rapidly progressive disease; however, five-year mortality was not significantly different in the familial and non-familial forms of NICM with optimal medical therapy.AIM To better define the characteristics and clinical outcomes of FDCM patients listed for heart transplantation(HT).METHODS We queried the United Network for Organ Sharing Registry to identify FDCM patients listed for HT between January 2008 and September 2015 and compared them to NICM and ischemic cardiomyopathy(ICM) patients. We included all patients ≥ 18 years old and we separated patients to three groups: FDCM, NICM and ICM. Chi-square test was used to compare between categorical variables, the t-test was used to compare between continues variables, and Cox-proportional hazards model was used to perform time-dependent survival analyses.RESULTS Of the 24809 adults listed for HT, we identified 677 patients(2.7%) with the diagnosis of FDCM. Compared to patients with NICM and ICM, FDCM patients were younger(FDCM 43.9 ± 13.5 vs NICM 50.9 ± 12.3, P < 0.001, vs ICM 58.5 ±8.1, P < 0.001), more frequently listed as status 2(FDCM 35.2% vs NICM 26.5%, P< 0.001), with significantly lower left ventricular assist device(LVAD) utilization(FDCM 18.4% vs NICM 25.1%, P < 0.001; vs ICM 25.6%, P < 0.001), but higher use of total artificial heart(FDCM 1.3% vs NICM 0.6%, P = 0.039; vs ICM 0.4%, P =0.002). Additionally, patients with FDCM were less frequently delisted for clinical deterioration or death and more likely to be transplanted compared to those with NICM [hazard ratio(HR): 0.617, 95% confidence interval(CI): 0.47-0.81; HR: 1.25,95%CI: 1.14-1.37, respectively], and ICM(HR: 0.5, 95%CI: 0.38-0.66; HR: 1.18,95%CI: 1.08-1.3, respectively). There was more frequent rejection among patients with FDCM(FDCM 11.4% vs NICM 9.8%, P = 0.28; vs ICM 8.4%, P = 0.034). One,three, and five post-tr

关键词： Familial dilated cardiomyopathy End-stage heart failure Wait list Transplant Outcomes

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