Thymosin ß4 increases cardiac cell proliferation, cell engraftment, and the reparative potency of human induced-pluripotent stem cell-derived cardiomyocytes in a porcine model of acute myocardial infarction.

Rationale: Previous studies have shown that human embryonic stem cell-derived cardiomyocytes improved myocardial recovery when administered to infarcted pig and non-human primate hearts. However, the engraftment of intramyocardially delivered cells is poor and the effectiveness of clinically relevant doses of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in large animal models of myocardial injury remains unknown. Here, we determined whether thymosin ß4 (Tb4) could improve the engraftment and reparative potency of transplanted hiPSC-CMs in a porcine model of myocardial infarction (MI). Methods: Tb4 was delivered from injected gelatin microspheres, which extended the duration of Tb4 administration for up to two weeks in vitro. After MI induction, pigs were randomly distributed into 4 treatment groups: the MI Group was injected with basal medium; the Tb4 Group received gelatin microspheres carrying Tb4; the CM Group was treated with 1.2 × 108 hiPSC-CMs; and the Tb4+CM Group received both the Tb4 microspheres and hiPSC-CMs. Myocardial recovery was assessed by cardiac magnetic resonance imaging (MRI), arrhythmogenesis was monitored with implanted loop recorders, and tumorigenesis was evaluated via whole-body MRI. Results: In vitro, 600 ng/mL of Tb4 protected cultured hiPSC-CMs from hypoxic damage by upregulating AKT activity and BcL-XL and promoted hiPSC-CM and hiPSC-EC proliferation. In infarcted pig hearts, hiPSC-CM transplantation alone had a minimal effect on myocardial recovery, but co-treatment with Tb4 significantly enhanced hiPSC-CM engraftment, induced vasculogenesis and the proliferation of cardiomyocytes and endothelial cells, improved left ventricular systolic function, and reduced infarct size. hiPSC-CM implantation did not increase incidence of ventricular arrhythmia and did not induce tumorigenesis in the immunosuppressed pigs. Conclusions: Co-treatment with Tb4-microspheres and hiPSC-CMs was safe and enhanced the reparative potency of hiPSC-CMs for myocardial repair in a large-animal model of MI.

Right-to-left shunt and subclinical ischemic brain lesions in Chinese migraineurs: a multicentre MRI study.

BACKGROUND: Migraine is considered as a risk factor for subclinical brain ischemic lesions, and right-to-left shunt (RLS) is more common among migraineurs. This cross-sectional study assessed the association of RLS with the increased prevalence of subclinical ischemic brain lesions in migraineurs. METHODS: We enrolled 334 migraineurs from a multicentre study from June 2015 to August 2016. Participants were all evaluated using contrast-enhanced transcranial Doppler, magnetic resonance imaging (MRI), and completed a questionnaire covering demographics, the main risk factors of vascular disease, and migraine status. RLS was classified into four grades (Grade 0 = Negative; Grade I = 1 ≤ microbubbles (MBs) ≤ 10; Grade II = MBs > 10 and no curtain; Grade III = curtain). Silent brain ischemic infarctions (SBI) and white matter hyperintensities (WMHs) were evaluated on MRI. RESULTS: We found no significant differences between migraineurs with RLS and migraineurs without RLS in subclinical ischemic brain lesions.SBI and WMHs did not increase with the size of the RLS(p for trend for SBI = 0.066, p for trend for WMHs = 0.543). Furthermore, curtain RLS in migraineurs was a risk factor for the presence of SBI (p = 0.032, OR = 3.47; 95%CI: 1.12-10.76). There was no association between RLS and the presence of WMHs. CONCLUSION: Overall, RLS is not associated with increased SBI or WMHs in migraineurs. However, when RLS is present as a curtain pattern, it is likely to be a risk factor for SBIs in migraineurs. TRIAL REGISTRATION: No. NCT02425696 ; registered on April 21, 2015.

Prevalence and extent of right-to-left shunt on contrast-enhanced transcranial Doppler in Chinese patients with migraine in a multicentre case-control study.

Background The association between RLS and migraine is still debated. The aim of this study is to investigate the prevalence and grade of RLS in Chinese patients with migraine and to evaluate the relationship between RLS and migraine. Methods A multi-center case-control study of contrast-enhanced transcranial Doppler was conducted in 931 consecutive patients with migraine (240 of 931 had migraine with aura and 691 of 931 were in the migraine without aura group) and 282 were healthy adults. Clinical trial no. NCT02425696. Results The prevalence of RLS was 63.8% and 39.9% in the migraine with aura group (MA+) and migraine without aura group (MA-), respectively, significantly higher than that of the healthy group (29.4%, p < 0.001; p < 0.001). The positive rate of large RLS in the MA+ group and MA- group was 32.1% and 16.5%, respectively, significantly higher than healthy group (6.4%, p < 0.001; p < 0.001). There was no difference among groups in terms of positive rate of permanent RLS ( p = 0.704). Conclusion This multi-centre case-control study suggested that there is an association between RLS and migraine with and without aura, especially when the shunt is large.

Small dense low-density lipoproteins and associated risk factors in patients with stroke.

OBJECTIVE: Low-density lipoproteins (LDL) are a heterogeneous group of particles, with small, dense particles being more atherogenic. It remains controversial whether elevated plasma levels of small dense LDL (sd-LDL) are risk factors for stroke. The aim of the present study was to examine the plasma levels of sd-LDL in patients with stroke and to investigate the associations in a large Chinese case-control study. METHODS: We recruited 299 stroke patients (159 cerebral thrombosis, 42 lacunar infarction, 98 intracerebral hemorrhage) and 299 controls. The semiquantitative analysis of plasma levels of sd-LDL was performed by nondenaturing gradient gel electrophoresis. RESULTS: (1) The plasma levels of sd-LDL in patients with ischemic stroke or hemorrhagic stroke were higher than in controls. (2) Multiple regression analysis showed that there were significant relationships between sd-LDL and triglyceride, high-density lipoprotein cholesterol, LDL cholesterol, systolic blood pressure and history of diabetes, and a significant relationship between sd-LDL and stroke (r = 0.286, p < 0.001) even after adjusting for these factors. (3) Compared with the controls, the calculation of odds ratios indicated relative risk estimates of 3.111 for ischemic stroke (OR = 3.111 , 95% CI = 1.891-5.117, p < 0.001) and 3.164 for hemorrhagic stroke (OR = 3.164, 95% CI = 1.632-6.137, p < 0.01). CONCLUSION: Plasma sd-LDL was independently associated with both thrombotic and hemorrhagic stroke, suggesting it may be an independent predictor of as well as a risk factor for stroke in Chinese people, justifying clinical trials for primary and secondary prevention of stroke using statins or fibrates.

[Characteristics of cardiac arrhythmia in patients with hypertrophic cardiomyopathy].

OBJECTIVE: To investigate the patterns of arrhythmias in patients with hypertrophic cardiomyopathy (HCM) and its relation with the pathology of heart. METHODS: The clinical data, electrical cardiogram (ECG), Holter ECG recordings, and echocardiograms of 85 patients with HCM were collected and analyzed. RESULTS: Seventy four (87%) of the 85 patients with HCM had various forms of arrhythmia, including tachycardia in 30 patients with a prevalence of 35.3%, and bradycardia in 21 patients with a prevalence of 24.7%. The incidence rates of intraventricular conduction block and tachycardiac arrhythmia of the 24 HCM patients with syncope history were 45.8% and 50.0% respectively, both significantly higher than those of the 61 HCM patients without syncope history (21.3% and 26.2% respectively, both P > 0.05). The incidence rate of bradycardiac arrhythmia of the 24 HCM patients with syncope history was 50.0%, significantly higher than that of the 61 patients without syncope history (14.8%, P < 0.001). Arrhythmia, especially bradycardia, was more frequent in the patients with hypertrophy in mid-low part of interventricular septum and cardiac apex. CONCLUSION: Most patients with HCM have various cardiac arrhythmias, and occurrence of syncope and cardiac sudden death in the patients may be caused not only by tachycardia but also by bradycardia. Bradycardia is more frequent in the patients with hypertrophy in mid-low part of interventricular and cardiac apex.

[Association between mutation of phospholamban gene and dilated cardiomyopathy].

Phospholamban (PLB) is a prominent regulator of myocardial contractility and a reversible inhibitor of the cardiac sarcoplasmic reticulum Ca2+ ATPase activity. In normal cardiac muscles, phospholamban can be phosphorylated at distinct sites by various protein kinases and release its inhibition to sarcoplasmic reticulum Ca2+ ATPase. The studies of pedigrees have shown dilated cardiomyopathy (DCM) is related with mutation of PLB. The aim of present study is to investigate the relationship between mutation of PLB gene and DCM. Sixty patients with idiotic DCM were enrolled in present study. The clinical data were collected, including clinical symptoms, ECG and echocardiography. Peripheral blood samples of all these subjects were collected to extract genome DNA. The fragments of PLB gene were amplified by PCR and PCR fragment sequencing was performed to study weather mutation of phospholamban gene exists. phospholamban gene did not show any mutation in these patients. Most Chinese DCM patients may not be related with mutation of PLB gene.