PD-L1 and AKT Overexpressing Adipose-Derived Mesenchymal Stem Cells Enhance Myocardial Protection by Upregulating CD25+ T Cells in Acute Myocardial Infarction Rat Model.

This study explores the synergistic impact of Programmed Death Ligand 1 (PD-L1) and Protein Kinase B (Akt) overexpression in adipose-derived mesenchymal stem cells (AdMSCs) for ameliorating cardiac dysfunction after myocardial infarction (MI). Post-MI adult Wistar rats were allocated into four groups: sham, MI, ADMSC treatment, and ADMSCs overexpressed with PD-L1 and Akt (AdMSC-PDL1-Akt) treatment. MI was induced via left anterior descending coronary artery ligation, followed by intramyocardial AdMSC injections. Over four weeks, cardiac functionality and structural integrity were assessed using pressure-volume analysis, infarct size measurement, and immunohistochemistry. AdMSC-PDL1-Akt exhibited enhanced resistance to reactive oxygen species (ROS) in vitro and ameliorated MI-induced contractile dysfunction in vivo by improving the end-systolic pressure-volume relationship and preload-recruitable stroke work, together with attenuating infarct size. Molecular analyses revealed substantial mitigation in caspase3 and nuclear factor-κB upregulation in MI hearts within the AdMSC-PDL1-Akt group. Mechanistically, AdMSC-PDL1-Akt fostered the differentiation of normal T cells into CD25+ regulatory T cells in vitro, aligning with in vivo upregulation of CD25 in AdMSC-PDL1-Akt-treated rats. Collectively, PD-L1 and Akt overexpression in AdMSCs bolsters resistance to ROS-mediated apoptosis in vitro and enhances myocardial protective efficacy against MI-induced dysfunction, potentially via T-cell modulation, underscoring a promising therapeutic strategy for myocardial ischemic injuries.

First-in-human pilot trial of combined intracoronary and intravenous mesenchymal stem cell therapy in acute myocardial infarction.

Background: Acute ST-elevation myocardial infarction (STEMI) elicits a robust cardiomyocyte death and inflammatory responses despite timely revascularization. Objectives: This phase 1, open-label, single-arm, first-in-human study aimed to assess the safety and efficacy of combined intracoronary (IC) and intravenous (IV) transplantation of umbilical cord-derived mesenchymal stem cells (UMSC01) for heart repair in STEMI patients with impaired left ventricular ejection fraction (LVEF 30-49%) following successful reperfusion by percutaneous coronary intervention. Methods: Consenting patients received the first dose of UMSC01 through IC injection 4-5 days after STEMI followed by the second dose of UMSC01 via IV infusion 2 days later. The primary endpoint was occurrence of any treatment-related adverse events and the secondary endpoint was changes of serum biomarkers and heart function by cardiac magnetic resonance imaging during a 12-month follow-up period. Results: Eight patients gave informed consents, of whom six completed the study. None of the subjects experienced treatment-related serious adverse events or major adverse cardiovascular events during IC or IV infusion of UMSC01 and during the follow-up period. The NT-proBNP level decreased (1362 ± 1801 vs. 109 ± 115 pg/mL, p = 0.0313), the LVEF increased (52.67 ± 12.75% vs. 62.47 ± 17.35%, p = 0.0246), and the wall motion score decreased (26.33 ± 5.57 vs. 22.33 ± 5.85, p = 0.0180) at the 12-month follow-up compared to the baseline values. The serial changes of LVEF were 0.67 ± 3.98, 8.09 ± 6.18, 9.04 ± 10.91, and 9.80 ± 7.56 at 1, 3, 6, and 12 months, respectively as compared to the baseline. Conclusion: This pilot study shows that combined IC and IV transplantation of UMSC01 in STEMI patients with impaired LVEF appears to be safe, feasible, and potentially beneficial in improving heart function. Further phase 2 studies are required to explore the effectiveness of dual-route transplantation of UMSC01 in STEMI patients.

Chronic Osteomyelitis Is Associated With Increased Risk of New-Onset Atrial Fibrillation: Evidence From a Nationwide Cohort of 23 Million People.

BACKGROUND: The objective of the study was to determine whether chronic osteomyelitis (COM) is associated with increased risk of new-onset atrial fibrillation (AF). METHODS: A national insurance claim data set of 23 million enrollees was used to identify 19,002 patients with newly-diagnosed COM and 76,008 randomly selected age- and sex-matched control subjects between January 1, 2000 and December 31, 2009 for comparing the risk and incidence of AF. The study end point was defined as the first diagnosis of AF, death, withdrawal from the insurance program, or the end of 2010. RESULTS: During a follow-up period of 91,927 person-years, the incidence of new-onset AF in COM cohort was 1.42-fold higher than for the non-COM cohort (4.54 vs 3.19 per 1000 person-years). After adjusting for age, sex, and classical AF risk factors such as hypertension, diabetes, heart failure, coronary artery disease, and valvular heart disease, the risk of new-onset AF remained significantly higher in the COM cohort (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.18-1.49; P < 0.0001). In age-stratified analysis, the younger population carried a higher risk for incident AF than the elderly population (from HR 2.05; 95% CI, 1.12-3.74 in age younger than 50 years to HR 1.19; 95% CI, 0.95-1.49 in age 80 years and older). The adjusted Kaplan-Meier analysis showed a lower AF-free survival rate in the COM group compared with the control group (log-rank P < 0.0001) during the follow-up period. CONCLUSIONS: This study showed that patients with COM carry an increased risk for developing new-onset AF, particularly in the younger population. Further studies are required to explore the underlying mechanisms that link COM and AF.

Peritoneal Dialysis is Associated With A Better Survival in Cirrhotic Patients With Chronic Kidney Disease.

Peritoneal dialysis (PD) can be an ideal treatment in cirrhotic patients with ascites and chronic kidney disease stage 5 (CKD 5D) who require dialysis. The survival of cirrhotic patients with CKD 5D on PD, however, is not clear. We compared the survival of cirrhotic patients with CKD 5D on PD and the survival of those on HD. Two datasets including a cohort study of China Medical University Hospital (CMUH) from 2004 to 2013 and the Longitudinal National Health Insurance Database for Catastrophic Illness Patients (LHID-CIP) of Taiwan from 1996 to 2011 were analyzed. The survival of cirrhotic patients on PD and the propensity score matched cirrhotic patients on HD were analyzed using Cox proportional hazards regression. In CMUH cohort of 85 PD and 340 HD patients, the all-cause mortality was lower in PD patients compared to it in HD patients (hazard ratio [HR]: 0.48, 95% confidence interval [CI]: 0.31-0.74, P < 0.01) after adjustments for confounders. The severity of liver cirrhosis defined by Child-Turcotte-Pugh (CTP) class (P < 0.01) was independently associated with all-cause mortality. The model for end-stage liver disease (MELD) score, however, was not associated with all-cause mortality. In the LHID-CIP cohort of 285 PD and 1140 HD patients, the HR of all-cause mortality in PD patients was 0.61 (95% CI: 0.47 - 0.79, P < 0.01), as compared with HD patients. PD in cirrhotic patients who need dialysis is associated with lower all-cause mortality than HD is. This association is independent of patients' comorbidity, severity of liver cirrhosis, and serum albumin levels.

Multidisciplinary care in patients with chronic kidney disease: A systematic review and meta-analysis.

BACKGROUND: Multidisciplinary care (MDC) was widely used in multiple chronic illnesses but the effectiveness of MDC in patients with chronic kidney disease (CKD) was inconclusive. The aim of this meta-analysis is to estimate the effectiveness of MDC for CKD. METHODS: We searched PubMed, Web of Science, Google Scholar, Cochrane Library, and China Journal Full-text Database for relevant articles published in English or Chinese. Studies investigating MDC and non-MDC in patients with CKD were included. Random effect model was used to compare all-cause mortality, dialysis, risk of temporal catheterization, and hospitalization in the two treatment entities. RESULTS: We analyzed 8853 patients of 18 studies in patients with CKD stages 3-5, aged 63±12 years. MDC was associated with lower risk of all-cause mortality with an odds ratio (OR) of 0.52 [95% confidence interval (CI): 0.44-0.88, p=0.01], mainly in cohort studies. MDC was associated with a lower risk of starting dialysis (p=0.02) and lower risk of temporal catheterization for dialysis (p<0.01). MDC was not associated with a higher chance of choosing peritoneal dialysis (p=0.18) or a lower chance of hospitalization for dialysis (p=0.13). CONCLUSIONS: Limited evidence from randomized controlled trials is currently available to support the benefit of MDC in patients with CKD. MDC is associated with lower all-cause mortality, lower risk of starting dialysis, and lower risk of temporal catheterization for dialysis in cohort studies. MDC is not associated with a higher chance of choosing peritoneal dialysis or a lower chance of hospitalization for dialysis. More studies are needed to determine the optimal professional that should be included in MDC.

Murine cardiosphere-derived cells are impaired by age but not by cardiac dystrophic dysfunction.

To be clinically relevant as a therapy for heart failure, endogenous progenitor cells must be isolated and expanded from aged and/or diseased tissue. Here, we investigated the effect of age and cardiac impairment resulting from lack of dystrophin on murine cardiosphere-derived cells (CDCs). CDCs were isolated and expanded from atrial biopsies from wild-type mice aged 1.5, 6, 18, and 24 months and from mdx mice aged 6 and 18 months. Cardiac function was measured in mdx mice and age-matched wild-type mice using high-resolution cine magnetic resonance imaging. CDCs could be isolated and expanded from all mice, however, the number of cells obtained, and their regenerative potential, decreased with age, as demonstrated by decreased expression of stem cell markers, c-kit and Sca-1, and decreased cell proliferation, migration, clonogenicity, and differentiation. Six-month-old mdx mice showed right ventricular (RV) dilation and reduced RV ejection fraction (EF) in comparison to wild-type mice. Older mdx mice displayed significant RV and left ventricular dilation and decreased EF in both ventricles, compared with age-matched wild-type mice. Mdx mouse hearts contained significantly more fibrotic tissue than age-matched wild-type mouse hearts. However, CDCs isolated from mice aged 6 and 18 months had the same number and regenerative potential from mdx mice and age-matched wild-type mice. Thus, the cardiac progenitor cell population is impaired by age but is not substantially altered by the progressive deterioration in function of the dystrophic heart.

Increased risk of coronary heart disease in patients with chronic osteomyelitis: a population-based study in a cohort of 23 million.

OBJECTIVES: Chronic inflammatory disease may trigger vascular atherosclerosis. This study aimed to determine whether chronic osteomyelitis (COM) is linked to an increased risk of coronary heart disease (CHD). METHODS: A national insurance claim dataset of more than 23 million enrolees was used to identify 15 054 patients with newly diagnosed COM and 60 216 randomly selected age-matched and gender-matched controls between 2001 and 2009 for comparing the risk and incidence of CHD. The study period was from the entry date to the first date of the following events: the diagnosis of CHD, death, withdrawal from the Taiwan National Health Insurance programme or the end of 2010. The analysis of the CHD risk was performed using Cox proportional hazards regression model. RESULTS: During a follow-up period of 67 927 person-years, the overall incidence rate of CHD in COM cohort was 1.95 times higher than non-COM cohort (16.66 vs 8.52 per 1000 person-years). After controlling age, gender and four comorbidities (hypertension, diabetes, hyperlipidaemia and stroke), the risk remained significantly higher in the COM cohort than the control group (adjusted HR=1.65, 95% CI 1.54 to 1.78, p<0.001). In age-stratified analysis, the younger population had a stronger association between COM and CHD risk than the elderly (from HR=3.42, 95% CI 1.60 to 7.32 in age <35 to HR 1.39, 95% CI 1.15 to 1.68 in age ≥80). CONCLUSIONS: This study demonstrates that COM is an independent risk factor for CHD, particularly in the younger population. Further studies are necessary to explore the underlying mechanisms linking COM and CHD.

Risk of pneumonia among patients with chronic kidney disease in outpatient and inpatient settings: a nationwide population-based study.

Patients with chronic kidney disease (CKD) are more at risk for pneumonia than the general population. Patients with pneumonia are usually treated as outpatients. However, previous studies were conducted on the basis of inpatient pneumonia. This method may underestimate the risk of pneumonia in patients with CKD. Therefore, we investigated the risk of pneumonia among CKD patients in both outpatient and inpatient settings. A total of 15,562 patients with CKD and 62,109 individuals without CKD (matched for age and gender) were taken as subjects in the Longitudinal Health Insurance Database of Taiwan National Insurance from 1996 to 2010. The incidence density rates of inpatient and outpatient pneumonia were calculated. The risk factors associated with pneumonia were analyzed using Cox proportional hazard models with adjustments for confounders. The incidence density rate of pneumonia was 65.6 per 1000 person-years in patients with CKD and 28.4 per 1000 person-years in individuals without CKD. The incidence density rate of inpatient pneumonia was 43.3 per 1000 person-years in patients with CKD and 16.6 per 1000 person-years in individuals without CKD. CKD was associated with increased risk of pneumonia (adjusted hazard ratio [aHR], 1.97; 95% confidence interval [CI], 1.89-2.05; P < 0.001), outpatient pneumonia (aHR, 1.40; 95% CI, 1.31-1.49), and inpatient pneumonia (aHR, 2.17; 95% CI, 2.07-2.29, P < 0.001). Patients' comorbidities, including diabetes, cardiovascular disease (CVD), asthma, and chronic obstructive pulmonary disease (COPD), were independently associated with increased risk of pneumonia.CKD is associated with the increased risk of both outpatient and inpatient pneumonia. This association is independent of comorbid diabetes, CVD, asthma, and COPD.

Stem cell-based therapy for ischemic heart disease.

Despite great advances in therapy over the past decades, ischemic heart disease (IHD) remains the leading cause of death worldwide because the decrease in mortality after acute myocardial infarction (AMI) leads to a longer life span in patients with chronic postinfarct heart failure (HF). There are no existing medical treatments that can cure chronic HF and the only currently available therapeutic option for end-stage HF is heart transplantation. However, transplantation is limited by the shortage of donor organs and patients require lifelong immunosuppression. In the past 10 years, stem cell-based cardiac therapy has been proposed as a promising approach for the treatment of IHD. There is a variety of potential stem cell types for cardiac repair and regeneration, including bone marrow cells (BMCs), resident cardiac stem cells (CSCs) and induced pluripotent stem cells (iPSCs). Stem cell-based therapy may comprise cell transplantation or cardiac tissue engineering (CTE), which might be an attractive alternative to solve the problems of low retention and poor survival of transplanted cells. This review focuses on the characteristics of stem cells from various sources and discusses the strategies of stem cell-based therapy for the treatment of IHD.