Amniotic Fluid Mesenchymal Stromal Cells Derived from Fetuses with Isolated Cardiac Defects Exhibit Decreased Proliferation and Cardiomyogenic Potential.

Amniotic fluid mesenchymal stromal cells (AF-MSCs) represent an autologous cell source to ameliorate congenital heart defects (CHDs) in children. The AF-MSCs, having cardiomyogenic potential and being of fetal origin, may reflect the physiological and pathological changes in the fetal heart during embryogenesis. Hence, the study of defects in the functional properties of these stem cells during fetal heart development will help obtain a better understanding of the cause of neonatal CHDs. Therefore, in the present study, we compared the proliferative and cardiomyogenic potential of AF-MSCs derived from ICHD fetuses (ICHD AF-MSCs) with AF-MSCs from structurally normal fetuses (normal AF-MSCs). Compared to normal AF-MSCs, the ICHD AF-MSCs showed comparable immunophenotypic MSC marker expression and adipogenic and chondrogenic differentiation potential, with decreased proliferation, higher senescence, increased expression of DNA-damaged genes, and osteogenic differentiation potential. Furthermore, the expression of cardiac progenitor markers (PDGFR-α, VEGFR-2, and SSEA-1), cardiac transcription factors (GATA-4, NKx 2-5, ISL-1, TBX-5, TBX-18, and MeF-2C), and cardiovascular markers (cTNT, CD31, and α-SMA) were significantly reduced in ICHD AF-MSCs. Overall, these results suggest that the AF-MSCs of ICHD fetuses have proliferation defects with significantly decreased cardiomyogenic differentiation potential. Thus, these defects in ICHD AF-MSCs highlight that the impaired heart development in ICHD fetuses may be due to defects in the stem cells associated with heart development during embryogenesis.

Prospective Longitudinal Characterization of the Relationship between Diabetes and Cardiac Structural and Functional Changes.

OBJECTIVES: In a cohort of type 2 diabetic (T2D) patients who underwent baseline cardiac magnetic resonance (CMR) and biomarker testing, during a median follow-up of 6 years, we aimed to determine longitudinal changes in the phenotypic expression of heart disease in diabetes, report clinical outcomes, and compare baseline clinical characteristics and CMR findings of patients who experienced major adverse cardiovascular events (MACE) to those remaining MACE free. BACKGROUND: T2D increases the risk of heart failure (HF) and cardiovascular mortality. The long-term impact of T2D on cardiac phenotype in the absence of cardiovascular disease and other clinical events is unknown. METHODS: Patients with T2D (n = 100) with no history of cardiovascular disease or hypertension were recruited at baseline. Biventricular volumes, function, and myocardial extracellular volume fraction (ECV) were assessed by CMR, and blood biomarkers were taken. Follow-up CMR was repeated in those without interim clinical events after 6 years. RESULTS: Follow-up was successful in 83 participants. Of those, 29 experienced cardiovascular/clinical events (36%). Of the remaining 59, 32 patients who experienced no events received follow-up CMR. In this cohort, despite no significant changes in blood pressure, weight, or glycated hemoglobin, significant reductions in biventricular end-diastolic volumes and ejection fractions occurred over time. The mean ECV was unchanged. Baseline plasma high-sensitivity cardiac troponin T (hs-cTnT) was significantly associated with a change in left ventricular (LV) ejection fraction. Patients who experienced MACE had higher LV mass and greater LV concentricity than those who remained event free. CONCLUSIONS: T2D results in reductions in biventricular size and systolic function over time even in the absence of cardiovascular/clinical events.

Male sex adversely affects the phenotypic expression of diabetic heart disease.

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of heart failure (HF) and cardiovascular mortality. A large-scale meta-analysis on HF found that diabetes was more frequent in women than men, and diabetes appeared to have attenuated the otherwise protective effect of female sex on progression of cardiomyopathy. The exact underlying mechanisms for this remain unclear. Here, we aimed to determine the effect of sex on the phenotypic expression of diabetic heart disease in patients with T2D. METHODS: A total of 62 male [mean age 44 ± 8 years, body mass index (BMI) 33 ± 5 kg/m2, mean HBA1c of 7.8 ± 1.8%] and 67 female (44 ± 10 years, BMI 35 ± 6 kg/m2, HBA1c 7.6 ± 1.2%) T2D patients on oral glucose-lowering treatment, and 16 male (48 ± 17 years, BMI 25 ± 3 kg/m2) and 14 female (50 ± 10 years, BMI 25 ± 4 kg/m2) controls were recruited. Left ventricular (LV) volumes, mass, function and deformation, and left atrial (LA) volumes and function were assessed using cardiac magnetic resonance imaging (CMR). RESULTS: Participants in all groups were of similar age, and there were no significant differences in blood pressure (BP), diabetes duration or metabolic profile between the two diabetes groups. Concentric remodeling was present in both sexes (p < 0.0001), with greater degree of concentric hypertrophy in males (12%, p = 0.0015). Biplane LA ejection fraction (LAEF) (p = 0.038), peak systolic circumferential strain (p < 0.0001) and diastolic strain rates (p = 0.001) were significantly reduced in men compared with women with T2D. There were no significant differences in biplane LAEF, peak systolic circumferential strain and diastolic strain rates in women with T2D compared with female controls. Whereas in women with T2D, glycaemic control was linked to LV contractile function, there was no such relationship in men with T2D. CONCLUSION: Male sex adversely affects the phenotypic expression of diabetic heart disease. The striking differences in the cardiac phenotype between male and female patients with T2D promote awareness of gender-specific risk factors in search of treatment and prevention of diabetes-associated HF. CONDENSED ABSTRACT: We aimed to determine the effect of sex on the phenotypic expression of diabetic heart disease in patients with T2D. While our findings support the notion that in T2D, male sex adversely affects the phenotypic expression of diabetic heart disease, this is in apparent conflict with the previous large-scale study showing diabetes attenuates the otherwise protective effect of female sex on progression of cardiomyopathy. Further longitudinal studies looking at gender differences in clinical outcomes in T2D patients are needed. These sex-related differences promote awareness of sex-specific risk factors in search of treatment and prevention of diabetes-associated HF.

A case report of acute myopericarditis associated with Graves' thyrotoxicosis.

BACKGROUND: The effects of hyperthyroidism on the heart are well documented, primarily consisting of supraventricular tachycardias, congestive heart failure, and dilated cardiomyopathy. Acute myopericarditis resulting from a hyperthyroid state is an uncommon but recognized association. CASE SUMMARY: A 29-year-old man with a history of Graves' disease presented with chest pain and electrocardiogram changes suggestive of an infero-lateral ST-elevation myocardial infarction. However, emergent coronary angiography and bedside echocardiography were normal. Troponin-I was found to be >25 000 ng/L (normal value <57). Thyroid function tests showed a significantly raised free T4 and undetectable thyroid-stimulating hormone. Cardiovascular magnetic resonance (CMR) showed extensive myocardial oedema and late gadolinium enhancement (LGE) in keeping with acute myopericarditis, alongside an enlarged thyroid gland consistent with goitre. Propylthiouracil in combination with an angiotensin-converting enzyme inhibitor and beta-blocker were commenced and eventually definitive treatment with thyroidectomy was performed. Follow-up CMR at 6 months showed complete resolution of the prior noted oedema and a reduction in the location and extent of LGE with significant residual fibrosis. DISCUSSION: Acute myopericarditis is a common diagnosis in young patients presenting with symptoms of chest pain with elevated troponin and is frequently related to a viral illness. Hyperthyroid states are also associated with acute myopericarditis and should be particularly considered in patients with a pre-existing thyroid condition or in those with symptoms suggestive of hyperthyroidism. Given the specific treatments required in a case of myopericarditis associated with hyperthyroidism, it is important to be aware of this association and consider screening where appropriate.

Amniotic fluid stem cells ameliorate cisplatin-induced acute renal failure through induction of autophagy and inhibition of apoptosis.

BACKGROUND: We have recently demonstrated that amniotic fluid stem cells (AFSC) express renal progenitor markers and can be differentiated in vitro into renal lineage cell types, viz, juxtaglomerular and renal proximal tubular epithelial-like cells. Here, we have evaluated the therapeutic efficacy of AFSC in a cisplatin-induced rat model of acute renal failure (ARF) and investigated the underlying mechanisms responsible for their renoprotective effects. METHODS: ARF was induced in Wistar rats by intra-peritoneal injection of cisplatin (7 mg/kg). Five days after cisplatin injection, rats were randomized into two groups and injected with either AFSC or normal saline intravenously. On days 8 and 12 after cisplatin injection, the blood biochemical parameters, histopathological changes, apoptosis and expression of pro-apoptotic, anti-apoptotic, and autophagy-related proteins in renal tissues were studied in both groups of rats. To further confirm whether the protective effects of AFSC on cisplatin-induced apoptosis were dependent on autophagy, chloroquine, an autophagy inhibitor, was administered by the intra-peritoneal route. RESULTS: Administration of AFSC in ARF rats resulted in improvement of renal function and attenuation of renal damage as reflected by significant decrease in blood urea nitrogen, serum creatinine levels, tubular cell apoptosis as assessed by Bax/Bcl2 ratio, and expression of the pro-apoptotic proteins, viz, PUMA, Bax, cleaved caspase-3, and cleaved caspase-9, as compared to the saline-treated group. Furthermore, in the AFSC-treated group as compared to the saline-treated group, there was a significant increase in the activation of autophagy as evident by increased expression of LC3-II, ATG5, ATG7, Beclin1, and phospho-AMPK levels with a concomitant decrease in phospho-p70S6K and p62 expression levels. Chloroquine administration led to significant reduction in the anti-apoptotic effects of the AFSC therapy and further deterioration in the renal structure and function caused by cisplatin. CONCLUSION: AFSC led to amelioration of cisplatin-induced ARF which was mediated by inhibition of apoptosis and activation of autophagy. The protective effects of AFSC were blunted by chloroquine, an inhibitor of autophagy, highlighting that activation of autophagy is an important mechanism of action for the protective role of AFSC in cisplatin-induced renal injury.

Comparison of the Cardiomyogenic Potency of Human Amniotic Fluid and Bone Marrow Mesenchymal Stem Cells.

BACKGROUND AND OBJECTIVES: Most studies in cardiac regeneration have explored bone marrow mesenchymal stem cells (BM-MSC) with variable therapeutic effects. Amniotic fluid MSC (AF-MSC) having extended self-renewal and multipotent properties may be superior to bone marrow MSC (BM-MSC). However, a comparison of their cardiomyogenic potency has not been studied yet. METHODS: The 5-azacytidine (5-aza) treated AF-MSC and BM-MSC were evaluated for the expression of GATA-4, Nkx2.5 and ISL-1 transcripts and proteins by quantitative RT-PCR and Western blotting, respectively as well as for the expression of cardiomyogenic differentiation markers cardiac troponin-T (cTNT), beta myosin heavy chain (ßMHC) and alpha sarcomeric actinin (ASA) by immunocytochemistry. RESULTS: The AF-MSC as compared to BM-MSC had significantly higher expression of GATA-4 (183.06±29.85 vs. 9.80±0.05; p<0.01), Nkx2.5 (8.3±1.4 vs. 1.82±0.32; p<0.05), and ISL-1 (39.59±4.05 vs. 4.36±0.39; p<0.01) genes as well as GATA-4 (2.01±0.5 vs. 0.6±0.1; p<0.05), NKx2.5 (1.9±0.14 vs. 0.8±0.2; p<0.01) and ISL-1 (1.7±0.3 vs. 0.9±0.1; p<0.05) proteins. The AF-MSC also had significantly elevated expression of cTNT (5.0×104±0.6×104 vs. 3.5×104±0.8×104; p<0.01), ß-MHC (15.7×104±0.9×104 vs. 8.2×104±0.6×104; p<0.01) and ASA (18.6×104±4.9×104 vs. 13.1×104±3.0×104; p<0.05) than BM-MSC. CONCLUSIONS: Our data suggest that AF-MSC have greater cardiomyogenic potency than BM-MSC, and thus may be a better source of MSC for therapeutic applications in cardiac regenerative medicine.

MRI phase contrast velocity and flow errors in turbulent stenotic jets.

PURPOSE: To clarify the use of MRI phase contrast (PC), as an alternative to Doppler echocardiography, when measuring high-velocity turbulent jets associated with stenotic valvular disease. MATERIALS AND METHODS: In vivo PC aortic stroke volume (SV) was compared with ventricular SV in 31 patients with moderate to severe aortic stenosis (AS). Two in vitro pipe experiments were conducted to evaluate errors in steady stenotic and nonstenotic turbulent flows. RESULTS: The average in vivo error in SV was -24% in the left-ventricular (LV) outflow tract (LVOT) and -41% in the aortic root. Errors were most prominent in patients with the highest Doppler peak velocities. In vitro nonstenotic flow experiments showed accurate flow measurement with an average error of 1.8%. Significant errors were found in the in vitro stenotic flow, which reduced with shorter echo times (TE): average error -166/-67/-25/-13/-8.8% for TEs of 4.8/4.0/3.3/2.2/2.0 msec. In both the in vivo and in vitro stenotic experiments the errors were associated with signal loss in the flow-compensated magnitude image. CONCLUSION: Signal loss is associated with flow errors in stenotic jets. Current clinically available PC pulse sequences with TE >2 msec may not accurately quantify flow for severe lesions.