INTRODUCTION: Diabetes mellitus is a major and rapidly growing worldwide health problem, causing mortality largely in developing countries such as South Africa. Diabetes induces life threatening cardiovascular complications including cardiac autonomic neuropathy, ventricular dysfunction and dyslipidaemia, which are dependent on the duration and severity of the diabetes. Most complications are identified at a late, irreversible stage following long-standing diabetes; therefore, early detection and treatment of cardiovascular complications may reverse impairments and improve outcomes. The early treatment of diabetic complications remains ineffective, as the associated underlying features, such as electrolyte disturbances, are poorly understood. A key electrolyte disturbance in diabetes is hypomagnesaemia, which is also an independent cardiovascular risk factor. However, the effects of magnesium (Mg²⁺) supplementation are unclear. Therefore, this study investigated the effects of Mg²⁺ treatment on the early manifestations of streptozotocin (STZ)-induced diabetic cardiac complications. METHODS: Adult male Wistar rats were treated once with STZ (50 mg/kg, i.p.) or vehicle (citrate), and daily for seven days with MgSO4 (270 mg/kg, i.p.) or saline. Blood glucose and body weight were monitored daily. On the eighth day, in vivo tail-pulse plethysmography was recorded for analysis of heart rate variability (HRV), a marker of cardiac autonomic function. Ex vivo, Langendorff-based left ventricular (LV) pressure-volume parameters were measured using an intraventricular balloon. Other hearts were stained with Masson's trichrome and haematoxylin and eosin for histological analysis. Cardiac tissue Mg²⁺ concentration as well as plasma lipid- and Mg²⁺ levels were measured by colorimetric assays. RESULTS: Diabetes reduced heart rate and increased the low-frequency (LF)/high-frequency (HF) power ratio. Mg²⁺ treatment prevented theses diabetes-induced changes in heart rate and in the low-frequency (LF)/high-frequency (HF) power ratio (p < 0.05, n = 9/group). In addition, Mg²⁺ restored orthostatic stress induced changes in heart rate, and LF/HF ratio in diabetic rats (p < 0.05, n = 9/group). In isolated hearts, Mg²⁺ reversed the diabetes-induced decrease in LV end-diastolic elastance (p < 0.05, n = 6/group) and the right shift of end diastolic equilibrium volume intercept from 49 ± 6 μ L to 25 ± 5 μL (p < 0.05, n = 6/group), without altering LV developed pressure or end systolic elastance. Diabetes significantly increased plasma triglyceride, total cholesterol and blood glucose (p < 0.05, n = 7/group), and significantly decreased body weight (p < 0.05, n ≥ 16/group) compared to control, but these changes were not prevented by Mg²⁺ treatment. Neither diabetes nor Mg²⁺ treatment altered plasma- and tissue Mg²⁺ levels. Histologically, diabetes and Mg²⁺ treatment also did not alter cardiomyocyte size or the amount of interstitial collagen in myocardial tissue. CONCLUSION: These results show that Mg²⁺ treatment attenuates diabetes-induced autonomic dysfunction and improves LV diastolic distensibility in short-term diabetes. However, the diabetic metabolic disturbances of hyperglycaemia and dyslipidaemia, the changes in cardiac microstructure or the plasma- and cardiac tissue Mg²⁺ levels were uninfluenced by Mg²⁺ treatment. This suggests that Mg²⁺ exerted its beneficial effects independent of these factors, highlighting the underling mechanisms remain to be clarified. The Mg²⁺ levels not measured in this study by which changes could have been mediated was intracellularly; an aspect that should be further explored in future studies. Furthermore, whether these effects would be translatable to chronic diabetes is an important next question. Thus, the results of this study suggest that Mg²⁺ may have a modulatory role in treating early diabetic cardiovascular complications, but future studies will need to clarify the underlying mechanisms.

The prevalence and incidence of aging-dependent dementia is increasing with the rapid growth rate of the aging population in our society. The present study aimed to test three hypotheses: (1) Aging is associated with increased micro-hemorrhages in the brain. (2) Aging-dependent dementia can be due to vascular disease. (3) The mouse is a valid model to study aging-dependent changes in the brain. To test these hypotheses, histology, MRI, and behavior methods were utilized in the C57BL/6JN mouse model to collect data at the cellular, anatomical, and behavioral levels. The results obtained support all three hypotheses. Furthermore, the present study, for the first time, demonstrates that the mouse thalamus is the most vulnerable brain region for age-dependent microhemorrhage accumulation. The thalamic damage is associated with aging-dependent increases in aortic stiffness, as well as recognition memory deficits. This study is relevant to researchers and physicians in that significant accumulation of brain lesion was observed in middle age, earlier than previously reported. / 2022-10-31T00:00:00Z

No description available.

No description available.

Approximately 50% of patients are classified as having heart failure with preserved ejection fraction (HFpEF). While HFpEF was formerly known as diastolic heart failure, it is now recognized as a complex syndrome characterized by impaired left atrial (LA) function and enlargement, increased left ventricle (LV) wall thickness, and elevated levels of natriuretic peptides sometimes accompanied by systolic dysfunction. Patients have a high prevelance of combordities, including systemic pulmonary hypertension, diabetes mellitus, atherosclerosis, and renal dysfunction. HFpEF is more prevalent in females compared to males. There are well known differences in the cardiac structure and morphology of male and females but how these sex-based differences are exacerbated, and the underlying mechanisms are unknown.Our lab has previously shown that aortic banding induced slow progressive pressure overload (PO) in male felines recapitulates key clinical features human HFpEF. PO in males induced a cardiopulmonary phenotype, including signs and symptoms of HF, elevated NT-proBNP, LA enlargement and dysfunction, LV hypertrophy and diastolic dysfunction, and pulmonary hypertension. Since male felines develop a robust response to PO, it became clear that evaluating the female response to PO was the next step. The goal of this study was to define any critical differences in the cardiopulmonary phenotype between male vs. female felines after slow progressive pressure overload. Female and male kittens underwent aortic banding or sham (normal) surgery following baseline echocardiography (ECHO), pulmonary function testing (PFT), and blood sampling. ECHO, PFT, and blood samples were repeated at 2- and 4-months post-surgery to allow for serial assessment of cardiopulmonary changes. At 4-months post surgery, terminal studies were performed and included invasive hemodynamics, pulmonary mechanics, and blood gas analyses. After all functional data was aquired, tissue was collected for morpholigcal analysis via histology, proteomic analysis via extracellular matrix mass spectrometry (ECM MS), and transcriptional profiling via singlue nucleus RNA sequencing (snRNAseq). Despite females weighing less at 4-months post-banding, both sexes of animals developed a comparable peak systolic pressure gradient across the arotic band, confirming comparable PO. LV EF was preserved throughout the entire study in all groups. Female and male banded animals developed comparable increased LV wall thickness, myocyte cross-sectional area, and heart weight to body weight ratio, all indicative of cardiac hypertrophy. Both sexes of banded animals had decreased LA EF and increased LA end systolic volume. While banded females did not develop elevated LV filling pressures like banded males, they had prolongation of tau, which is another parameter of diastolic dysfunction. Female and male banded animals had similar percentages LV fibrotic area, which developed in a gradient decreasing from the endocardium to epicardium. Both sexes had decreased pulmonary compliance at 4-months post-banding, with trends towards abnormal pulmonary function and structure in several other parameters. These results show that in a model of slow progressive PO, female and male felines develop a similar cardiopulmonary phenotype. / Biomedical Sciences

Background & Rationale: Tissue residing macrophages (TRMs) guard normal physiology in the steady-state heart, and can be important for coordinating inflammatory events at the onset of injuries like myocardial infarction (MI). Following an ischemic attack though, TRMs become outnumbered by circulating myeloid cells and monocyte (mon) derived macrophages (mf), which function to clear injury debris and instruct cardiac repair to mitigate heart failure (HF) severity. The major goal of this work is to investigate how TRM and post MI mf are regulated to participate in cardiac health and post injury repair. Epidermal growth factor receptor (EGFR) is a cell surface tyrosine kinase receptor governing numerous cell processes, and though it has been historically studied as an oncogene, EGFR is implicated in cardiac physiology, and has been shown to regulate mf activation, survival and function. Objectives: Here, we investigated how the loss of EGFR in mf would impact basal cardiac structure, and function, as well as post MI remodeling, repair, and HF development. Methods & Results: By using a myeloid-specific cre, we generated mice with EGFR knockout in mf and other myeloid cells (EGFRmylKO), and performed comparative analyses between these and control mice. We identified that the loss of EGFR in myeloid cells, including cardiac TRMs, resulted in modest signs of stress at baseline, namely enlarged cardiomyocytes and elevated stress associated fetal gene transcripts. Though the loss of EGFR did not impact TRM subtype distribution in basal hearts, whole transcriptomic analyses of these cells revealed over 700 differentially expressed in EGFRmylKO relative to control. Among these are insulin like growth factor (IGF) binding proteins (IGFBP) family members 5 and 7, which are known to regulate not only IGF availability, but also IGF and other cytokine receptor activation, all key players in cardiac hypertrophy. Indeed, EGFRmylKO hearts exhibited enhanced extracellular signal-regulated kinase (ERK)1/2 activation relative to control. Additionally, in response to MI, EGFRmylKO mice experienced a hastened decline in cardiac function, coupled with exacerbated hypertrophic remodeling, and limited angiogenic repair. Analyses of the inflammatory response in EGFRmylKO injured hearts revealed a greater percentage of inflammatory CCR2/Ly6Chi mf even at 7 days into the injury, resulting in significantly reduced transcripts of reparative factors like interleukin (IL)-10. Conclusions: In sum, we propose novel roles for mf EGFR in cardiac physiology and pathology. TRM EGFR regulates several transcripts, required to maintain cardiac homeostatic integrity. In ischemic injury, mf EGFR is key to promoting repair and limiting HF severity. / Biomedical Sciences

No description available.

No description available.

No description available.

No description available.