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The kidneys in people living with HIV (PLWH) are constantly exposed to highly antiretroviral therapy (HAART) which may cause renal dysfunction. Cystatin C (CystC), a biomarker of renal function, is well associated with renal impairment in various populations, however, it is underexplored in the South African population of PLWH, as compared to creatinine-based measurements. Creatinine-based measurements for assessing kidney function in people with HIV can be limited due to the influence of muscle wasting, altered creatinine metabolism, and the potential for certain antiretroviral medications to impact creatinine secretion. Therefore, the current study aimed to explore the effect of HAART on renal function among PLWH with the use of Cyst C-based measures. We conducted a cross-sectional study of 111 adults PLWH, 84 on HAART, and 27 on HAART-naïve. The cluster of differentiation 4 (CD4 +) count, plasma CystC, as well as the estimated glomerular filtration rate (eGFR) using the chronic kidney disease-epidemiology collaboration (CKD-EPI) formula, were determined. In the present study, no significant differences were observed between HAART-treated and HAART-naïve groups in terms of plasma CystC and eGFRCystC. Participants who were on HAART for > 5 years were significantly associated with eGFRCystC < 90 mL/min/1.73 m2, as indicated by substantial odds ratio of 4.39 (confidence interval: 1.60–12.02, p = 0.004) in the unadjusted analysis and even after adjustment for age, sex and smoking status, with odds ratio of 4.10 (confidence interval: 1.41–11.86, p = 0.009). Advanced World Health Organization (WHO) clinical stage significantly associated with eGFRCystC < 90 mL/min/1.73 m2 as indicated by odds ratio of 11.73 (confidence interval: 2.27–60.75, p = 0.003) in the unadjusted analysis. Even after adjusting for confounders which included age, sex, and smoking status, the association persisted, with an odds ratio of 16.71 (confidence interval: 2.57–108.75, p = 0.003). In conclusion, CystC and eGFRCystC levels were not different between PLWH on HAART and not on HAART but prolonged HAART use for over five years and advanced HIV disease were associated with reduced renal function in this population of PLWH on HAART, as assessed using CystC-based measures. These findings may suggest that HAART had initial beneficial effects and long-term adverse effects. The future risk of progressive eGFR decline may be increased in this HIV population on HAART due to the cumulative effect of prolonged tenofovir disoproxil fumarate (TDF) use. These findings remain important to guide future research with larger populations on the management of conditions related to renal function decline in PLWH. Highlights.Highlights: There was no difference in eGFRCystC between the HAART-treated and HAART-naïve groups. Prolonged HAART use (especially with TDF) for more than five years and advanced HIV disease were associated with reduced renal function. These findings may reflect the initial benefit of HAART on renal function and long-term harmful effects due to the potential adverse effects of TDF. The PLWH on HAART may be at an increased risk of progressive renal function decline. This highlights the need for regular monitoring of renal function in this population and consideration of less nephrotoxic treatment options. [ABSTRACT FROM AUTHOR]

High-fat diet (HFD) feeding in rodents has become an essential tool to critically analyze and study the pathological effects of obesity, including mitochondrial dysfunction and insulin resistance. Peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) regulates cellular energy metabolism to influence insulin sensitivity, beyond its active role in stimulating mitochondrial biogenesis to facilitate skeletal muscle adaptations in response to HFD feeding. Here, some of the major electronic databases like PubMed, Embase, and Web of Science were accessed to update and critically discuss information on the potential role of PGC-1α during metabolic adaptations within the skeletal muscle in response to HFD feeding in rodents. In fact, available evidence suggests that partial exposure to HFD feeding (potentially during the early stages of disease development) is associated with impaired metabolic adaptations within the skeletal muscle, including mitochondrial dysfunction and reduced insulin sensitivity. In terms of implicated molecular mechanisms, these negative effects are partially associated with reduced activity of PGC-1α, together with the phosphorylation of protein kinase B and altered expression of genes involving nuclear respiratory factor 1 and mitochondrial transcription factor A within the skeletal muscle. Notably, metabolic abnormalities observed with chronic exposure to HFD (likely during the late stages of disease development) may potentially occur independently of PGC-1α regulation within the muscle of rodents. Summarized evidence suggests the causal relationship between PGC-1α regulation and effective modulations of mitochondrial biogenesis and metabolic flexibility during the different stages of disease development. It further indicates that prominent interventions like caloric restriction and physical exercise may affect PGC-1α regulation during effective modulation of metabolic processes. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that epicardial fat thickness (EFT) may be a critical feature to understand cardiac health and determine the risk of heart failure. The current review critically assesses and discusses evidence on the efficiency of measuring EFT, in comparison to the well-known markers B-type natriuretic peptide (BNP) and its N-terminal fragment pro-B-type natriuretic peptide (NT-proBNP), as a prognostic and diagnostic approach in individuals with or at risk of heart failure. A systematic approach was undertaken to search major databases, PubMed, Scopus, Google Scholar and the Cochrane library to identify studies that quantified EFT and serum BNP/NT-proBNP levels in individuals with or at risk of heart failure. Twelve studies met the inclusion criteria and a total of 1983 participants were included in this systematic review. Evidence shows a clear association between increased EFT and elevated BNP/NT-proBNP levels in individuals with metabolic disease and suggests that both methods can be used for heart failure diagnosis and prognosis. However, due to the broad spectrum of challenges linked with measuring EFT, BNP/Pro-BNP is the predominant method used for heart failure diagnosis and prognosis in clinical practice. Nonetheless, measuring EFT provides a powerful and reproducible diagnostic tool for risk stratification and heart failure diagnosis and prognosis. Importantly, measuring EFT proves valuable to validate BNP/NT-proBNP levels to predict heart failure, especially due to its non-invasive nature. [ABSTRACT FROM AUTHOR]

Metformin is considered a safe anti-hyperglycemic drug for patients with type 2 diabetes (T2D); however, information on its impact on heart failure–related outcomes remains inconclusive. The current systematic review explored evidence from randomized clinical trials (RCTs) reporting on the impact of metformin in modulating heart failure–related markers in patients with or without T2D. Electronic databases such as MEDLINE, Cochrane Library, and EMBASE were searched for eligible studies. Included studies were those assessing the use of metformin as an intervention, and also containing the comparison group on placebo, and all articles had to report on measurable heart failure–related indices in individuals with or without T2D. The modified Downs and Black checklist was used to evaluate the risk of bias. Overall, nine studies met the inclusion criteria, enrolling a total of 2486 patients. Although summarized evidence showed that metformin did not affect left ventricular function, this antidiabetic drug could improve myocardial oxygen consumption concomitant to reducing prominent markers of heart failure such as n-terminal pro-brain natriuretic peptide and low-density lipoprotein levels, inconsistently between diabetic and nondiabetic patients. Effective modulation of some heart failure–related outcomes with metformin treatment was related to its beneficial effects in ameliorating insulin resistance and blocking pro-inflammatory markers such as the aging-associated cytokine CCL11 (C-C motif chemokine ligand 11). Overall, although such beneficial effects were observed with metformin treatment, additional RCTs are necessary to improve our understanding on its modulatory effects on heart failure–related outcomes especially in diabetic patients. [ABSTRACT FROM AUTHOR]

Introduction: Heart failure is the leading cause of death in patients with diabetes. No treatment currently exists to specifically protect these patients at risk of developing cardiovascular complications. Accelerated oxidative stress-induced tissue damage due to persistent hyperglycemia is one of the major factors implicated in deteriorated cardiac function within a diabetic state. N-acetyl cysteine (NAC), through its enhanced capacity to endogenously synthesize glutathione, a potent antioxidant, has displayed abundant health-promoting properties and has a favorable safety profile.Objective: An increasing number of experimental studies have reported on the strong ameliorative properties of NAC. We systematically reviewed the data on the cardioprotective potential of this compound to provide an informative summary.Methods: Two independent reviewers systematically searched major databases, including PubMed, Cochrane Library, Google scholar, and Embase for available studies reporting on the ameliorative effects of NAC as a monotherapy or in combination with other therapies against diabetes-associated cardiovascular complications. We used the ARRIVE and JBI appraisal guidelines to assess the quality of individual studies included in the review. A meta-analysis could not be performed because the included studies were heterogeneous and data from randomized clinical trials were unavailable.Results: Most studies support the ameliorative potential of NAC against a number of diabetes-associated complications, including oxidative stress. We discuss future prospects, such as identification of additional molecular mechanisms implicated in diabetes-induced cardiac damage, and highlight limitations, such as insufficient studies reporting on the comparative effect of NAC with common glucose-lowering therapies. Information on the comparative analysis of NAC, in terms of dose selection, administration mode, and its effect on different cardiovascular-related markers is important for translation into clinical studies.Conclusions: NAC exhibits strong potential for the protection of the diabetic heart at risk of myocardial infarction through inhibition of oxidative stress. The effect of NAC in preventing both ischemia and non-ischemic-associated cardiac damage is also of interest. Consistency in dose selection in most studies reported remains important in dose translation for clinical relevance. [ABSTRACT FROM AUTHOR]

Platelet activation has been described in patients with chronic inflammation, however in type 2 diabetes mellitus it remains controversial. We compared levels of platelet leucocyte aggregates, monocyte and granulocyte activation across glucose tolerance statuses in mixed ancestry South Africans. Individuals (206) were recruited from Bellville-South, Cape Town, and included 66% with normal glucose tolerance, 18.7% pre-diabetes, 8.7% screen-detected diabetes and 6.3% known diabetes. Monocyte and neutrophil activation were measured by calculating the percentage of cells expressing CD142 and CD69 while platelet monocyte aggregates were defined as CD14++ CD42b+ events and platelet neutrophil aggregates as CD16++ CD42b+ events. The percentage of monocytes and neutrophils expressing CD69 and CD142 was significantly higher in known diabetes and prediabetes, but, lowest in screen-detected diabetes (both p ≤ 0.016). The pattern was similar for platelet monocyte and neutrophil aggregates (both p ≤ 0.003). In robust linear regressions adjusted for age and gender, known diabetes was significantly and positively associated with the percentage of monocytes expressing CD69 [beta 11.06 (p = 0.016)] and CD42b (PMAs) [19.51 (0.003)] as well as the percentage of neutrophils expressing CD69 [14.19 (<0.0001)] and CD42b [17.7 (0.001)]. We conclude that monitoring platelet activation in diagnosed diabetic patients may have a role in the management and risk stratification. [ABSTRACT FROM AUTHOR]