Nour Mounira Zakaria Bakkar

Introduction: Prediabetes is increasingly recognised as a stage at which cardiovascular and renal dysfunction begin to develop despite the absence of overt metabolic disease. The mechanisms underlying these early alterations remain poorly understood. Because adipose tissues surrounding blood vessels and kidneys can locally generate components of the renin–angiotensin system (RAS), we hypothesised that subclinical RAS activation contributes to early cardiorenal dysfunction in prediabetes. Methods: Using a pre‐established normotensive, non‐obese rat model of prediabetes induced by 12 weeks of mild hypercaloric feeding, we examined the impact of systemic angiotensin II (AngII) elevation and angiotensin‐converting enzyme (ACE) inhibition on cardio‐, cerebro‐ and renovascular function by invasive hemodynamics, ex vivo pressure myography, and ex vivo renal perfusion experiments, respectively. Results: Prediabetic rats exhibited impaired parasympathetic baroreceptor sensitivity and altered renovascular endothelium‐dependent vasodilation despite preserved blood pressure and cardiac function. Systemic AngII infusion further exacerbated autonomic and renovascular dysfunction. In contrast, treatment with a non‐hypotensive dose of the ACE inhibitor captopril restored baroreceptor sensitivity, improved renovascular endothelial function, reduced brainstem inflammation, and attenuated renal tubular fibrosis. Examination of perivascular and perirenal adipose tissues revealed significantly higher protein concentration of ACE1 in prediabetic rats compared to controls. Conclusion: These findings are consistent with an early activation of RAS contributing to subclinical cardiovascular and renal dysfunction during prediabetes independently of hypertension. Targeting RAS signalling at this early stage may therefore represent a strategy to limit progression of cardiorenal complications along the continuum from prediabetes to diabetes.

Individuals with metabolic syndrome have a high risk of developing cardiovascular disorders that is closely tied to visceral adipose tissue dysfunction, as well as an altered interaction between adipose tissue and the cardiovascular system. In metabolic syndrome, adipose tissue dysfunction is associated with increased hypertrophy, reduced vascularization, and hypoxia of adipocytes, leading to a pro‐oxidative and pro‐inflammatory environment. Among the pathways regulating adipose tissue homeostasis is the wingless‐type mammary tumor virus integration site family (Wnt) signaling pathway, with both its canonical and non‐canonical arms. Various modulators of the Wnt signaling have been identified to contribute to the development of metabolic diseases and their cardiovascular complications, with a particularly significant role played by Glycogen Synthase Kinase‐3β (GSK‐3β). GSK‐3β levels and activities have various and often contrasting roles in obesity and related metabolic disorders, as well as their cardiovascular sequelae. Here, we explore the possibility that altered Wnt signaling and GSK‐3β activities could serve as a connection between adipose tissue dysfunction and the development of cardiovascular disease in individuals with metabolic syndrome. We attempt to define a context‐specific approach for intervention, which could possibly serve as a novel disease modifying therapy for the mitigation of such complications.

Sodium-glucose transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 (GLP-1) receptor agonists are newer antidiabetic drug classes, which were recently shown to decrease cardiovascular (CV) morbidity and mortality in diabetic patients. CV benefits of these drugs could not be directly attributed to their blood glucose lowering capacity possibly implicating a pleotropic effect as a mediator of their impact on cardiovascular disease (CVD). Particularly, preclinical and clinical studies indicate that SGLT-2i(s) and GLP-1 receptor agonists are capable of differentially modulating distinct adipose pools reducing the accumulation of fat in some depots, promoting the healthy expansion of others, and/or enhancing their browning, leading to the suppression of the metabolically induced inflammatory processes. These changes are accompanied with improvements in markers of cardiac structure and injury, coronary and vascular endothelial healing and function, vascular remodeling, as well as reduction of atherogenesis. Here, through a summary of the available evidence, we bring forth our view that the observed CV benefit in response to SGLT-2i or GLP-1 agonists therapy might be driven by their ameliorative impact on adipose tissue inflammation.

Diabetic patients present established cardiovascular disease at the onset of diagnostic metabolic symptoms. While premature autonomic and vascular deterioration considered risk factors for major cardiovascular complications of diabetes, present in initial stages of metabolic impairment, their early detection remains a significant challenge impeding timely intervention. In the present study, we examine the utility of beat-to-beat blood pressure variability (BPV) parameters in capturing subtle changes in cardiac autonomic and vascular control distinguishing between various risk categories, independent of the average BP. A rat model of mild hypercaloric (HC) intake was used to represent the insidious cardiovascular changes associated with early metabolic impairment. Invasive hemodynamics were used to collect beat-to-beat BP time series in rats of either sex with different durations of exposure to the HC diet. Linear (standard deviation and coefficient of variation) and nonlinear (approximate entropy, ApEn, and self-correlation of detrended fluctuation analysis, α) BPV parameters were calculated to assess the impact of early metabolic impairment across sexes and feeding durations. HC-fed male, but not female, rats developed increased fat:lean ratio as well as hyperinsulinemia. Unlike linear parameters, multivariate analysis showed that HC-fed rats possessed lower ApEn and higher α, consistent with early changes in heart rate variability and blunting of parasympathetic baroreceptor sensitivity, particularly in males. Moreover, logistic regression demonstrated the superiority of nonlinear parameters of diastolic BPV in predicting a prediabetic disease state. Our findings support the use of nonlinear beat-to-beat BPV for early detection of cardiovascular derangements in the initial stages of metabolic impairment.

Introduction Alterations in linear and non-linear parameters of beat-to-beat blood pressure variability (BPV) have been shown to predict disease prognosis and distinguish between risk categories in various pathological conditions, independently of average blood pressure levels. Obesity places subjects at elevated risk of vascular diseases, including hypertension, resulting in serious cardiac, respiratory and cerebral events. However, little is known about the status of vascular dynamics in obese and morbidly obese adults. Methods and analysis In this present quasi-experimental longitudinal study, changes in beat-to-beat BPV, using continuous, non-invasive blood pressure monitoring, in obese subjects undergoing bariatric surgery are characterised. The capacity of linear and non-linear measures of BPV to detect differences between hypertensive, prehypertensive and normotensive obese subjects prebariatric and postbariatric surgery are tested. Additionally, potential correlations between beat-to-beat BPV and age, body mass index, gender and comorbidities will be investigated. In parallel, the impact of the unsteady fluctuations of beat-to-beat blood pressure on the dynamic stresses imparted by blood flow on blood vessel walls will be explored. We expect to find altered BPV profiles in hypertensive and prehypertensive subjects as compared with normotensive subjects. We also expect to see differential normalisation in BPV profiles between hypertensive, prehypertensive and normotensive subjects over time. Ethics and dissemination The study has been approved by the Institutional Review Board at the American University of Beirut (IRB ID: BIO-2018-0040). Study results will be made available to the public through publications in peer-reviewed journals and conference papers and/or presentations.

Blood pressure (BP) varies on the long, short and very-short term. Owing to the hidden physiological and pathological information present in BP time-series, increasing interest has been given to the study of continuous, beat-to-beat BP variability (BPV) using invasive and noninvasive methods. Different linear and nonlinear parameters of variability are employed in the characterization of BP signals in health and disease. Although linear parameters of beat-to-beat BPV are mainly measures of dispersion, such as standard deviation (SD), nonlinear parameters of BPV quantify the degree of complexity/irregularity- using measures of entropy or self-similarity/correlation. In this review, we summarize the value of linear and nonlinear parameters in reflecting different information about the pathophysiology of changes in beat-to-beat BPV independent of or superior to mean BP. We then provide a comparison of the relative power of linear and nonlinear parameters of beat-to-beat BPV in detecting early and subtle differences in various states. The practical advantage and utility of beat-to-beat BPV monitoring support its incorporation into routine clinical practices.

Cardiac autonomic neuropathy (CAN) is one of the earliest complications of type 2 diabetes (T2D), presenting a silent cause of cardiovascular morbidity and mortality. Recent research relates the pathogenesis of cardiovascular disease in T2D to an ensuing chronic, low-grade proinflammatory and pro-oxidative environment, being the hallmark of the metabolic syndrome. Metabolic inflammation emerges as adipose tissue inflammatory changes extending systemically, on the advent of hyperglycemia, to reach central regions of the brain. In light of changes in glucose and insulin homeostasis, dysbiosis or alteration of the gut microbiome (GM) emerges, further contributing to inflammatory processes through increased gut and blood–brain barrier permeability. Interestingly, studies reveal that the determinants of oxidative stress and inflammation progression exist at the crossroad of CAN manifestations, dictating their evolution along the natural course of T2D development. Indeed, sympathetic and parasympathetic deterioration was shown to correlate with markers of adipose, vascular, and systemic inflammation. Additionally, evidence points out that dysbiosis could promote a sympatho-excitatory state through differentially affecting the secretion of hormones and neuromodulators, such as norepinephrine, serotonin, and γ-aminobutyric acid, and acting along the renin–angiotensin–aldosterone axis. Emerging neuronal inflammation and concomitant autophagic defects in brainstem nuclei were described as possible underlying mechanisms of CAN in experimental models of metabolic syndrome and T2D. Drugs with anti-inflammatory characteristics provide potential avenues for targeting pathways involved in CAN initiation and progression. The aim of this review is to delineate the etiology of CAN in the context of a metabolic disorder characterized by elevated oxidative and inflammatory load.