Peritoneal Dialysis Aggravates and Accelerates Atherosclerosis in Uremic ApoE-/- Mice.

BACKGROUND: Atherosclerosis is highly prevalent in people with chronic kidney disease (CKD), including those receiving peritoneal dialysis (PD). Although it is lifesaving, PD induces profound systemic inflammation, which may aggravate atherosclerosis. Therefore, the hypothesis is that this PD-induced inflammation aggravates atherosclerosis via immune cell activation. METHODS AND RESULTS: ApoE-/- mice were subjected to a 5/6 nephrectomy to induce CKD. Three weeks later, mice were fed a high-cholesterol diet. Half of the nephrectomized mice then received daily peritoneal infusions of 3.86% Physioneal for 67 further days (CKD+PD) until the end of the experiment, and were compared with mice without CKD. Sham operated and PD-only mice were additional controls. CKD+PD mice displayed more severe atherosclerotic disease than control mice. Plaque area increased, and plaques were more advanced with a vulnerable phenotype typified by decreased collagen content and decreased fibrous cap thickness. Increased CD3+ T-cell numbers were present in plaques and perivascular adipose tissue of CKD and CKD+PD mice. Plaques of CKD+PD mice contained more iNOS+ immune cells. Spleens of CKD+PD mice showed more CD4+ central memory, terminally differentiated type 1 T-helper (Th1), Th17, and CX3C motif chemokine receptor 1+ (CX3CR1) CD4+ T-cells with less regulatory and effector T-cells. CONCLUSIONS: PD-fluid exposure in uremic mice potentiates systemic and vascular T-cell-driven inflammation and aggravates atherosclerosis. PD polarized CD4+ T-cells toward an inflammatory Th1/Th17 phenotype, and increased CX3CR1+ CD4+ T-cells, which are associated with vascular homing in CKD-associated atherosclerosis. Targeting CD4+ T-cell activation and CX3CR1+ polarization has the potential to attenuate atherosclerosis in PD patients.

Associations of Metabolic Syndrome and Abdominal Obesity with Anion Gap Metabolic Acidosis among US Adults.

Background: Obesity is a recently identified risk factor for metabolic acidosis and anion gap elevations in the absence of CKD. Metabolic acidosis is a treatable condition with substantial adverse effects on human health. Additional investigations are needed to characterize at-risk populations and explore potential mechanisms. We hypothesized metabolic syndrome (MetS) and waist circumference (WC) would be closely associated with this pathology. Methods: Adult participants from NHANES 1999-2018 meeting study criteria were compiled as main (n=31,163) and fasting (n=12,860) cohorts. Regression models adjusted for dietary acid, eGFR, and other factors examined associations of WC and MetS features with anion gap metabolic acidosis and its components (serum bicarbonate ≤23 mEq/L and anion gap >95th percentile). Results: Greater WC and MetS features were associated with progressively lower bicarbonate, higher anion gap, and greater odds ratios (OR) of metabolic acidosis (MA) and anion gap metabolic acidosis (AGMA). Compared with the reference, participants with the highest WC had ORs for MA and AGMA of 2.26; 95% CI, 1.96 to 2.62 and 2.89; 95% CI, 1.97 to 4.21; those with three and four versus zero MetS features had ORs for AGMA of 2.52; 95% CI, 1.95 to 2.94 and 3.05; 95% CI, 2.16 to 3.82. Associations of body mass index with outcomes were attenuated or absent after adjustment for WC or MetS. Findings were preserved after excluding eGFR <90 ml/min per 1.73 m2 and albuminuria. A lower MA cutoff (<22 mEq/L) raised the estimate of association between MetS and MA (OR for three and four vs zero features: 3.56; 95% CI, 2.53 to 5.02 and 5.44; 95% CI, 3.66 to 8.08). Conclusions: Metabolic diseases are characterized by metabolic acidosis and anion gap elevations. Metabolic dysfunction may predispose patients without CKD to systemic acidosis from endogenous sources. Comprehensive acid-base analyses may be informative in patients with metabolic diseases.

Anti-Galectin-2 Antibody Treatment Reduces Atherosclerotic Plaque Size and Alters Macrophage Polarity.

BACKGROUND: Galectins have numerous cellular functions in immunity and inflammation. Short-term galectin-2 (Gal-2) blockade in ischemia-induced arteriogenesis shifts macrophages to an anti-inflammatory phenotype and improves perfusion. Gal-2 may also affect other macrophage-related cardiovascular diseases. OBJECTIVES: This study aims to elucidate the effects of Gal-2 inhibition in atherosclerosis. METHODS: ApoE -/- mice were given a high-cholesterol diet (HCD) for 12 weeks. After 6 weeks of HCD, intermediate atherosclerotic plaques were present. To study the effects of anti-Gal-2 nanobody treatment on the progression of existing atherosclerosis, treatment with two llama-derived anti-Gal-2 nanobodies (clones 2H8 and 2C10), or vehicle was given for the remaining 6 weeks. RESULTS: Gal-2 inhibition reduced the progression of existing atherosclerosis. Atherosclerotic plaque area in the aortic root was decreased, especially so in mice treated with 2C10 nanobodies. This clone showed reduced atherosclerosis severity as reflected by a decrease in fibrous cap atheromas in addition to decreases in plaque size.The number of plaque resident macrophages was unchanged; however, there was a significant increase in the fraction of CD206+ macrophages. 2C10 treatment also increased plaque α-smooth muscle content, and Gal-2 may have a role in modulating the inflammatory status of smooth muscle cells. Remarkably, both treatments reduced serum cholesterol concentrations including reductions in very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein while triglyceride concentrations were unchanged. CONCLUSION: Prolonged and frequent treatment with anti-Gal-2 nanobodies reduced plaque size, slowed plaque progression, and modified the phenotype of plaque macrophages toward an anti-inflammatory profile. These results hold promise for future macrophage modulating therapeutic interventions that promote arteriogenesis and reduce atherosclerosis.

Novel Nutritional and Dietary Approaches to Weight Loss for the Prevention of Cardiovascular Disease: Ketogenic Diet, Intermittent Fasting, and Bariatric Surgery.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is highly associated with obesity and cardiometabolic dysfunction. This review will focus on three novel therapies that have been identified for potential treatment of obesity and its associated CVD risk factors. RECENT FINDINGS: Intermittent fasting (IF) studies in animal models have shown improvements in cardiometabolic factors, including improved glucose metabolism, reduced inflammation, and reduced blood pressure. However, there is still a lack of prospective human trials to support results from animal-based studies and observational data. Studies of ketogenic diets in humans have produced mixed effects in CVD risk factors. It has been shown that the ketogenic diet (KD) increases low-density lipoprotein cholesterol (LDL-C) but decreases triglycerides. Additionally, implementation of KD in rodent studies have demonstrated increased insulin resistance and glucose intolerance. Bariatric surgery is a useful tool to help patients with obesity lose significant amounts of weight while alleviating CVD risk factors such as hypertension, LDL-C levels, triglyceride levels, and diabetes. The type of procedure influences degree of improvement in weight and CVD risk factors, yet complications remain possible. IF and bariatric surgery offer potential for weight loss and treatment of CVD risk factors. Negative cardiovascular effects of KD have been noted and should be considered before recommending this diet to patients, particularly those with established cardiovascular disease.

BMI as a Risk Factor for Clinical Outcomes in Patients Hospitalized with COVID-19 in New York.

OBJECTIVE: This study examined the association between BMI and clinical outcomes among patients with coronavirus disease 2019 (COVID-19) infection. METHODS: A total of 10,861 patients with COVID-19 infection who were admitted to the Northwell Health system hospitals between March 1, 2020, and April 27, 2020, were included in this study. BMI was classified as underweight, normal weight, overweight, and obesity classes I, II, and III. Primary outcomes were invasive mechanical ventilation (IMV) and death. RESULTS: A total of 243 (2.2%) patients were underweight, 2,507 (23.1%) were normal weight, 4,021 (37.0%) had overweight, 2,345 (21.6%) had obesity class I, 990 (9.1%) had obesity class II, and 755 (7.0%) had obesity class III. Patients who had overweight (odds ratio [OR] = 1.27 [95% CI: 1.11-1.46]), obesity class I (OR = 1.48 [95% CI: 1.27-1.72]), obesity class II (OR = 1.89 [95% CI: 1.56-2.28]), and obesity class III (OR = 2.31 [95% CI: 1.88-2.85]) had an increased risk of requiring IMV. Underweight and obesity classes II and III were statistically associated with death (OR = 1.44 [95% CI: 1.08-1.92]; OR = 1.25 [95% CI: 1.03-1.52]; OR = 1.61 [95% CI: 1.30-2.00], respectively). Among patients who were on IMV, BMI was not associated with inpatient deaths. CONCLUSIONS: Patients who are underweight or who have obesity are at risk for mechanical ventilation and death, suggesting that pulmonary complications (indicated by IMV) are a significant contributor for poor outcomes in COVID-19 infection.