Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice.

BACKGROUND: Much of what we know about insulin resistance is based on studies from metabolically active tissues such as the liver, adipose tissue, and skeletal muscle. Emerging evidence suggests that the vascular endothelium plays a crucial role in systemic insulin resistance; however, the underlying mechanisms remain incompletely understood. Arf6 (ADP ribosylation factor 6) is a small GTPase that plays a critical role in endothelial cell function. Here, we tested the hypothesis that the deletion of endothelial Arf6 will result in systemic insulin resistance. METHODS: We used mouse models of constitutive endothelial cell-specific Arf6 deletion (Arf6f/- Tie2Cre+) and tamoxifen-inducible Arf6 knockout (Arf6f/f Cdh5CreER+). Endothelium-dependent vasodilation was assessed using pressure myography. Metabolic function was assessed using a battery of metabolic assessments including glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. We used a fluorescence microsphere-based technique to measure tissue blood flow. Skeletal muscle capillary density was assessed using intravital microscopy. RESULTS: Endothelial Arf6 deletion impaired insulin-stimulated vasodilation in white adipose tissue and skeletal muscle feed arteries. The impairment in vasodilation was primarily due to attenuated insulin-stimulated nitric oxide bioavailability but independent of altered acetylcholine-mediated or sodium nitroprusside-mediated vasodilation. Endothelial cell-specific deletion of Arf6 also resulted in systematic insulin resistance in normal chow-fed mice and glucose intolerance in high-fat diet-fed obese mice. The underlying mechanisms of glucose intolerance were reductions in insulin-stimulated blood flow and glucose uptake in the skeletal muscle and were independent of changes in capillary density or vascular permeability. CONCLUSIONS: Results from this study support the conclusion that endothelial Arf6 signaling is essential for maintaining insulin sensitivity. Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.

Physiological determinants of mechanical efficiency during advanced ageing and disuse.

This study aimed to determine which physiological factors impact net efficiency (ηnet) in oldest-old individuals at different stages of skeletal muscle disuse. To this aim, we examined ηnet, central haemodynamics, peripheral circulation, and peripheral factors (skeletal muscle fibre type, capillarization and concentration of mitochondrial DNA [mtDNA]). Twelve young (YG; 25 ± 2 years), 12 oldest-old mobile (OM; 87 ± 3 years), and 12 oldest-old immobile (OI; 88 ± 4 years) subjects performed dynamic knee extensor (KE) and elbow flexors (EF) exercise. Pulmonary oxygen uptake, photoplethysmography, Doppler ultrasound and muscle biopsies of the vastus lateralis and biceps brachii were used to assess central and peripheral adaptations to advanced ageing and disuse. Compared to the YG (12.1 ± 2.4%), the ηnet of lower-limb muscle was higher in the OM (17.6 ± 3.5%, P < 0.001), and lower in the OI (8.9 ± 1.9%, P < 0.001). These changes in ηnet during KE were coupled with significant peripheral adaptations, revealing strong correlations between ηnet and the proportion of type I muscle fibres (r = 0.82), as well as [mtDNA] (r = 0.77). No differences in ηnet were evident in the upper-limb muscles between YG, OM and OI. In view of the differences in limb-specific activity across the lifespan, these findings suggest that ηnet is reduced by skeletal muscle inactivity and not by chronological age, per se. Likewise, this study revealed that the age-related changes in ηnet are not a consequence of central or peripheral haemodynamic adaptations, but are likely a product of peripheral changes related to skeletal muscle fibre type and mitochondrial density. KEY POINTS: Although the effects of ageing and muscle disuse deeply impact the cardiovascular and skeletal muscle function, the combination of these factors on the mechanical efficiency are still a matter of debate. By measuring both upper- and lower-limb muscle function, which experience differing levels of disuse, we examined the influence of central and peripheral haemodynamics, and skeletal muscle factors linked to mechanical efficiency. Across the ages and degree of disuse, upper-limb muscles exhibited a preserved work economy. In the legs the oldest-old without mobility limitations exhibited an augmented mechanical efficiency, which was reduced in those with an impairment in ambulation. These changes in mechanical efficiency were associated with the proportion of type I muscle fibres. Recognition that the mechanical efficiency is not simply age-dependent, but the consequence of inactivity and subsequent skeletal muscle changes, highlights the importance of maintaining physical activity across the lifespan.

In type 2 diabetes, glargine and liraglutide each improved glycemic outcomes at 5 y vs. glimepiride or sitagliptin.

SOURCE CITATION: GRADE Study Research Group; Nathan DM, Lachin JM, Balasubramanyam A, et al. Glycemia reduction in type 2 diabetes-glycemic outcomes. N Engl J Med. 2022;387:1063-74. 36129996.

In type 2 diabetes, liraglutide reduced CV events at 5 y vs. glargine, glimepiride, or sitagliptin.

SOURCE CITATION: GRADE Study Research Group; Nathan DM, Lachin JM, Buse JB, et al. Glycemia reduction in type 2 diabetes-microvascular and cardiovascular outcomes. N Engl J Med. 2022;387:1075-88. 36129997.

Is It Good to Have a Stiff Aorta with Aging? Causes and Consequences.

Aortic stiffness increases with advancing age, more than doubling during the human life span, and is a robust predictor of cardiovascular disease (CVD) clinical events independent of traditional risk factors. The aorta increases in diameter and length to accommodate growing body size and cardiac output in youth, but in middle and older age the aorta continues to remodel to a larger diameter, thinning the pool of permanent elastin fibers, increasing intramural wall stress and resulting in the transfer of load bearing onto stiffer collagen fibers. Whereas aortic stiffening in early middle age may be a compensatory mechanism to normalize intramural wall stress and therefore theoretically "good" early in the life span, the negative clinical consequences of accelerated aortic stiffening beyond middle age far outweigh any earlier physiological benefit. Indeed, aortic stiffness and the loss of the "windkessel effect" with advancing age result in elevated pulsatile pressure and flow in downstream microvasculature that is associated with subclinical damage to high-flow, low-resistance organs such as brain, kidney, retina, and heart. The mechanisms of aortic stiffness include alterations in extracellular matrix proteins (collagen deposition, elastin fragmentation), increased arterial tone (oxidative stress and inflammation-related reduced vasodilators and augmented vasoconstrictors; enhanced sympathetic activity), arterial calcification, vascular smooth muscle cell stiffness, and extracellular matrix glycosaminoglycans. Given the rapidly aging population of the United States, aortic stiffening will likely contribute to substantial CVD burden over the next 2-3 decades unless new therapeutic targets and interventions are identified to prevent the potential avalanche of clinical sequelae related to age-related aortic stiffness.

Therapeutic strategies targeting the endothelial glycocalyx.

PURPOSE OF REVIEW: This review will highlight recent studies that have examined the endothelial glycocalyx in a variety of health conditions, as well as potential glycocalyx-targeted therapies. RECENT FINDINGS: A degraded glycocalyx is present in individuals that consume high sodium diet or have kidney disease, diabetes, preeclampsia, coronavirus disease 2019 (COVID-19), or sepsis. Specifically, these conditions are accompanied by elevated glycocalyx components in the blood, such as syndecan-1, syndecans-4, heparin sulfate, and enhanced heparinase activity. Impaired glycocalyx barrier function is accompanied by decreased nitric oxide bioavailability, increased leukocyte adhesion to endothelial cells, and vascular permeability. Glycocalyx degradation appears to play a key role in the progression of cardiovascular complications. However, studies that have used glycocalyx-targeted therapies to treat these conditions are scarce. Various therapeutics can restore the glycocalyx in kidney disease, diabetes, COVID-19, and sepsis. Exposing endothelial cells to glycocalyx components, such as heparin sulfate and hyaluronan protects the glycocalyx. SUMMARY: We conclude that the glycocalyx is degraded in a variety of health conditions, although it remains to be determined whether glycocalyx degradation plays a causal role in disease progression and severity, and whether glycocalyx-targeted therapies improve patient health outcomes. Future studies are warranted to investigate therapeutic strategies that target the endothelial glycocalyx.

The role of hyaluronan in endothelial glycocalyx and potential preventative lifestyle strategy with advancing age.

The endothelial glycocalyx (EG) is a gel-like structure that forms a layer in between the surface of the endothelium and lumen. EG was once thought to be merely a structural support for the endothelium. However, in recent years, the importance of EG as a first line of defense and a key regulator to endothelial integrity has been illuminated. With advanced age, EG deterioration becomes more noticeable and at least partially associated with endothelial dysfunction. Hyaluronan (HA), one of the critical components of the EG, has distinct properties and roles to the maintenance of EG and endothelial function. Therefore, given the intimate relationship between the EG and endothelium during the aging process, HA may serve as a promising therapeutic target to prevent endothelial dysfunction.

In persons at intermediate risk for CVD, polypills reduce a composite of CV events at 5 y.

SOURCE CITATION: Joseph P, Roshandel G, Gao P, et al. Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis. Lancet. 2021;398:1133-46. 34469765.

In acute ischemic stroke, thrombectomy was not noninferior to alteplase + thrombectomy for 90-d functional independence.

SOURCE CITATION: Fischer U, Kaesmacher J, Strbian D, et al. Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial. Lancet. 2022;400:104-15. 35810756.

In non-critically ill patients with COVID-19, therapeutic anticoagulation improved survival to discharge without organ support.

SOURCE CITATION: Lawler PR, Goligher EC, Berger JS, et al. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N Engl J Med. 2021;385:790-802. 34351721.

In critically ill patients with COVID-19, therapeutic anticoagulation did not increase organ support-free days.

SOURCE CITATION: Goligher EC, Bradbury CA, McVerry BJ, et al. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N Engl J Med. 2021;385:777-89. 34351722.

In patients with acute HF and iron deficiency, IV ferric carboxymaltose improved quality of life at 4 to 24 wk.

SOURCE CITATION: Jankowska EA, Kirwan BA, Kosiborod M, et al. The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study. Eur Heart J. 2021;42:3011-20. 34080008.

In hyponatremia, rapid intermittent bolus vs. slow continuous infusion of hypertonic saline did not differ for overcorrection of serum sodium.

SOURCE CITATION: Baek SH, Jo YH, Ahn S, et al. Risk of overcorrection in rapid intermittent bolus vs slow continuous infusion therapies of hypertonic saline for patients with symptomatic hyponatremia: the SALSA randomized clinical trial. JAMA Intern Med. 2021;181:81-92. 33104189.

T cells mediate cell non-autonomous arterial ageing in mice.

KEY POINTS: Increased large artery stiffness and impaired endothelium-dependent dilatation occur with advanced age. We sought to determine whether T cells mechanistically contribute to age-related arterial dysfunction. We found that old mice exhibited greater proinflammatory T cell accumulation around both the aorta and mesenteric arteries. Pharmacologic depletion or genetic deletion of T cells in old mice resulted in ameliorated large artery stiffness and greater endothelium-dependent dilatation compared with mice with T cells intact. ABSTRACT: Ageing of the arteries is characterized by increased large artery stiffness and impaired endothelium-dependent dilatation. T cells contribute to hypertension in acute rodent models but whether they contribute to chronic age-related arterial dysfunction is unknown. To determine whether T cells directly mediate age-related arterial dysfunction, we examined large elastic artery and resistance artery function in young (4-6 months) and old (22-24 months) wild-type mice treated with anti-CD3 F(ab'2) fragments to deplete T cells (150 µg, i.p. every 7 days for 28 days) or isotype control fragments. Old mice exhibited greater numbers of T cells in both aorta and mesenteric vasculature when compared with young mice. Old mice treated with anti-CD3 fragments exhibited depletion of T cells in blood, spleen, aorta and mesenteric vasculature. Old mice also exhibited greater numbers of aortic and mesenteric IFN-γ and TNF-α-producing T cells when compared with young mice. Old control mice exhibited greater large artery stiffness and impaired resistance artery endothelium-dependent dilatation in comparison with young mice. In old mice, large artery stiffness was ameliorated with anti-CD3 treatment. Anti-CD3-treated old mice also exhibited greater endothelium-dependent dilatation than age-matched controls. We also examined arterial function in young and old Rag-1-/- mice, which lack lymphocytes. Rag-1-/- mice exhibited blunted increases in large artery stiffness with age compared with wild-type mice. Old Rag-1-/- mice also exhibited greater endothelium-dependent dilatation compared with old wild-type mice. Collectively, these results demonstrate that T cells play an important role in age-related arterial dysfunction.

Remdesivir improved time to recovery in adults hospitalized with COVID-19 and lower respiratory tract involvement.

SOURCE CITATION: Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19-preliminary report. N Engl J Med. 2020. [Epub ahead of print]. 32445440.

Recommendations for caring for patients with severe and nonsevere COVID-19.

SOURCE CITATION: Ye Z, Rochwerg B, Wang Y, et al. Treatment of patients with nonsevere and severe coronavirus disease 2019: an evidence-based guideline. CMAJ. 2020;192:E536-45. 32350002.

Adding NT-proBNP to the Revised Cardiac Risk Index improved prediction of CV events after noncardiac surgery.

SOURCE CITATION: Duceppe E, Patel A, Chan MTV, et al. Preoperative N-terminal pro-B-type natriuretic peptide and cardiovascular events after noncardiac surgery: a cohort study. Ann Intern Med. 2020;172:96-104. 31869834.

Supplementation with vitamin D plus calcium reduces fracture risk; vitamin D alone does not.

SOURCE CITATION: Yao P, Bennett D, Mafham M, et al. Vitamin D and calcium for the prevention of fracture: a systematic review and meta-analysis. JAMA Netw Open. 2019;2:e1917789. 31860103.

Incidence, outcomes, and predictors of in-hospital acute coronary syndrome following endovascular transcatheter aortic valve replacement in the United States.

BACKGROUND: Incidence and outcomes of acute coronary syndrome (ACS) immediately following transcatheter aortic valve replacement (TAVR) remain largely unknown. OBJECTIVES: This study sought to assess the incidence, clinical characteristics, and outcomes of ACS following TAVR. METHODS: We queried the National Readmission Database from January 2012 to September 2015 for TAVR admissions with and without ACS, creating a propensity-matched cohort to compare outcomes. RESULTS: A total of 48,454 patients underwent TAVR, with 1,332 (2.75%) developing ACS. TAVR patients with ACS compared to those without ACS had a significantly higher incidence of acute kidney injury (24.7 vs. 19.2%; p = .001), ischemic stroke (3.7 vs. 2.3%; p = .04), vascular complications (8.6 vs. 5.8%; p = .008), cardiogenic shock (9.8 vs. 1.9%; p < .001), cardiac arrest (5.1 vs. 2.8%; p = .002), mechanical circulatory support (8.1 vs. 1.5%; p < .001), and in-hospital mortality (9.6 vs. 3.4%; p < .001). Additionally, TAVR with ACS had longer lengths of stay (median 10 days vs. 6 days; p < .001) and hospital charges (median $23,200 vs. $19,000; p < .001). Positive predictors of ACS were history of PCI (odds ratio, 1.43; 95% CI: 1.25-1.63), hyperlipidemia (odds ratio, 1.20; 95% CI: 1.07-1.34), chronic blood loss anemia (odds ratio, 2.16; 95% CI: 1.54-3.03), chronic kidney disease (odds ratio, 1.17; 95% CI: 1.04-1.31), fluid and electrolyte disorders (odds ratio, 1.65; 95% CI: 1.47-1.85), and weight loss (odds ratio, 1.53; 95% CI: 1.22-1.91). Heart failure (34%) was the most common reason for readmission in the ACS cohort. CONCLUSION: ACS after TAVR is uncommon but is associated with worse clinical outcomes and increased healthcare resource utilization.

Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease.

Advancing age promotes cardiovascular disease (CVD), the leading cause of death in the United States and many developed nations. Two major age-related arterial phenotypes, large elastic artery stiffening and endothelial dysfunction, are independent predictors of future CVD diagnosis and likely are responsible for the development of CVD in older adults. Not limited to traditional CVD, these age-related changes in the vasculature also contribute to other age-related diseases that influence mammalian health span and potential life span. This review explores mechanisms that influence age-related large elastic artery stiffening and endothelial dysfunction at the tissue level via inflammation and oxidative stress and at the cellular level via Klotho and energy-sensing pathways (AMPK [AMP-activated protein kinase], SIRT [sirtuins], and mTOR [mammalian target of rapamycin]). We also discuss how long-term calorie restriction-a health span- and life span-extending intervention-can prevent many of these age-related vascular phenotypes through the prevention of deleterious alterations in these mechanisms. Lastly, we discuss emerging novel mechanisms of vascular aging, including senescence and genomic instability within cells of the vasculature. As the population of older adults steadily expands, elucidating the cellular and molecular mechanisms of vascular dysfunction with age is critical to better direct appropriate and measured strategies that use pharmacological and lifestyle interventions to reduce risk of CVD within this population.