Sebastian Larion

Genetic Deletion of NADPH Oxidase 1 Rescues Microvascular Function in Mice with Metabolic Disease

Rationale: Early vascular changes in metabolic disease that precipitate the development of cardiovascular complications are largely driven by reactive oxygen species accumulation, yet the extent to which excess reactive oxygen species derive from specific NADPH oxidase isoforms remains ill defined. Objective: Identify the role of Nox1 in the development of microvascular dysfunction in metabolic disease. Methods and Results: Four genotypes were generated by breeding Nox1 knockout mice with db/db mice: lean (HdbWnox1), lean Nox1 knockout (HdbKnox1), obese (KdbWnox1), and obese KK (KdbKnox1). The degree of adiposity, insulin resistance, and dyslipidemia in KW mice was not influenced by Nox1 deletion as determined by nuclear magnetic resonance spectroscopy, glucose tolerance tests, and plasma analyses. Endothelium-dependent responses to acetylcholine in pressurized mesenteric arteries were reduced in KW versus HW (P<0.01), whereas deletion of Nox1 in KW mice normalized dilation. Vasodilator responses after inhibition of NO synthase blunted acetylcholine responses in KK and lean controls, but had no impact in KW, attributing recovered dilatory capacity in KK to normalization of NO. Acetylcholine responses were improved (P<0.05) with Tempol, and histochemistry revealed oxidative stress in KW animals, whereas Tempol had no impact and reactive oxygen species staining was negligible in KK. Blunted dilatory responses to an NO donor and loss of myogenic tone in KW animals were also rescued with Nox1 deletion. Conclusions: Nox1 deletion reduces oxidant load and restores microvascular health in db/db mice without influencing the degree of metabolic dysfunction. Therefore, targeted Nox1 inhibition may be effective in the prevention of vascular complications.

Clinical studies investigating the effect of vitamin E therapy in patients with NASH

Nonalcoholic steatohepatitis (NASH) is the inflammatory sequelae of fatty liver disease that is characterized histologically by steatosis with ballooning degeneration and lobular hepatitis. NASH and particularly fibrosis development are significantly associated with increased all-cause and liver-related mortality. By 2030, NASH is projected to affect more than 27 million patients in the United States and be attributed to 10.9% of all patient deaths. Despite this major public health burden, no U.S. Food and Drug Administration–approved medications exist for the specific treatment of NASH, identifying an unmet need for a further understanding of disease-causing processes.

Effect of myostatin deletion on cardiac and microvascular function

The objective of this study is to test the hypothesis that increased muscle mass has positive effects on cardiovascular function. Specifically, we tested the hypothesis that increases in lean body mass caused by deletion of myostatin improves cardiac performance and vascular function. Echocardiography was used to quantify left ventricular function at baseline and after acute administration of propranolol and isoproterenol to assess β‐adrenergic reactivity. Additionally, resistance vessels in several beds were removed, cannulated, pressurized to 60 mmHg and reactivity to vasoactive stimuli was assessed. Hemodynamics were measured using in vivo radiotelemetry. Myostatin deletion results in increased fractional shortening at baseline. Additionally, arterioles in the coronary and muscular microcirculations are more sensitive to endothelial‐dependent dilation while nonmuscular beds or the aorta were unaffected. β‐adrenergic dilation was increased in both coronary and conduit arteries, suggesting a systemic effect of increased muscle mass on vascular function. Overall hemodynamics and physical characteristics (heart weight and size) remained unchanged. Myostatin deletion mimics in part the effects of exercise on cardiovascular function. It significantly increases lean muscle mass and results in muscle‐specific increases in endothelium‐dependent vasodilation. This suggests that increases in muscle mass may serve as a buffer against pathological states that specifically target cardiac function (heart failure), the β‐adrenergic system (age), and nitric oxide bio‐availability (atherosclerosis). Taken together, pharmacological inhibition of the myostatin pathway could prove an excellent mechanism by which the benefits of exercise can be conferred in patients that are unable to exercise.

Does colectomy predispose to small intestinal bacterial (SIBO) and fungal overgrowth (SIFO)

Objectives: After subtotal colectomy, 40% of patients report chronic gastrointestinal symptoms and poor quality of life. Its etiology is unknown. We determined whether small intestinal bacterial overgrowth (SIBO) or small intestinal fungal overgrowth (SIFO) cause gastrointestinal symptoms after colectomy. Methods: Consecutive patients with unexplained abdominal pain, gas, bloating and diarrhea (>1 year), and without colectomy (controls), and with colectomy were evaluated with symptom questionnaires, glucose breath test (GBT) and/or duodenal aspiration/culture. Baseline symptoms, prevalence of SIBO/SIFO, and response to treatment were compared between groups. Results: Fifty patients with colectomy and 50 controls were evaluated. A significantly higher (p = 0.005) proportion of patients with colectomy, 31/50 (62%) had SIBO compared to controls 16/50 (32%). Patients with colectomy had significantly higher (p = 0.017) prevalence of mixed SIBO/SIFO 12/50 (24%) compared to controls 4/50 (8%). SIFO prevalence was higher in colectomy but not significant (p = 0.08). There was higher prevalence of aerobic organisms together with decreased anaerobic and mixed organisms in the colectomy group compared to controls (p = 0.008). Patients with colectomy reported significantly greater severity of diarrhea (p = 0.029), vomiting (p < 0.001), and abdominal pain (p = 0.05) compared to controls, at baseline. After antibiotics, 74% of patients with SIBO/SIFO in the colectomy and 69% in the control group improved (p = 0.69). Conclusion: Patients with colectomy demonstrate significantly higher prevalence of SIBO/SIFO and greater severity of gastrointestinal symptoms. Colectomy is a risk factor for SIBO/SIFO.