Revisión del tratamiento del síndrome obesidad hipoventilación / Review of the treatment of obesity hypoventilation syndrome

El síndrome de obesidad hipoventilación (SOH) se define como la coexistencia de obesidad (índice de masa corporal≥ 30 kg/mg²), alteraciones respiratorias durante el sueño e hipoventilación alveolar crónica que acarrea hipercapnia diurna(pCO2 ≥ 45 mmHg), cuando otras causas de hipoventilación han sido excluidas. Los pilares de tratamiento para el SOH sonla pérdida de peso y la presión positiva en la vía aérea (PAP) durante el sueño. El manejo de estos pacientes ha de sermultidisciplinario, con modificación de hábitos de vida, intensificación de la actividad física y estrategias de intervenciónfarmacológica o quirúrgica para la pérdida de peso, individualizando las terapias según cada paciente y sus comorbilidades.El modo de inicio de la PAP dependerá de la coexistencia de apnea obstructiva del sueño (AOS), considerando que apro-ximadamente el 90% de los pacientes con SOH presentan concomitantemente AOS, aunque de estos el 73% se consideraAOS grave. En aquellos pacientes con SOH y AOS grave en situación de estabilidad clínica se inclinará por inicio conpresión positiva continua en la vía aérea. Por otra parte, en aquellos pacientes sin AOS grave o durante una hospitalización,se recomienda iniciar directamente ventilación mecánica no invasiva. El seguimiento del paciente debe contemplar loscambios de estrategia necesarios para intentar un control óptimo del peso y el cumplimiento de la PAP.(AU)

Obesity hypoventilation syndrome (OHS) is defined as the coexistence of obesity (body mass index ≥ 30 kg/mg²), respiratorydisturbances during sleep and chronic alveolar hypoventilation leading to daytime hypercapnia (pCO2 ≥ 45 mmHg), whenother causes of hypoventilation have been excluded. The mainstays of treatment for OHS are weight loss and positive airwaypressure (PAP) during sleep. The management of these patients must be multidisciplinary, with modification of lifestyle habits,intensification of physical activity and pharmacological or surgical intervention strategies for weight loss, individualizing thera-pies according to each patient and their comorbidities. The mode of onset of PAP will depend on the coexistence of obstruc-tive sleep apnea (OSA), considering that approximately 90% of patients with OHS present concomitant OSA, although 73%of these are considered severe OSA. In those patients with OHS and severe OSA in a situation of clinical stability, it is recom-mended to start with continuous positive airway pressure. On the other hand, it is recommended to start non invasive mecha-nical ventilation directly for those patients without severe OSA or during hospitalization. The follow-up of the patient mustconsider the necessary changes in strategy to try to achieve optimal weight control and compliance with the PAP.(AU)

Lipotoxicity, glucotoxicity and some strategies to protect vascular smooth muscle cell against proliferative phenotype in metabolic syndrome.

Metabolic syndrome (MetS) is a risk factor for the development of cardiovascular disease (CVD) and atherosclerosis through a mechanism that involves vascular smooth muscle cell (VSMC) proliferation, lipotoxicity and glucotoxicity. Several molecules found to be increased in MetS, including free fatty acids, fatty acid binding protein 4, leptin, resistin, oxidized lipoprotein particles, and advanced glycation end products, influence VSMC proliferation. Most of these molecules act through their receptors on VSMCs by activating several signaling pathways associated with ROS generation in various cellular compartments. ROS from NADPH-oxidase and mitochondria have been found to promote VSMC proliferation and cell cycle progression. In addition, most of the natural or synthetic substances described in this review, including pharmaceuticals with hypoglycemic and hypolipidemic properties, attenuate VSMC proliferation by their simultaneous modulation of cell signaling and their scavenging property due to the presence of a phenolic ring in their structure. This review discusses recent data in the literature on the role that several MetS-related molecules and ROS play in the change from contractile to proliferative phenotype of VSMCs. Hence the importance of proposing an appropriate strategy to prevent uncontrolled VSMC proliferation using antioxidants, hypoglycemic and hypolipidemic agents.

Endogenous Liver Protections Against Lipotoxicity and Oxidative Stress to Avoid the Progression of Non-alcoholic Fatty Liver to more Serious Disease.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by an ectopic accumulation of lipids in at least 5% of hepatocytes. The first phase of the disease, called hepatic steatosis, progresses over time to chronic conditions, such as steatohepatitis, cirrhosis, and finally, hepatic insufficiency and cancer. The accumulation of free fatty acids in hepatocytes, particularly saturated fatty acids, is a key process in the development and progression of NAFLD. Furthermore, the accumulation of oxidative stress markers in NAFLD is closely linked to lipotoxicity due to impaired lipid metabolism and increased generation of reactive oxygen species (ROS). However, endogenous mechanisms are activated early in the liver to protect against lipotoxicity and oxidative stress, thus preventing liver mass loss and disease progression. Thus, in order to develop appropriate therapies, the purpose of this review is to discuss recent data from the literature regarding the importance of intrinsic mechanisms deployed by the liver in protecting itself against the adverse effects related to chronic lipid accumulation and ROS generation.

Palmitoyl-CoA effect on cytochrome c release, a key process of apoptosis, from liver mitochondria of rat with sucrose diet-induced obesity.

Cytochrome c (cyt-c) release from the mitochondria to the cytosol is a key process in the initiation of hepatocyte apoptosis involved in the progression of non-alcoholic fatty liver disease (NAFLD) to fibrosis, cirrhosis and hepatocellular carcinoma. Hepatocyte apoptosis may be related to lipotoxicity due to the accumulation of palmitic acid and palmitoyl-CoA (Pal-CoA). Therefore, the aim of this study is to examine whether Pal-CoA induces cyt-c release from liver mitochondria of sucrose-fed rat (SF). Pal-CoA-induced cyt-c release was sensitive to cyclosporine A indicating the involvement of the mitochondrial membrane permeability transition (mMPT). In addition, cyt-c release from SF mitochondria remains significantly lower than C mitochondria despite the increased rate of H2O2 generation in SF mitochondria. The decreased cyt-c release from SF may be also related to the increased proportion of the palmitic acid-enriched cardiolipin, due to the high availibilty of palmitic acid in SF liver. The enrichment of cardiolipin molecular species with palmitic acid makes cardiolipin more resistant to peroxidation, a mechanism involved in the dissociation of cyt-c from mitochondrial inner membrane. These results suggest that Pal-CoA may participate in the progression of NAFLD to more severe disease through mechanisms involving cyt-c release and mMPT, a key process of apoptosis.

Encephalopathy in severe SARS-CoV2 infection: Inflammatory or infectious?

Concerning the letter by Moriguchi et al., we describe our experience with a case of encephalopathy with and atypical damage on magnetic resonance imaging (MRI) in a patient with severe infection due to the SARS-CoV2 virus. A 56-year-old woman, without previous pathologies, developed cough, fever, and respiratory failure for five days, after returning from a 6-day trip to Venice. Chest radiography shows a large bilateral interstitial infiltrate. In the first 24 hours, she was admitted to the Intensive Care Unit (ICU) for severe respiratory failure and positive protein chain reaction-PCR in nasal exudate. She needed intubation for ten days. In the first 48 hours outside the ICU, she developed an acute confusional syndrome (hyperactive delirium). Neurological examination showed temporal-spatial disorientation and incoherent fluent speech. An electroencephalogram (EEG) showed generalized hypovoltaic activity. Cranial magnetic resonance imaging showed a bilateral and symmetrical increase in the supratentorial white matter's signal intensity, with a discrete thickening of both temporal lobes, with a slight increase in signal intensity and a sequence of normal diffusion. The lumbar puncture showed no changes (glucose 71 mg/dL, protein 30 mg/dL, 1 leukocyte). Within 72 hours of starting symptoms, she was neurologically asymptomatic. Our final diagnosis was an inflammatory encephalopathy related to a SARS-CoV2 infection.

Kidney dysfunction induced by a sucrose-rich diet in rat involves mitochondria ROS generation, cardiolipin changes, and the decline of autophagy protein markers.

The mechanistic link between obesity and renal failure has been proposed to involve mitochondria reactive oxygen species generation and lipotoxicity. These pathological conditions make mitochondria of particular interest in the regulation of cell function and death by both apoptosis and autophagy. Therefore, this work was undertaken to investigate mitochondria function, autophagy, and apoptosis protein markers in the kidney from a rat model of intra-abdominal obesity and renal damage induced by a high-sucrose diet. Mitochondria from sucrose-fed (SF) kidneys in the presence of pyruvate-malate generated H2O2 at a higher rate than from control (79.81 ± 4.98 vs. 65.84 ± 1.95 pmol·min-1·mg protein-1). With succinate, the release of H2O2 was significantly higher compared with pyruvate-malate, and it remained higher in SF than in control mitochondria (146.4 ± 8.8 vs. 106.1 ± 5.9 pmol·min-1·mg protein-1). However, cytochrome c release from SF kidney mitochondria was lower than from control. In addition, cardiolipin, a mitochondria-specific phospholipid, was found increased in SF mitochondria due to the enhanced amount of both cardiolipin synthase and tafazzin. Cardiolipin was also found enriched with saturated and monounsaturated fatty acids, which are less susceptible to peroxidative stress involved in cytochrome c release. Furthermore, beclin-1 and light chain 3-B, as autophagy protein markers, and caspase-9, as apoptosis protein marker, were found decreased in SF kidneys. These results suggest that the decline of autophagy protein markers and the lack of apoptosis process could be a pathological mechanism of cell dysfunction leading to the progression of renal disease in SF rats.

Reactive Oxygen Species from NADPH Oxidase and Mitochondria Participate in the Proliferation of Aortic Smooth Muscle Cells from a Model of Metabolic Syndrome.

In metabolic diseases, the increased reactive oxygen species (ROS) represents one of the pathogenic mechanisms for vascular disease probably by promoting vascular smooth muscle cell (SMC) proliferation that contributes to the development of arterial remodeling and stenosis, hypertension, and atherosclerosis. Therefore, this work was undertaken to evaluate the participation of ROS from NADPH oxidase and mitochondria in the proliferation of SMCs from the aorta in a model of metabolic syndrome induced by sucrose feeding in rats. After 24 weeks, sucrose-fed (SF) rats develop hypertension, intra-abdominal obesity, hyperinsulinemia, and hyperleptinemia. In addition SMCs from SF rats had a higher growth rate and produce more ROS than control cells. The treatment of SMCs with DPI and apocynin to inhibit NADPH oxidase and with tempol to scavenge superoxide anion significantly blocked the proliferation of both SF and control cells suggesting the participation of NADPH oxidase as a source of superoxide anion. MitoTEMPO, which targets mitochondria within the cell, also significantly inhibited the proliferation of SMCs having a greater effect on cells from SF than from the control aorta. The higher rate of cell growth from the SF aorta is supported by the increased content of cyclophilin A and CD147, proteins involved in the mechanism of cell proliferation. In addition, caldesmon, α-actin, and phosphorylated myosin light chain, contractile phenotype proteins, were found significantly lower in SF cells in no confluent state and increased in confluent state but without difference between both cell types. Our results suggest that ROS from NADPH oxidase and mitochondria significantly participate in the difference found in the rate of cell growth between SF and control cells.

Cell Death and Heart Failure in Obesity: Role of Uncoupling Proteins.

Metabolic diseases such as obesity, metabolic syndrome, and type II diabetes are often characterized by increased reactive oxygen species (ROS) generation in mitochondrial respiratory complexes, associated with fat accumulation in cardiomyocytes, skeletal muscle, and hepatocytes. Several rodents studies showed that lipid accumulation in cardiac myocytes produces lipotoxicity that causes apoptosis and leads to heart failure, a dynamic pathological process. Meanwhile, several tissues including cardiac tissue develop an adaptive mechanism against oxidative stress and lipotoxicity by overexpressing uncoupling proteins (UCPs), specific mitochondrial membrane proteins. In heart from rodent and human with obesity, UCP2 and UCP3 may protect cardiomyocytes from death and from a state progressing to heart failure by downregulating programmed cell death. UCP activation may affect cytochrome c and proapoptotic protein release from mitochondria by reducing ROS generation and apoptotic cell death. Therefore the aim of this review is to discuss recent findings regarding the role that UCPs play in cardiomyocyte survival by protecting against ROS generation and maintaining bioenergetic metabolism homeostasis to promote heart protection.

Cytochrome c release from rat liver mitochondria is compromised by increased saturated cardiolipin species induced by sucrose feeding.

Cytochrome c release from mitochondria has been described to be related to reactive oxygen species (ROS) generation. With ROS generation being increased in fatty liver from sucrose-fed (SF) rats, we hypothesized that cytochrome c release might be positively associated with H2O2 generation from SF mitochondria. Surprisingly, cytochrome c release from mitochondria of SF liver was found to be significantly lower compared with control (C) mitochondria oxidizing pyruvate/malate or succinate. Exposure of mitochondria to exogenous superoxide radical generated by the xanthine/xanthine oxidase system elicits a dose-response cytochrome c release in both control and SF mitochondria, but cytochrome c release remains lower in SF mitochondria compared with C mitochondria. Furthermore, the addition of ebselen, PEG-catalase, or catalase, a H2O2 scavenger, significantly reduces cytochrome c release from C and SF mitochondria. Our results suggest that both intra- and extramitochondrial H2O2 are involved in cytochrome c release, but the persisting difference between C and SF levels can be attributed to the differences in cardiolipin compositions. Indeed, the ratio of palmitic acid-rich cardiolipin species was found to be increased in lipid membrane from SF mitochondria compared with C mitochondria, whereas that of linoleic acid-rich cardiolipin species was found decreased. In addition, the content of tafazzin, a protein responsible for cardiolipin remodeling, was decreased in SF mitochondria. Therefore, we conclude that the changes observed in the composition of cardiolipin molecular species in SF mitochondria may be involved in cytochrome c interaction with mitochondrial inner membrane lipid and in its reduced release from SF mitochondria.

[Peripartum cardiomyopathy]. / Miocardiopatia periparto.

The Peripartum Cardiomyopathy is a rare form of heart disease, of uncertain etiology, more common in black and multiparous women, older than thirty years old. Is defined as development of maternal congestive heart failure, in the last month of pregnancy or within five months after delivery, with documented left ventricular systolic dysfunction, in the absence of a demonstrable cause for heart failure in a previously healthy woman. The diagnosis is commonly established with chest radiography, electrocardiogram and echocardiography. Treatment consist in medical therapy with inotropic support, afterload and preload redution, and anticoagulation. Surgical care with cardiac transplantation is indicated in severe cases with progressive left ventricular dysfunction, despite medical therapy. Prognosis seems dependent on recovery of left ventricular function and maternal mortality rates could reach 50%. Future pregnancy is not recommended in woman with persistent ventricular dysfunction. The authors present a case report in a black nuliparous woman at term, with 33 years old, without previous heart disease that presents a sudden heart failure, with ventricular dysfunction on echocardiography, after the caesarean, with recovery of normal ventricular function at 11th day of puerperium.