RESUMO
BACKGROUND: Many patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells. METHODS: We used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC ß1 subunit (sGCß1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress. RESULTS: Obese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCß1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCß1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCß1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH. CONCLUSIONS: In heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCß1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCß1-cGMP signaling and ameliorate EIPH.
Assuntos
Fator de Ligação a CCAAT/metabolismo , Insuficiência Cardíaca/etiologia , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/etiologia , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , MicroRNAs/genética , Espécies Reativas de Oxigênio/metabolismo , Guanilil Ciclase Solúvel/genética , Animais , Animais Geneticamente Modificados , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Exercício Físico , Regulação da Expressão Gênica , Insuficiência Cardíaca/diagnóstico , Humanos , Síndrome Metabólica/complicações , Mitocôndrias Cardíacas , Miócitos de Músculo Liso/metabolismo , Fenótipo , Ratos , Transdução de Sinais , Estresse Fisiológico , Volume Sistólico , Disfunção Ventricular DireitaRESUMO
The nitrate-nitrite-NO pathway regulates NO synthase-independent vasodilation and NO signaling. Ingestion of inorganic nitrite has vasodilatory and blood pressure-lowering effects. Preclinical studies in rodent models suggest there may be a benefit of nitrite in lowering serum triglyceride levels and improving the metabolic syndrome. In a phase 2 study, we evaluated the safety and efficacy of chronic oral nitrite therapy in patients with hypertension and the metabolic syndrome. Twenty adult subjects with stage 1 or 2 hypertension and the metabolic syndrome were enrolled in an open-label safety and efficacy study. The primary efficacy end point was blood pressure reduction; secondary end points included insulin-dependent glucose disposal and endothelial function measured by flow-mediated dilation of the brachial artery and intima-media diameter of the carotid artery. Chronic oral nitrite therapy (40 mg/3× daily) was well tolerated. Oral nitrite significantly lowered systolic, diastolic, and mean arterial pressures, but tolerance was observed after 10 to 12 weeks of therapy. There was significant improvement in the intima-media thickness of the carotid artery and trends toward improvements in flow-mediated dilation of the brachial artery and insulin sensitivity. Chronic oral nitrite therapy is safe in patients with hypertension and the metabolic syndrome. Despite an apparent lack of enzymatic tolerance to nitrite, we observed tolerance after 10 weeks of chronic therapy, which requires additional mechanistic studies and possible therapeutic dose titration in clinical trials. Nitrite may be a safe therapy to concominantly improve multiple features of the metabolic syndrome including hypertension, insulin resistance, and endothelial dysfunction. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01681810.
Assuntos
Artéria Braquial , Endotélio Vascular , Hipertensão , Síndrome Metabólica , Nitrito de Sódio , Adulto , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Artéria Braquial/diagnóstico por imagem , Artéria Braquial/fisiopatologia , Espessura Intima-Media Carotídea , Endotélio Vascular/diagnóstico por imagem , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Resistência à Insulina , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/fisiopatologia , Nitrito de Sódio/administração & dosagem , Nitrito de Sódio/efeitos adversos , Nitrito de Sódio/farmacologia , Resultado do Tratamento , Triglicerídeos/sangue , Vasodilatação/efeitos dos fármacosRESUMO
PURPOSE: Ultrasound (US) is a burgeoning diagnostic tool and is often the only available imaging modality in low- and middle-income countries (LMICs). However, bedside providers often lack training to acquire or interpret US images. We conducted a study to determine if a remote tele-intensivist could mentor geographically removed LMIC providers to obtain quality and clinically useful US images. MATERIALS AND METHODS: Nine Haitian non-physician health care workers received a 20-minute training on basic US techniques. A volunteer was connected to an intensivist located in the USA via FaceTime. The intensivist remotely instructed the non-physicians to ultrasound five anatomic sites. The tele-intensivist evaluated the image quality and clinical utility of performing tele-ultrasound in a LMIC. RESULTS: The intensivist agreed (defined as "agree" or "strongly agree" on a five-point Likert scale) that 90% (57/63) of the FaceTime images were high quality. The intensivist felt comfortable making clinical decisions using FaceTime images 89% (56/63) of the time. CONCLUSIONS: Non-physicians can feasibly obtain high-quality and clinically relevant US images using video chat software in LMICs. Commercially available software can connect providers in institutions in LMICs to geographically removed intensivists at a relatively low cost and without the need for extensive training of local providers.