RESUMEN
BACKGROUND: Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipid metabolism, it is unknown whether its exogenous administration could avoid MCM onset. We investigated whether chronic treatment with recombinant Sirt1 (rSirt1) could halt MCM progression. METHODS: db/db mice, an established model of MCM, were supplemented with intraperitoneal rSirt1 or vehicle for 4 weeks and compared with their db/ + heterozygous littermates. At the end of treatment, cardiac function was assessed by cardiac ultrasound and left ventricular samples were collected and processed for molecular analysis. Transcriptional changes were evaluated using a custom PCR array. Lipidomic analysis was performed by mass spectrometry. H9c2 cardiomyocytes exposed to hyperglycaemia and treated with rSirt1 were used as in vitro model of MCM to investigate the ability of rSirt1 to directly target cardiomyocytes and modulate malondialdehyde levels and caspase 3 activity. Myocardial samples from diabetic and nondiabetic patients were analysed to explore Sirt1 expression levels and signaling pathways. RESULTS: rSirt1 treatment restored cardiac Sirt1 levels and preserved cardiac performance by improving left ventricular ejection fraction, fractional shortening and diastolic function (E/A ratio). In left ventricular samples from rSirt1-treated db/db mice, rSirt1 modulated the cardiac lipidome: medium and long-chain triacylglycerols, long-chain triacylglycerols, and triacylglycerols containing only saturated fatty acids were reduced, while those containing docosahexaenoic acid were increased. Mechanistically, several genes involved in lipid trafficking, metabolism and inflammation, such as Cd36, Acox3, Pparg, Ncoa3, and Ppara were downregulated by rSirt1 both in vitro and in vivo. In humans, reduced cardiac expression levels of Sirt1 were associated with higher intramyocardial triacylglycerols and PPARG-related genes. CONCLUSIONS: In the db/db mouse model of MCM, chronic exogenous rSirt1 supplementation rescued cardiac function. This was associated with a modulation of the myocardial lipidome and a downregulation of genes involved in lipid metabolism, trafficking, inflammation, and PPARG signaling. These findings were confirmed in the human diabetic myocardium. Treatments that increase Sirt1 levels may represent a promising strategy to prevent myocardial lipid abnormalities and MCM development.
Asunto(s)
Diabetes Mellitus , Cardiomiopatías Diabéticas , Insuficiencia Cardíaca , Animales , Humanos , Ratones , Diabetes Mellitus/metabolismo , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/prevención & control , Insuficiencia Cardíaca/metabolismo , Inflamación/metabolismo , Lipidómica , Lípidos , Miocitos Cardíacos/metabolismo , PPAR gamma/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Volumen Sistólico , Triglicéridos/metabolismo , Función Ventricular IzquierdaRESUMEN
AIMS: Endothelial dysfunction and plaque formation are features of atherosclerosis. Inhibition of L-type calcium channels or HMG-CoA pathway improves endothelial function and reduces plaque size. Thus, we investigated in stable coronary artery disease (CAD) the effects of a calcium antagonist on coronary endothelial function and plaque size. METHODS AND RESULTS: In 454 patients undergoing PCI, acetylcholine (10(-6) to 10(-4) M) was infused in a coronary segment without significant CAD. Changes in coronary diameter were measured and an intravascular ultrasound examination (IVUS) was performed. On top of statin therapy, patients were randomized in a double-blind fashion to placebo or nifedipine GITS 30-60 mg/day and followed for 18-24 months. Blood pressure was lower on nifedipine than on placebo by 5.8/2.1 mmHg (P < 0.001) as was total and LDL cholesterol (4.8 mg/dL; P = 0.495), while HDL was higher (3.6 mg/dL; P = 0.026). In the most constricting segment, nifedipine reduced vasoconstriction to acetylcholine (14.0% vs. placebo 7.7%; P < 0.0088). The percentage change in plaque volume with nifedipine and placebo, respectively, was 1.0 and 1.9%, ns. CONCLUSION: The ENCORE II trial demonstrates in a multi-centre setting that calcium channel blockade with nifedipine for up to 2 years improves coronary endothelial function on top of statin treatment, but did not show an effect of nifedipine on plaque volume.
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Vasos Coronarios/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Nifedipino/uso terapéutico , Acetilcolina , Adulto , Anciano , Angioplastia Coronaria con Balón , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/efectos adversos , Terapia Combinada , Enfermedad de la Arteria Coronaria/patología , Enfermedad de la Arteria Coronaria/fisiopatología , Enfermedad de la Arteria Coronaria/terapia , Vasos Coronarios/fisiopatología , Progresión de la Enfermedad , Método Doble Ciego , Endotelio Vascular/fisiopatología , Femenino , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Nifedipino/efectos adversos , Vasodilatadores , Sistema Vasomotor/efectos de los fármacos , Sistema Vasomotor/fisiopatologíaRESUMEN
Intake of coffee, one of the most common beverages worldwide, is often reported as a cardiovascular risk factor; however, definitive data are lacking. Acute intake of coffee or beverages containing caffeine can increase blood pressure, heart minute volumes, and cardiac index, as well as activate the sympathetic nervous system in nonhabitual coffee drinkers. Interestingly, this is not observed in habitual coffee drinkers. Restriction of coffee or caffeinated beverages is no longer indicated in the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines for the treatment of hypertension. In fact, no clear association between coffee and the risk of hypertension, myocardial infarction, or other cardiovascular diseases has been demonstrated. In contrast to early studies, recent research indicates that habitual moderate coffee intake does not represent a health hazard and may even be associated with beneficial effects on cardiovascular health.