Advances in extracardiac mechanisms for heart failure with preserved ejection fraction / 中南大学学报(医学版)

Heart failure with preserved ejection fraction (HFpEF) is a syndrome with highly heterogeneous clinical symptoms, and its incidence has been increasing in recent years. Compared with heart failure with reduced ejection fraction (HFrEF), HFpEF has a worse prognosis. Traditional therapies targeting the internal mechanisms of the heart show limited or inefficacy on HFpEF, and new therapeutic targets for HFpEF are expected to be found by focusing on the extracardiac mechanisms. Recent studies have shown that cardiopulmonary pathophysiological interaction exacerbates the progression of HFpEF. Hypertension, systemic vascular injury, and inflammatory response lead to coronary microvascular dysfunction, myocardial hypertrophy, and coronary microvascular remodeling. Acute kidney injury affects myocardial energy production, induces oxidative stress and catabolism of myocardial protein, which leads to myocardial dysfunction. Liver fibrosis mediates heart injury by abnormal protein deposition and inflammatory factors production. Skeletal muscle interacts with the sympathetic nervous system by metabolic signals. It also produces muscle factors, jointly affecting cardiac function. Metabolic syndrome, gut microbiota dysbiosis, immune system diseases, and iron deficiency promote the occurrence and development of HFpEF through metabolic changes, oxidative stress, and inflammatory responses. Therefore, the research on the extracardiac mechanisms of HFpEF has certain implications for model construction, mechanism research, and treatment strategy formulation.

Interleukin-6 contributes to myocardial damage in pregnant rats with reduced uterine perfusion pressure

Preeclampsia is one of the most frequent and difficult illnesses in pregnancy, which jeopardizes both mother and fetus. There are several diagnostic criteria for preeclampsia. However, the preeclampsia-associated myocardial damage has not been described. In this study, we employed reduced uterine perfusion pressure (RUPP) to generate a rat model of preeclampsia for the evaluation of myocardial damage in late-gestation rats. The expressions of cardiac injury markers were analyzed by immunohistochemistry and ELISA. The arterial pressure and myocardial tissue velocities were also measured. The role of interleukin (IL)-6 in RUPP-associated myocardial damage was further explored. The results showed that RUPP rats had significant myocardial damage, as demonstrated by the high expressions of myoglobin, creatine kinase isoenzyme, cardiac troponin I, and brain natriuretic peptide. In addition, RUPP increased the mean arterial pressure and the early transmitral flow velocity to mitral annulus early diastolic velocity ratio (E/Ea). Furthermore, IL-6 deteriorated these abnormalities, whereas inhibition of IL-6 significantly relieved them. In conclusion, our study demonstrated that RUPP rats displayed myocardial damage in an IL-6-dependent manner.

L-Arginine attenuates oxidative stress condition during cardiomyopathy.

Increased production of oxygen free radicals and decreased oxidant capacity occur in coronary artery diseases (CAD). This pro-oxidant shift in intracellular redox state may induce cell death by either direct cell membrane damage by lipid peroxidation or apoptosis through activation of transcription factors. These changes occur not only in cardiomyocytes, but also in cardiac sympathetic nerves, which are very sensitive to oxidative damage. Patients with heart failure encounter reduced peripheral blood flow at rest, during exercise and in response to endothelium-dependent vasodilators. Current treatments of cardiomyopathy, a degenerative condition of the myocardium frequently associated with heart failure have done little to enhance patient survival. Decreased myocardial contractility and altered regulation of peripheral circulation along with oxidative conditions are important contributors to the symptoms and prognosis of the disease process. Nitric oxide formed from L-arginine (2-amino-5 guanidinovaleric acid) metabolism in endothelial cells contributes to regulation of blood flow under these conditions. L-Arginine is the precursor of nitric oxide, an endogenous messenger molecule involved in a variety of endothelium-mediated physiological effects in the vascular system. In the present study, we investigated the effect of oral administration of L-arginine (3 g/day) on the intracellular redox status of the patients of ischemic cardiomyopathy aged 45-60 yrs. The enzymatic and non-enzymatic antioxidant parameters like superoxide dismutase, catalase, total thiols (TSH) and ascorbic acid along with pro-oxidant parameters, such as xanthine oxidase, as well as index of oxidative stress as protein carbonyl content and malondialdehyde (a marker of lipid peroxidation) were investigated in the plasma and RBC lysate. L-Arginine (3 g/day) administration was found to improve the levels of these parameters in the patients and regulate the blood flow, as evident by the improved blood pressure of the patients. Thus, it is inferred that L-arginine attenuates the oxidative stress conditions along with maintaining the blood pressure rate of patients suffering from cardiomyopathy.

La vía de señalización Rho a/ Rho kinasa se encuentra activada en el miocardio en ratas con fibrosis cardíaca inducida por isoprotenerol / Rho A/ Rho kinase pathway is activated in the myocardium of rats with isoprotenerol - induced fibrosis

Antecedentes: En pacientes con insuficiencia cardíaca la actividad adrenérgica está aumentada, lo que induce en el largo plazo, a cardiotoxicidad y mayor deterioro de la función ventricular. La administración experimental de Isoprotenerol, un agonista beta-adrenérgico, produce hipertrofia ventricular, daño y fibrosis miocárdica. La vía de señalización intracelular RhoA/Rho-Kinasa (ROCK) participa en el remodelamiento cardiovascular, no estando clara la relación entre la activación de esta vía y el desarrollo de fibrosis miocárdica. Objetivo: Determinar si existe activación de la vía ROCK en ratas con fibrosis miocárdica inducida experimentalmente por Isoprotenerol, mediante cuantificación de la fosforilación de la proteína blanco 1 de la fosfatasa de la miosina (MYPT1). Métodos: Se utilizaron ratas Sprague-Dawley machos (100 +/- 10 gr.); 10 como grupo control con administración de suero fisiológico y 10 en el grupo experimental con inyección subcutánea de Isoprotenerol Hemisulfato, 5 mg/kilo de peso por día, por un período de 10 días. Se determinó la presión arterial sistólica (PAS), la masa relativa ventricular izquierda (MRVI), la activación de ROCK a través de niveles de MYPT1 por Western Blot y se cuantificó la fibrosis en Ventrículo Izquierdo por análisis morfométrico del colágeno (en tinciones con Rojo de Picrosirio). Resultados (promedio +/- ES, =p<0,05): Los resultados en Presión Arterial Sistólica fueron 119,6 +/- 8,1 mmHg en el grupo control y 113,8 +/- 5,2 mmHg en el grupo tratado con Isoprotenerol, la MRVI fue de 358,3 +/- 10,9 mg/g en las controles y 495,3 +/- 42,02 mg/g en ratas Iso. La fracción volumétrica de colágeno (FVC) en miocardio y subendocardio fueron 3 +/- 0,3 y 3,3 +/- 0,4 en ratas control; en ratas Iso fueron 5,2 +/- 0,7 y 7,4 +/- 1,3 respectivamente.

Background: Patients with heart failure have increased adrenergic activity, which in turn induces cardiotoxicity, and further damage to the myocardium. lsoprotenerol induces ventricular hypertrophy with myocardial fibrosis. RHO A/ RHO Kinase pathway (ROCK) participates in myocardial remodeling, but it is not known whether ROCK is involved in the fibrotic process.Aim: To ascertain whether ROCK is activated in rats with Isoprotenerol -induced myocardial fibrosis, measuring ROCK by phosphon/ation of the myosin phosphatase (MYPTI). Methods: We used male Sprague-Dawley rats (100 +/- 10 g); 10 rats were used as controls and received sq saline,- 10 rats in the experimental group received sq Isoprotenerol (ISO rats) 5 mg/k body weight/day, during 10 days. We measured systolic blood pressure (SBP), left ventricular mass (LVM) and ROCK, which was measured by phophorylation of the MYPTI protein using Western Blot. Myocardial fibrosis was measured by morphometry of collagen in Picrosirius red stained samples, and was expressed as collagen volume fraction (CVF). Results were expressed as average +/- SEM; =p<005Results: SBP was 119,6 +/- 8,1 mmHg in controls and 113,8 +/- 5,2 mmHg in ISO rats; LVM was 358,3 +/- 10,9 mg/g in controls and 495,3 +/- 42,02 mg/g in ISO rats. CVF in the myocardium and subendocardium were 3 +/- 0,3 and 3,3 +/- 0,4 in control rats; values in ISO rats were 2 +/- 0,7 y 7,4 +/- 1,3 respectively. Total CVF were 3,2 +/- 0,4 in controls and 6,3 +/- 1,6 in ISO rats. ROCK, expressed as phosphorylated MYPTI /total MYPTI in control rats was 2,5 +/- 0,8 and 4,7 +/- 2,2 in ISO rats. Conclusion: ROCK pathway is significantly activated in the myocardium of ISO rats. ROCK antagonists for preventing myocardial fibrosis should be evaluated in this experimental model.

Disposiçäo cinética dos estereoisômeros do R, S-sotalol em miocardiopatas crônicos portadores de taquiarritmias cardíacas / Kinetic disposition of the R, S-sotalol enantiomers in chronic cardiac patients with tachyarrhythmias

Estudou-se no presente trabalho a disposiçäo cinética dos enantiômeros do sotalol em 13 pacientes miocardiopatas crônicos portadores de taquiarritmias, utilizando método analítico em cromatografia líquida de alta eficiência com detector de fluorescência, após derivatizaçäo do fármaco para resoluçäo dos isômeros R(-)- e S(+)-sotalol. Os pacientes estavam sob regime de dose múltipla de 320 mg/dia p.o. de cloridrato de sotalol. Após coleta seriada de sangue, a disposiçäo cinética do R,S-sotalol foi avaliada aplicando-se modelo monocompartimental aberto. Obtiveram-se os seguintes valores, para R,S-, R(-)- e S(+)-sotalol, para os parâmetros cinéticos relativos às fases de absorçäo, (expressos através de Média ñ DP): 'K IND. ab (1,081 ñ 0,134, 1,06 ñ 0,18, 1,17 ñ 0,17 h-û); disponibilidade sistêmica, 'AUC IND.T POT.SS' (14386,9 ñ 1308,2, 6959,3 ñ 597, 7387,3 ñ 711 ng.h/mL), 'C POT.SS IND.MAX'(2046,4 ñ 179,3, 1006,6 ñ 87, 1040,0 ñ 94,2ng/mL), ...