High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles transport cholesterol in plasma and play an important role in cellular cholesterol homeostasis, which influences cell ...function. The risk of coronary artery disease (CAD) associated with high levels of LDL-cholesterol (LDL-C) can be reduced by treatment with statins, which reduce LDL-C levels by inhibiting cellular cholesterol synthesis. However, patients who are treated with high doses of statins, especially secondary CAD prevention, regardless of their resulting LDL-C levels, are still at high risk of CAD. Therefore, there has been growing interest in HDL-directed therapies. Inhibitors of cholesteryl ester transfer protein (CETP) substantially increase HDL-C levels (by 31–138%). However, it is still unclear whether or not CETP inhibitors can reduce the risk of CAD associated with low HDL-C levels, while reconstituted HDL or apolipoprotein A-I mimetic peptides increase the functionality of HDL. Low levels of HDL-C are often complicated with metabolic disorders, including hypertriglyceridemia, metabolic syndrome, and type 2 diabetes mellitus, and lifestyle changes are effective for correcting these conditions. Physical activity and exercise training increase HDL-C levels, especially HDL2-C levels, by multiple mechanisms. Therefore, although using HDL-directed therapies that increase HDL-C levels and/or improve the function of HDL is a reasonable approach for reducing the residual risk of CAD as a complement to LDL-C-lowering therapy, lifestyle modifications including exercise to improve metabolic disorders should be considered as the first option. (Circ J 2013; 77: 2651–2663)
The presence of a bystander witness is a crucial predictor of patient survival after out-of-hospital cardiac arrest (OHCA). However, the differences in survival and neurological outcomes among ...different types of citizen bystanders are not well understood.
We analysed data from the All-Japan Utstein Registry, a prospective, nationwide, population-based, observational study that was started in January 2005.
The registry includes all patients with OHCA who were transported to the hospital by emergency medical service (EMS) in Japan. The type of citizen bystander was classified as family member, friend, colleague, passerby or other.
We analysed 210 642 patients in the registry who were 18 years or older and experienced OHCA of cardiac origin witnessed by a citizen bystander between 2005 and 2014.
The main outcomes were 1 month survival and 1 month survival with minimal neurological impairment.
Of the citizen bystander-witnessed cases, 65.1% (137 147/210 642) were witnessed by a family member. However, among patients who survived to 1 month and who had a favourable 1 month neurological outcome, much lower proportions (53.9% (10 907/20 239) and 48.9% (5722/11 696)) were witnessed by a family member. Witness by a friend, colleague or passerby was associated with good 1 month neurological function, after controlling for the patient's age, first recorded rhythm, gender, bystander cardiopulmonary resuscitation (CPR), use of a public-access automated external defibrillator, dispatcher instructions, collapse-call time and response time compared with witness by a family member (friend: OR 1.35, 95% CI 1.24 to 1.46, colleague: OR 1.63, 95% CI 1.33 to 1.98, passerby: OR 1.60, 95% CI 1.39 to 1.84).
One-month survival and favourable1 month neurological outcome of patients with OHCA of cardiac origin witnessed by a family member were worse than those in cases witnessed by a friend, colleague or passerby, independent of the patient characteristics and the response of EMS.
Abstract There is some evidence in prospective randomized clinical trials that the administration of adrenaline (AD) before admission for the treatment of out-of-hospital cardiac arrest did not ...improve survival to hospital discharge. The aim of this study was to evaluate our real-world experience regarding the efficacy of intravenous AD in out-of-hospital cardiac arrest at our university hospital. In this retrospective study, we enrolled and divided 644 patients into AD (AD administration before arrival at the hospital) and non-AD (no AD administration before arrival at the hospital) groups. The patient characteristics including age, sex, percentage of cardiac cause, location of cardiac arrest, and witnessed arrest were similar between the AD and non-AD groups. There were no significant differences between the AD and non-AD groups with regard to return of spontaneous circulation, survival to hospital admission, survival to hospital discharge, or good neurologic recovery at hospital discharge in all patients. In addition, we excluded the data of patients with extrinsic cause. We analyzed whether intravenous AD before arrival in patients with intrinsic cause was effective. The outcomes in the AD group were similar to those in the non-AD group. In conclusion, our study indicated that AD administration before arrival at the hospital for the treatment of out-of-hospital cardiac arrest did not improve the clinical outcome.
The purpose of the present study was to evaluate the electrophysiologic properties within the pulmonary vein (PV) and at the PV–left atrial (LA) junction.
It has been recognized that atrial ...fibrillation (AF) can originate from PVs. However, the electrophysiologic properties of the PV have not been well characterized.
Thirty-two bipolar electrograms were recorded simultaneously from a basket catheter placed in 81 PVs of 48 patients with paroxysmal AF. The programmed stimulation was performed in the distal PV and PV-LA junction. Activation maps of PVs were analyzed from episodes of spontaneous onset of AF and initiation of induced AF by a single extrastimulus.
The effective refractory period (ERP) of the distal PV was significantly shorter than that of the PV-LA junction (177 ± 43 vs. 222 ± 30 ms, p < 0.0001). The conduction delay from the distal PV to the PV-LA junction was significantly longer than that from the PV-LA junction to distal PV (73 ± 40 vs. 32 ± 17 ms, p < 0.0001). During initiation of AF, a short coupled extrastimulus or rapid, repetitive focal activities originating from the PV formed a PV-LA reciprocating re-entrant circuit involving exit and entrance breakthrough points at the PV-LA junction. Also, an unstable re-entrant circuit within the PV was observed.
The presence of ERP heterogeneity and anisotropic conduction properties within the PV and at the PV-LA junction may be crucial to promote re-entry formation and thus might play an important role as a substrate for the maintenance of AF.
Highlights ► We analyzed the antiatherogenic effects of ETC-642 against the plaque burden. ► ETC-642 inhibited the progression of aortic atherosclerosis. ► ETC-642 remodeled small dense LDL to large ...and buoyant LDL. ► HDL-based therapy may be useful for preventing the progression of plaque volume.
The angiotensin II type 1 (AT(1)) receptor blocker (ARB) candesartan strongly reduces blood pressure (BP) in patients with hypertension and has been shown to have cardioprotective effects. A new ARB, ...azilsartan, was recently approved and has been shown to provide a more potent 24-h sustained antihypertensive effect than candesartan. However, the molecular interactions of azilsartan with the AT(1) receptor that could explain its strong BP-lowering activity are not yet clear. To address this issue, we examined the binding affinities of ARBs for the AT(1) receptor and their inverse agonist activity toward the production of inositol phosphate (IP), and we constructed docking models for the interactions between ARBs and the receptor. Azilsartan, unlike candesartan, has a unique moiety, a 5-oxo-1,2,4-oxadiazole, in place of a tetrazole ring. Although the results regarding the binding affinities of azilsartan and candesartan demonstrated that these ARBs interact with the same sites in the AT(1) receptor (Tyr(113), Lys(199) and Gln(257)), the hydrogen bonding between the oxadiazole of azilsartan-Gln(257) is stronger than that between the tetrazole of candesartan-Gln(257), according to molecular docking models. An examination of the inhibition of IP production by ARBs using constitutively active mutant receptors indicated that inverse agonist activity required azilsartan-Gln(257) interaction and that azilsartan had a stronger interaction with Gln(257) than candesartan. Thus, we speculate that azilsartan has a unique binding behavior to the AT(1) receptor due to its 5-oxo-1,2,4-oxadiazole moiety and induces stronger inverse agonism. This property of azilsartan may underlie its previously demonstrated superior BP-lowering efficacy compared with candesartan and other ARBs.
The renin-angiotensin system hormone angiotensin II Ang II plays a central role in the pathophysiology of vasoconstriction, cardiovascular hypertrophy and hyperplasia. Two distinct subtypes of Ang II ...receptor, type 1 AT1 and type 2 AT2, have been identified, and both have been shown to belong to the G protein-coupled receptors (GPCRs) superfamily. AT1 and AT2 receptors may have antagonistic action. While the crystal structures of GPCRs obtained from the rhodopsin, opsin, and ß1 and ß2- adrenergic receptors have recently been described in different conformational states, the crystal structures of Ang II receptors have not been elucidated. The conformation range and dynamics of the effects of ligands on GPCRs may differ from one receptor to another. This review focuses on the structure and function of Ang II receptors, such as the movement of transmembrane helices, functional selectivity for AT1 receptor activation, the possibility of constitutive activity of wild-type Ang II receptors and the homo- and hetero-dimerization of Ang II receptors.
The angiotensin II type 1 (AT1) receptor is a G protein‐coupled receptor that has a crucial role in the development of load‐induced cardiac hypertrophy. Here, we show that cell stretch leads to ...activation of the AT1 receptor, which undergoes an anticlockwise rotation and a shift of transmembrane (TM) 7 into the ligand‐binding pocket. As an inverse agonist, candesartan suppressed the stretch‐induced helical movement of TM7 through the bindings of the carboxyl group of candesartan to the specific residues of the receptor. A molecular model proposes that the tight binding of candesartan to the AT1 receptor stabilizes the receptor in the inactive conformation, preventing its shift to the active conformation. Our results show that the AT1 receptor undergoes a conformational switch that couples mechanical stress‐induced activation and inverse agonist‐induced inactivation.
Angiotensin II (Ang II) type 1 (AT1) receptor is a member of the G protein-coupled receptor superfamily and contains 359 amino acids. AT1 receptor blockers (ARBs, e.g., eprosartan, losartan, ...candesartan, valsartan, telmisartan, olmesartan, irbesartan, and azilsartan) have been developed and are available for clinical use, and basic and clinical studies have shown that ARBs are useful for preventing the development of cardiovascular disease. While most ARBs have common molecular structures (biphenyl-tetrazol and imidazole groups), they also show slightly different structures. Some of the benefits conferred by ARBs may not be class-specific effects, and instead may be molecule-specific effects. Their common molecular structures are thought to be responsible for their class effects, whereas their slightly different structures may be important for promoting molecule-specific effects. This review focuses on current evidence regarding the class- and molecule-specific differential effects of ARBs from basic experiments to clinical settings.
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