Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Crucial role of circadian nuclear receptor RORα signaling

Exercise‐induced physiological hypertrophy provides protection against cardiovascular disease, whereas disease‐induced pathological hypertrophy leads to heart failure. Emerging evidence suggests pleiotropic roles of melatonin in cardiac disease; however, the effects of melatonin on physiological vs pathological cardiac hypertrophy remain unknown. Using swimming‐induced physiological hypertrophy and pressure overload‐induced pathological hypertrophy models, we found that melatonin treatment significantly improved pathological hypertrophic responses accompanied by alleviated oxidative stress in myocardium but did not affect physiological cardiac hypertrophy and oxidative stress levels. As an important mediator of melatonin, the retinoid‐related orphan nuclear receptor‐α (RORα) was significantly decreased in human and murine pathological hypertrophic cardiomyocytes, but not in swimming‐induced physiological hypertrophic murine hearts. In vivo and in vitro loss‐of‐function experiments indicated that RORα deficiency significantly aggravated pathological cardiac hypertrophy, and notably weakened the anti‐hypertrophic effects of melatonin. Mechanistically, RORα mediated the cardioprotection of melatonin in pathological hypertrophy mainly by transactivation of manganese‐dependent superoxide dismutase (MnSOD) via binding to the RORα response element located in the promoter region of the MnSOD gene. Furthermore, MnSOD overexpression reversed the pro‐hypertrophic effects of RORα deficiency, while MnSOD silencing abolished the anti‐hypertrophic effects of RORα overexpression in pathological cardiac hypertrophy. Collectively, our findings provide the first evidence that melatonin exerts an anti‐hypertrophic effect on pathological but not physiological cardiac hypertrophy via alleviating oxidative stress through transactivation of the antioxidant enzyme MnSOD in a RORα‐dependent manner.     

抵抗素与病理性心肌肥厚的研究进展

心力衰竭是各种心血管疾病的终末阶段，而病理性心肌肥厚是心力衰竭进程的一个关键时期。研究发现抵抗素与病理性心肌肥厚的进展密切相关，其内在涉及多条信号传导通路。详细了解其相关机制，有助于寻找新的治疗靶点，延缓病理性心肌肥厚的进展。     

Angiotensin-Converting Enzyme Inhibitors in Hypertension: To Use or Not to Use?

Most guidelines for the management of patients with cardiovascular disease recommend angiotensin-converting enzyme (ACE) inhibitors as first-choice therapy, whereas angiotensin receptor blockers (ARBs) are merely considered an alternative for ACE inhibitor–intolerant patients. The aim of this review was to compare outcomes and adverse events between ACE inhibitors and ARBs in patients. In patients with hypertension and hypertension with compelling indications, we found no difference in efficacy between ARBs and ACE inhibitors with regard to the surrogate endpoint of blood pressure and outcomes of all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and end-stage renal disease. However, ACE inhibitors remain associated with cough and a very low risk of angioedema and fatalities. Overall withdrawal rates because of adverse events are lower with ARBs than with ACE inhibitors. Given the equal outcome efficacy but fewer adverse events with ARBs, risk-to-benefit analysis in aggregate indicates that at present there is little, if any, reason to use ACE inhibitors for the treatment of hypertension or its compelling indications.     

Sequential Echocardiographic Study Prior and During Antihypertensive Therapy in Children with Severe Hypertension

This study was performed to assessmyocardial involvement in 18 children with severe hypertension (HT), using two dimensional (2 D) guided M mode echocardiography, prior and during therapy. All patients but 2 had renal or renovascular disease. Septal diastolic thickness (SDI) was utilized as a serial marker. Except for one case, all patients had increased SDT initially (1.03 ± .26 cm/m², p < .01 vs normal). Evolution under therapy allowed subdivision of patients : Group I : 12 patients showed left ventricular (LV) hypertrophy regression, within a follow-up period of 20 ± 9 months (final SDI : .78 ± .12 cm/m2 vs initial 1.09 ± .28, p<.01). Blood pressure (BP) was normalized in 9 patients, and borderline in 3. Therapy consisted on acebutolol (n=10), captopril (n=1), and renal artery surgery (n=1). Group II : LV hypertrophy was unchanged (n=3) or increased (n=3), within a follow-up period of 19 ± 8 months, with persistent severe (n=3) or mild (n=3) HT, under acebutolol (n=5). Treatment was changed to captopril with subsequent normal BP and echocardiogram improvement (n=3). In the overall population, final SDT was significantly correlated to the final BP (r= .69, p<.01). In conclusion, echocardiographic follow-up allowed serial non invasive assessment of LV hypertrophy in our severely hypertensive pediatric population. At first echocardiogram, LV hypertrophy was present in all patients but one. Antihypertensive therapy allowed simultaneous decrease of BP and LV hypertrophy in 12 patients, 10 under acebutolol.     

鼻内镜下小儿腺样体切除术临床疗效探讨

目的对鼻内镜下小儿腺样体切除术的优势与临床疗效进行探讨。方法通过对100例小儿腺样体肥大患者进行鼻内镜下腺样体切除术,对术后的临床反应进行观察和统计。结果采用鼻内镜下小儿腺样体切除术可将腺样体彻底切除,无残留物,术后无出血、无并发症及损伤鼻咽部等组织的现象,大部分患儿痊愈。结论鼻内镜下小儿腺样体切除术与传统手术法相比具有不可比拟的优势,避免了因视野不清造成的各种不良情况,提高了手术的准确性与安全性,术后并发症少,恢复时间短,疗效显著。     

Isolated Perfused Mesenteric Arteries of Hypertensive and Normotensive Rats; Response to Norepinephrine,Lysine Vasopressin and Angiotensin II

The aim of this study was to assess the pressure response of mesenteric arteries isolated from various hypertensive rat models to the 3 pressor agonists norepinephrine, lysinevasopressin and angiotensin II. The isolated mesenteric arterial beds were perfused with a Krebs-solution and then exposed to increasing doses of the 3 different pressor agents. Compared to Wistar Kyoto controls, spontaneously hypertensive rats exhibited a clearly enhanced vascular response to norepinephrine and lysine vasopressin but not to angiotensin II. In animals with hypertension produced by angiotensin II continuously released by an osmotic micropump, the vascular response to lysine vasopressin and angiotensin II was increased while that to norepinephrine was unchanged. Rats rendered hypertensive by the administration of deoxycorticosterone and salt exhibited an increased vascular response exclusively to angiotensin II. In all models taken together, the magnitude of the vascular response to norepinephrine and lysine vasopressin was related to the blood pressure of the intact animal but this was not the case for angiotensin II. These observations are not incompatible with the concept that changes in the vascular response are predominantly due to structural changes of the vascular wall. However, they suggest that more specific alterations of responsiveness of the vascular smooth muscle must also take place.     

Angiotensin I Converting Enzyme Gene Cosegregates with Blood Pressure and Heart Weight in F2 Progeny Derived from Spontaneously Hypertensive and Normotensive Wistar-Kyoto Rats

The present investigation examines the association of angiotesin I converting enzyme (ACE) genotypes with blood pressure and heart weight in an F2 population of rats derived from a cross between spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. ACE genotype of rats in the F2 population was determined using a microsatellite polymorphism. Our investigation revealed that cardiac mass was not correlated with blood pressure at 12 weeks of age within the SHR, WKY, F1 or F2 groups of rats. In male rats, ACE genotype accounted for approximately 20% of the difference in mean blood pressure between SHR and WKY rats. There was no effect in females. It was also responsible for 21%-29% of the difference in heart weight both in female and male animals. The allele derived from the SHR parent appeared recessive to the allele from WKY parent for both heart weight and blood pressure. These results suggest that a gene in the region of the ACE locus is one of the genetic factors influencing blood pressure and heart weight in SHR.     

Mitochondrial Energy Metabolism in the Left Ventricular Tissue of Spontaneously Hypertensive Rats: Abnormalities in both Adeninenucleotide and Phosphate Translocators and Enzyme Adenylate-Kinase and Creatine-Phosphokinase Activities

The aim of this study was to investigate the oxidative phosphorylation and additional adenosinetriphosphate (ATP) production mechanisms in mitochondria isolated from hypertrophied left ventricles of spontaneously hypertensive rats (SHR). Measurements of adenosinediphosphate (ADP)/ ATP and inorganic phosphate (Pi) carrier activities showed a significant reduction of Vmax values thus suggesting a general decrease of ATP supply in the hypertrophied ventricles. Investigation of mitochondrial enzyme activities showed 45% and 90% increases of adenylate-kinase and 80% and 110% increases of creatine-phosphokinase in 5- and 24-week-old SHR, before and after the development of the hypertensive state, respectively. The abnormalities found in SHR at the mitochondrial level suggest a profound rearrangement of energy production mechanisms in this model of left ventricular hypertrophy; whether the defects are determined genetically, and then worsen with the hypertensive state, remains to be determined.