The biochemical pharmacology of renin inhibitors: Implications for translational medicine in hypertension, diabetic nephropathy and heart failure: Expectations and reality

The renin-angiotensin-aldosterone system (RAAS) plays a dominant role in the pathophysiology of hypertension, Diabetes mellitus (DM), chronic kidney disease (CKD) and chronic heart failure (CHF). Therefore, drugs that block key components of the RAAS such as ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) have gained wide clinical use for these indications. Despite progress, the morbidity and mortality of patients treated with ACEi or ARBs remain high. Small molecules that directly inhibit renin (DRI) and are orally active have also been developed and one such drug, aliskiren, was introduced into clinical use for treatment of hypertension in 2007. Further clinical trials aimed to expand the therapeutic use of aliskiren are in progress for CKD-DM and CHF. In this review we analyze and review the translational medicine prospects of aliskiren in respect to the biochemical pharmacology of the RAAS, the marketed RAAS modulators and the new emerging science regarding the role of prorenin, renin and renin receptors in cardiovascular biology and disease. The information already gained with aliskiren, raises questions regarding the advantages of DRIs as monotherapy compared to marketed ACEis and ARBs, their potential added value in combination with other RAAS modulators and other unproven benefits in relation to prorenin and renin receptor biology. This review will also indicate basic and clinical research needs that are critical to determine whether DRIs can provide meaningful added medical benefits over contemporary medicines that regulate the RAAS, and the need to identify patients that are more likely to benefit from DRIs and any possible long term adverse effects.     

卡托普利对CHF患者MMP-9/TIMP-1水平和BNP的干预作用

目的观察卡托普利对CHF患者MMP-9/TIMP-1水平和BNP的影响。方法将181例患者随机分为2组。对照组94例予洋地黄药物、β-受体阻滞剂、利尿剂等的基础治疗;治疗组87例,加用卡托普利片25mg日三次口服,视患者情况调整药物用量。2组患者均于治疗前和治疗8周后,分别测定血清MMP-9、TIMP-1、BNP含量。结果与治疗前相比,治疗后两组的MMP-9、MMP-9/TIMP-1、BNP含量均有明显降低(P<0.05),但治疗组的降低更明显(P<0.05)。结论卡托普利可以降低心衰患者MMP-9、MMP-9/TIMP-1含量,从而降低血清BNP水平,改善心功能。     

黄芪注射液足三里穴位注射治疗慢性心力衰竭的临床观察

目的:研究黄芪注射液足三里穴位注射对慢性心力衰竭(CHF)患者心功能的影响。方法:37例CHF患者采用常规抗心衰加黄芪注射液足三里穴位注射为治疗组,同期48例CHF患者采用常规抗心衰治疗为对照组。两组治疗前后评价心功能、采用超声心动图检测心功能参数。结果:经1个疗程治疗后,两组心功能明显改善,治疗组优于对照组(P0.05)。治疗后心脏每搏输出量、左心室舒张末期内径、左室射血分数两组均有显著改善,治疗组均优于对照组,差异有统计学意义(P0.05)。结论:联合应用黄芪注射液足三里穴位注射治疗CHF有显著疗效,能明显改善心功能。     

Autonomic and hemodynamic effects of a new selective dopamine agonist, CHF1035, in patients with chronic heart failure

Dopamine agonists have been studied in chronic heart failure, but earlier reports with non-selective compounds demonstrated unfavourable long-term effects. CHF 1035 is an orally active, new selective dopamine agonist, primarily activating DA₂ ^– and ₂ receptors, thereby inhibiting norepinephrine release, which may be beneficial in heart failure. We conducted a double-blind, placebo-controlled comparison of CHF 1035 (10 mg/day, n = 20) and placebo (n = 9) in patients with mild to moderate chronic heart failure (left ventricular ejection fraction <0.45). Patients were clinically stable on diuretics and angiotensin converting enzyme inhibitors. Both acute and chronic assessments were made, including plasma neurohormones and 24-hr Holter monitoring for heart rate variability analysis. CHF1035 was generally well tolerated during the study. After 10 days, there were no significant changes between the groups regarding heart rate and blood pressure. Compared to placebo, plasma norepinephrine levels decreased on CHF1035, both in the first 4 hours and after 10 days (p < 0.05 between groups). Other neurohormones (natriuretic peptides, renin, aldosteron and endothelin) were not significantly affected. Heart rate variability parameters generally increased on CHF1035, but were unaffected by placebo (p < 0.05 between groups). Short-term treatment with the selective dopaminergic agonist CHF1035 is well tolerated, reduces plasma norepinephrine concentrations and increases heart rate variability in mild chronic heart failure.An erratum to this article can be found at     

小剂量甲状腺素对老年慢性心力衰竭伴低甲状腺激素水平患者心功能的影响观察

目的:探讨小剂量甲状腺素在老年慢性心力衰竭(CHF)伴低甲状腺激素水平患者中对心功能的影响。方法:将92例CHF伴低甲状腺激素水平患者随机分为观察组(n=46)与对照组(n=46),对照组给予常规抗心力衰竭治疗,观察组在对照组基础上加用小剂量左甲状腺素钠治疗,对比两组患者心功能变化。结果:观察组总有效率为89.1%(41/46),显著高于对照组的67.4%(31/46)(P<0.05);两组患者治疗后每搏输出量(SV)、每分输出量(CO)、心脏指数(CI)、左室射血分数(LVEF)、舒张早期速度峰值(VE)/舒张晚期速度峰值(VA)等心功能指标均有显著改善(P<0.01),但治疗后观察组仍显著优于对照组(P<0.05)。结论:在常规抗心力衰竭治疗基础上加用低剂量甲状腺素将有效改善老年CHF伴低甲状腺激素血症患者心功能,降低死亡率,提高患者生活质量。     

The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: A systematic review

Objective

To perform a systematic review of the literature regarding the epidemiology of the association between systemic lupus erythematosus (SLE) and atherosclerotic cardiovascular disease (CVD), including the increased risk for CVD, as well as the risk factors responsible for development of CVD in patients with SLE.

Methods

We followed the PRISMA guidelines to systematically search the PubMed database from inception to June 2012. Studies were selected using predefined eligibility criteria, and 2 authors independently extracted data. The risk of bias was measured for each study using a domain-based assessment.

Results

We report on 28 studies that met criteria for inclusion in our analysis. We found strong epidemiologic evidence that SLE patients have an increased relative risk of CVD compared to controls. There is limited information regarding relative CVD mortality risks among SLE patients. Traditional CVD risk factors, including age, male sex, hyperlipidemia, smoking, hypertension, and CRP, are associated with CVD risk among SLE patients. Several SLE-specific factors, including disease activity and duration, and possibly specific manifestations and therapies, further increase risk. Several risk factors, such as disease activity and glucocorticoid use, are closely associated, making it difficult to disentangle their effects.

Conclusions

CVD risk among SLE patients compared to the general population is at least doubled. While older SLE patients appear to have the highest absolute risks of CVD, young women have alarmingly high relative risks, given the rarity of CVD in the comparison general population. Both traditional and SLE-specific risk factors are important, although there are discrepancies within the literature.     

Congestive Heart Failure and Treatment in Thalassemia Major

The homozygous β-thalassemias are a group of genetically inherited hemoglobin (Hb) disorders characterized by dyserythropoietic anemia. According to the degree of anemia, two main forms, sharing a common basic molecular mechanism, are distinguished: thalassemia major (TM) and thalassemia intermedia (TI). The severity of the clinical phenotype differentiates the two forms. Thalassemia major usually presents as a severe anemia requiring life-long transfusion therapy for survival.

The dramatic improvement in life expectancy of β-thalassemia (thal) patients achieved during the past few decades by virtue of therapeutic advances, has motivated investigators' interest in a better understanding of the clinical consequences of this genetic defect. Heart complications still represent the leading cause of mortality from the disease. The mechanisms of cardiac injury along with its treatment and prevention have attracted the main research efforts in this field. In this review, we present existing knowledge and our personal experience of 30 years of follow-up of over 1,000 thalassemic patients, regarding the basis of the cardiac injury, the clinical findings and the global strategy of the therapeutic intervention in TM patients who develop congestive heart failure (CHF).     

美托洛尔和卡托普利联合应用对慢性心力衰竭的治疗观察

目的:观察美托洛尔和卡托普利联用治疗慢性充血性心力衰竭(CHF)的疗效和副作用.方法:将41例CHF患者随机分成治疗组和对照组,治疗组在常规应用强心、利尿、扩血管药治疗的基础上,加用美托洛尔和卡托普利口服,对照组应用常规治疗.结果:治疗组和对照组的总有效率分别为90.5%和65%,二者差异有显著性.个别治疗组出现副作用但不影响疗效.结论:联合应用美托洛尔和卡托普利治疗CHF疗效明显且副作用少.