Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats

Background and purpose:

The association between torcetrapib and its off-target effects on blood pressure suggested a possible class-specific effect. The effects of dalcetrapib (RO4607381/JTT-705) and torcetrapib on haemodynamics and the renin-angiotensin-aldosterone system (RAAS) were therefore assessed in a rat model.

Experimental approach:

Arterial pressure (AP) and heart rate were measured by telemetry in normotensive and spontaneously hypertensive rats (SHR) receiving torcetrapib 10, 40 or 80 mg·kg⁻¹·day⁻¹; dalcetrapib 100, 300 or 500 mg⁻¹·kg·day⁻¹; or vehicle (placebo) for 5 days. Expression of RAAS genes in adrenal gland, kidney, aorta and lung from normotensive rats following 5 days'' treatment with torcetrapib 40 mg·kg⁻¹·day⁻¹, dalcetrapib 500 mg·kg⁻¹·day⁻¹ or vehicle was measured by quantitative polymerase chain reaction.

Key results:

Torcetrapib transiently increased mean AP in normotensive rats (+3.7 ± 0.1 mmHg), whereas treatment in SHR resulted in a dose-dependent and sustained increase [+6.5 ± 0.6 mmHg with 40 mg·kg⁻¹·day⁻¹ at day 1 (P < 0.05 versus placebo)], which lasted over the treatment period. No changes in AP or heart rate were observed with dalcetrapib. Torcetrapib, but not dalcetrapib, increased RAAS-related mRNAs in adrenal glands and aortas.

Conclusions and implications:

In contrast to torcetrapib, dalcetrapib did not increase blood pressure or RAAS-related gene expression in rats, suggesting that the off-target effects of torcetrapib are not a common feature of all compounds acting on cholesteryl ester transfer protein.     

Incidence of T Wave Alternation After Acute Myocardial Infarction and Correlation with Other Prognostic Parameters: Results of a Prospective Study

Tachycardia induced alternation of the T wave (TWA) has been associated with arrhythmia morbidity in mixed patient populations. However, less is known concerning the general incidence of TWA and its usefulness in risk stratification early after acute myocardial infarction (MI). TWA was prospectively and systematically assessed in 140 consecutive patients 15 +/- 6 days after acute MI and prior to discharge. Results of TWA measurements were compared to other noninvasive risk markers, LV function, and coronary angiography. Sustained TWA was present at rest or inducible during exercise in 27% of patients. The patient-specific heart rate for the onset of TWA was 98 +/- 9 beats/min. After multivariate analysis, TWA correlated with age (P = 0.02) and LV function (P = 0.002) and occurred more often in patients after nonanterior MI (P = 0.03). Acute results of Holter monitoring, late potentials by signal-averaged ECG, and heart rate variability were unrelated to the TWA status. During follow-up (451 +/- 210 days) two major arrhythmic events occurred. The incidence of TWA early after MI is about 25%. TWA is related to age and LV function but not to other common arrhythmia markers. Although TWA does not appear to be related to excessive cardiac morbidity, evaluation of the prognostic significance of TWA requires further study.     

Morphology Discrimination: A Beat-to-Beat Algorithm for the Discrimination of Ventricular from Supraventricular Tachycardia by Implantable Cardioverter Defibrillators

Inappropriate therapy of SVTs by ICDs remains a major clinical problem despite enhanced detection criteria like "sudden onset" and "rate stability" in third-generation devices. Electrogram morphology discrimination offers an additional approach to improve discrimination of supraventricular tachycardia (SVT) from ventricular tachycardia (VT). In a prospective, multicenter study, patients received an ICD with a beat-to-beat algorithm for morphological analysis of the intracardiac electrogram (Morphology Discrimination, MD). A nominal programmingfor standard enhancement criteria and morphology discrimination was required at implant. Electrogram storage of tachycardia episodes irrespective of delivery of therapy was used to assess sensitivity and specificity of the morphology algorithm alone and in combination with established detection criteria. During a 126 6-month follow-up, 886 episodes of device stored electrograms from 82 of 256patients were evaluated. Atnominal settings, the MD algorithm correctly identified 423 of 551 episodes as VT resulting in sensitivity of 77%. The classification of SVT was met in 239 of 335 episodes resulting in specificity of 71%. In combination with sudden onset, sensitivityincreased to 99.5% at the expense of specificity (48%). In conclusion, SVT-VT discrimination based on morphological analysis alone results in limited sensitivity and specificity. Programming the monitor mode allows individual assessment of the performance of this detection enhancement feature during clinical follow-up without compromising device safety. Only in patients with documented efficacy of morphology discrimination should this feature be subsequently activated.     

脱钙骨联合干细胞移植修复兔股骨缺损

目的:观察骨髓间充质干细胞与脱钙骨复合修复兔股骨的长段骨-骨膜缺损,以及修复负重骨缺损的可行性。方法:实验于2002-09/2003-10在哈尔滨医科大学中心实验室完成。①将24只新西兰大白兔从自体骨髓中分离出骨髓间充质干细胞,将第2代骨髓基质干细胞5×108L-1中加入小牛脱钙骨,轻轻混匀后用注射器抽吸走离心管内6～8mL空气,人为造成管内负压,培养4h,使细胞进入小牛脱钙骨孔隙内,制成骨髓基质干细胞复合物。②制备成兔双侧股骨中段10mm骨-骨膜缺损模型,常规钢板螺钉固定;取其中20只兔右侧股骨缺损处植入复合物作为实验组,左侧股骨缺损处植入小牛脱钙骨作为对照组,空白组不植入任何材料。③在8,12,16和24周各时间点(实验组和对照组各取5只)分别行标本的大体观察和骨密度测试,比较其修复骨缺损的能力。结果:①各组骨缺损修复标本大体观察:实验组8周骨缺损处有部分修复,12,16周骨缺损完全修复,对照组在8周时有少量新骨形成,12,16周植入物部分被新骨代替,骨缺损区塑形差;空白组骨缺损未修复。②实验组、对照组骨标本的骨密度值:8,12和16周时实验组的骨密度值均大于对照组(0.936±0.056比0.618±0.034,1.238±0.024比1.052±0.037,1.605±0.062比1.227±0.047,P<0.05);24周时实验组骨密度与对照组比较,差异无统计学意义(1.635±0.033,1.563±0.112,P>0.05)。结论:骨髓间充质干细胞构建的组织工程骨早期修复骨缺损能力较强,且较单纯小牛脱钙骨成骨量大、迅速,能够对负重骨缺损进行有效的修复。     

Interleukin-3, GM-CSF, and G-CSF receptor expression on cell lines and primary leukemia cells: receptor heterogeneity and relationship to growth factor responsiveness

Recombinant human granulocyte-macrophage (GM) colony-stimulating factor (GM-CSF), G-CSF, and interleukin-3 (IL-3) labeled with 125I were used to study the characteristics and distribution of receptors for these factors on in vitro cell lines and on cells from patients with acute nonlymphocytic leukemia (ANL) and acute lymphocytic leukemia (ALL). Receptors for GM-CSF and G-CSF were restricted to a subset of myelomonocytic cell lines whereas IL-3 receptors were also found on pre- B- or early B-cell lines. Receptors for all three CSFs were broadly distributed on ANL cells, with considerable variability in levels of expression. Measurement of the colony-forming ability of ANL cells in response to the CSFs showed that there was no direct correlation between the ability of the cells to respond to a growth factor and the absolute number of receptors expressed for that growth factor. Binding of radiolabeled IL-3 and GM-CSF to ANL cells produced complex biphasic curves. Further analysis showed that both IL-3 and GM-CSF were able to partially compete for specific binding of the heterologous radiolabeled ligand to cells from several ANL patients, suggesting that heterogeneity may exist in human CSF receptors. These results provide new insights into the complex role that CSFs may play in ANL.     

Impact of Age and Basic Heart Rate on Heart Rate Turbulence in Healthy Persons

Postextrasystolic acceleration of heart rate (HR), known as HR turbulence (HRT) is attenuated in patients with coronary artery disease at increased risk of adverse events. The influence of age and basic HR on HRT have not been evaluated in a large cohort of persons. In 95 healthy individuals, HRT onset (TO) and slope (TS) were calculated from 24-hour ambulatory electrocardiograms, as well as the turbulence timing (TT). Gender specific differences in TO and TS were compared in simple, linear, weighted regression model. The influence of age and the basic HR preceding ventricular premature contractions on HRT were examined. We found that, in men and women, TO decreases as basic HR increases (P < 0.01). In contrast, in men, TS decreased as basic HR increases, whereas in women, basic HR influenced TS only slightly (P < 0.01). A multiple, linear regression model revealed a decrease in HRT with increasing age in men. In conclusion, physiological acceleration of the HR within the first 11 beats after premature ventricular complex (VPC) was observed in >75% of healthy individuals. An accelerating HR preceding the VPC influenced HRT in men. An increasing age was associated with a decrease in HRT in men and a decrease in TO in women. These results illustrate the importance of physiological modulations of HRT when used for risk stratification, especially in older populations.     

Sleep-Disordered Breathing in Recipients of Implantable Defibrillators

Study Objectives: To examine the prevalence and clinical significance of sleep-disordered breathing in patients with implantable cardioverter defibrillators (ICD).
Methods and Results: Overnight sleep studies were performed in 129 ICD recipients who had no history of sleep apnea. The mean left ventricular ejection fraction (LVEF) was 29 ± 11%. Mild, moderate, and severe sleep apnea was diagnosed in the presence of an apnea/hypopnea index (AHI) of 5–15/h, 15.1–30/h, and >30/h, respectively. No sleep apnea was present in 49 patients (38%), 57 (44%) had central sleep apnea (CSA), and 23 patients (18%) had obstructive sleep apnea (OSA). Mild, moderate, and severe sleep apnea were present in 25%, 31%, and 44% of patients with CSA, compared with 52%, 22%, and 26% of patients with OSA (P < 0.05). LVEF was similar in patients with versus without OSA or CSA. Patients with CSA were significantly older and had a higher prevalence of ischemic cardiomyopathy than patients without sleep apnea.
Conclusions: Previously undiagnosed CSA is common in ICD recipients. Severely disordered breathing during sleep was more prevalent among patients with CSA than patients with OSA. This prospective, observational study will examine the long-term clinical significance of sleep-disordered breathing in ICD recipients.     

Influence of exercise training frequency on cardiac and hepatic oxidative stress in rats

The present study investigated the influence of different frequencies of moderate exercise (13 weeks of treadmill running at 60% of maximal oxygen consumption) on oxidative stress in the heart and liver in rats. Oxidative stress was evaluated by chemiluminescence and lipid peroxidation (LPO) through thiobarbituric acid reactive substances. Activities of superoxide dismutase (SOD), glutathione peroxidase (GHPx) and catalase (CAT) were also measured. The animals were divided into four groups: control (C), acute ([A], only one exercise session at the end of 13 weeks), low frequency ([LF], one session a week for 13 weeks) and high frequency ([HF], five sessions a week for 13 weeks). Chronic exercise promoted cardiac hypertrophy in the HF group. Myocardial LPO in groups A and LF was increased, whereas in the HF group, it was decreased when compared with group C. The HF group demonstrated decreased myocardial SOD and GHPx activities and increased CAT activity. All exercise groups exhibited an increase in LPO in the liver compared with group C. SOD activity in liver was lower in the HF group and higher in the LF group as compared with group C. GHPx activity was higher in group A in relation to group C. Hepatic CAT activity was higher in groups A, LF and HF. It is suggested that chronic exercise training at a submaximal level is better than infrequent exercise bursts to promote metabolic adaptations that minimize oxidative stress.