Is Treatment with Trimetazidine Beneficial in Patients with Chronic Heart Failure?

Background

Whether additional benefit can be achieved with the use of trimetazidine (TMZ) in patients with chronic heart failure (CHF) remains controversial. We therefore performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of TMZ treatment in CHF patients.

Methods

We searched PubMed, EMBASE, and Cochrane databases through October 2013 and included 19 RCTs involving 994 CHF patients who underwent TMZ or placebo treatment. Risk ratio (RR) and weighted mean differences (WMD) were calculated using fixed or random effects models.

Results

TMZ therapy was associated with considerable improvement in left ventricular ejection fraction (WMD: 7.29%, 95% CI: 6.49 to 8.09, p<0.01) and New York Heart Association classification (WMD: −0.55, 95% CI: −0.81 to −0.28, p<0.01). Moreover, treatment with TMZ also resulted in significant decrease in left ventricular end-systolic volume (WMD: −17.09 ml, 95% CI: −20.15 to −14.04, p<0.01), left ventricular end-diastolic volume (WMD: −11.24 ml, 95% CI: −14.06 to −8.42, p<0.01), hospitalization for cardiac causes (RR: 0.43, 95% CI: 0.21 to 0.91, p = 0.03), B-type natriuretic peptide (BNP; WMD: −157.08 pg/ml, 95% CI: −176.55 to −137.62, p<0.01) and C-reactive protein (CRP; WMD: −1.86 mg/l, 95% CI: −2.81 to −0.90, p<0.01). However, there were no significant differences in exercise duration and all-cause mortality between patients treated with TMZ and placebo.

Conclusions

TMZ treatment in CHF patients may improve clinical symptoms and cardiac function, reduce hospitalization for cardiac causes, and decrease serum levels of BNP and CRP.     

Metabolic and Kidney Disorders Correlate with High Atazanavir Concentrations in HIV-Infected Patients: Is It Time to Revise Atazanavir Dosages?

Introduction

Ritonavir-boosted atazanavir (ATV/r) is a relatively well tolerated antiretroviral drug. However, side effects including hyperbilirubinemia, dyslipidemia, nephrolithiasis and cholelithiasis have been reported in the medium and long term. Unboosted ATV may be selected for some patients because it has fewer gastrointestinal adverse effects, less hyperbilirubinemia and less impact on lipid profiles.

Methods

We investigated the distribution of ATV plasma trough concentrations according to drug dosage and the potential relationship between ATV plasma trough concentrations and drug-related adverse events in a consecutive series of 240 HIV-infected patients treated with ATV/r 300/100 mg (68%) or ATV 400 mg (32%).

Results

43.9% of patients treated with ATV/r 300/100 mg had ATV concentrations exceeding the upper therapeutic threshold. A significant and direct association has been observed between the severity of hyperbilirubinemia and ATV plasma trough concentrations (ATV concentrations: 271 [77–555], 548 [206–902], 793 [440–1164], 768 [494–1527] and 1491 [1122–1798] ng/mL in patients with grade 0, 1, 2, 3 and 4 hyperbilirubinemia, respectively). In an exploratory analysis we found that patients with dyslipidemia or nephrolitiasis had ATV concentrations significantly higher (582 [266–1148], and 1098 [631–1238] ng/mL, respectively) (p<0.001), as compared with patients with no ATV-related complications (218 [77–541] ng/mL).

Conclusions

A significant proportion of patients treated with the conventional dosage of ATV (300/100) had plasma concentrations exceeding the upper therapeutic threshold. These patients that are at high risk to experience ATV-related complications may benefit from TDM-driven adjustments in ATV dosage with potential advantages in terms of costs and toxicity.     

The Prognostic Role of Para-Aortic Lymph Nodes in Patients with Colorectal Cancer: Is It Regional or Distant Disease?

Introduction

Visible para-aortic lymph nodes of ≥2 mm in size are common metastatic patterns of colorectal cancer (CRC) seen on imaging. Their prognostic value, however, remains inconclusive. We aimed to assess the prognostic role of visible para-aortic lymph nodes (PALNs).

Methods

Patients with confirmed pathologic diagnosis of CRC were enrolled. Correlations among clinicopathologic variables were analyzed using the χ² test. The Cox proportional hazards model was applied for univariate and multivariate analyses. Survival was estimated using the Kaplan-Meier method and log-rank test. A prognostic model for visible PALNs in CRC patients was established.

Results

In total, 4527 newly diagnosed CRC patients were enrolled. Patients with visible PALNs had inferior overall survival compared to those without visible PALNs (5-year overall survival, 67% vs. 76%, P = 0.015). Lymphovascular invasion (LVI) (hazard ratio = 1.865, P = 0.015); nodal disease (pN+) status (hazard ratio = 2.099, P = 0.006); elevated preoperative serum carcinoembryonic antigen (CEA) levels (hazard ratio = 2.263, P < 0.001); and visible PALNs ≥10 mm (hazard ratio = 1.638, P = 0.031) were independent prognostic factors for patients with visible PALNs. If each prognostic factor scored one point, 5-year overall survival of lower- (prognostic score 0–1), intermediate- (prognostic score 2), and high- (prognostic score 3–4) risk groups were, 78%. 54%, and 25% respectively (P < 0.001).

Conclusions

The prognostic model, which included LVI, pN+ status, preoperative serum CEA level, and the size of visible PALNs, could effectively distinguish the outcome of patients with visible PALNs.     

Sex: Is Giardia Doing It in the Dark?

The protist Giardia has long been considered strictly asexual. Now genes specific for meiotic recombination have been found in the Giardia genome, but their consequences for genetics, epidemiology and evolution remain unknown.     

Clathrin‐Dependent or Not: Is It Still the Question?

Whether the endocytic uptake of a given molecule is mediated through clathrin-coated pits or not is a classical criterion used to characterize its endocytic pathway(s). Hence, clathrin-dependent endocytosis has been associated with highly selective and efficient uptake, whereas clathrin-independent endocytosis appeared to be confined to bulk uptake of fluid-phase markers. This scholastic view has recently been challenged using newly developed molecular tools that allow for the first time a functional and mechanistic analysis of these less well-characterized clathrin-independent pathways, including caveolar uptake and macropinocytosis. Furthermore, several studies point to a critical role of lateral lipid asymmetry – lipid rafts/microdomains – in membrane sorting. We will discuss the potential role of these structures in endocytosis and the possibility that differential sorting at the plasma membrane predisposes the ensuing intracellular fate of a given molecule as well as its physiological function.     

Is High Temporal Resolution Achievable for Paediatric Cardiac Acquisitions during Several Heart Beats? Illustration with Cardiac Phase Contrast Cine-MRI

Background

During paediatric cardiac Cine-MRI, data acquired during cycles of different lengths must be combined. Most of the time, Feinstein’s model is used to project multiple cardiac cycles of variable lengths into a mean cycle.

Objective

To assess the effect of Feinstein projection on temporal resolution of Cine-MRI.

Methods

1/The temporal errors during Feinstein’s projection were computed in 306 cardiac cycles fully characterized by tissue Doppler imaging with 6-phase analysis (from a population of 7 children and young adults). 2/The effects of these temporal errors on tissue velocities were assessed by simulating typical tissue phase mapping acquisitions and reconstructions. 3/Myocardial velocities curves, extracted from high-resolution phase-contrast cine images, were compared for the 6 volunteers with lowest and highest heart rate variability, within a population of 36 young adults.

Results

1/The mean of temporal misalignments was 30 ms over the cardiac cycle but reached 60 ms during early diastole. 2/During phase contrast MRI simulation, early diastole velocity peaks were diminished by 6.1 cm/s leading to virtual disappearance of isovolumic relaxation peaks. 3/The smoothing and erasing of isovolumic relaxation peaks was confirmed on tissue phase mapping velocity curves, between subjects with low and high heart rate variability (p = 0.05).

Conclusions

Feinstein cardiac model creates temporal misalignments that impair high temporal resolution phase contrast cine imaging when beat-to-beat heart rate is changing.     

Myocyte Autophagy in Heart Disease: Friend or Foe?

In the setting of hemodynamic stress, such as occurs in hypertension or following myocardial infarction, the heart undergoes a compensatory hypertrophic growth response. Left unchecked, this hypertrophic response triggers myocyte death, ventricular dilation, diminished contractile performance, and a clinical syndrome of heart failure. For some years, autophagy has been implicated in heart failure. More recently, mechanistic studies have emerged which provide new insights into the molecular underpinnings of hemodynamic stress-induced cardiomyocyte autophagy. Further, these studies have begun to provide clues as to whether cardiomyocyte autophagy is adaptive, mitigating disease pathogenesis, or maladaptive, contributing to disease progression. Here, we discuss recent studies that both answer questions and pose new ones.

Addendum to:

Cardiac Autophagy is a Maladaptive Response to Hemodynamic Stress

H. Zhu, P. Tannous, J.L. Johnstone, Y. Kong, J.M. Shelton, J.A. Richardson, V. Le, B. Levine, B.A. Rothermel and J.A. Hill

J Clin Invest 2007;117:1782-93     

Secondary Prevention in Patients with Coronary Heart Diseases: What Factors Are Associated with Health Status in Usual Primary Care?

Background

For patients with coronary heart diseases a substantial part of secondary prevention is delivered in primary care. Along with the growing importance of prevention, health-related quality of life (HRQoL) is an indicator of patient-centered care that has gained increased attention. Different approaches for reorganization in primary care have been associated with improvements in HRQoL. However, these are often results of complex interventions. Evidence on aspects concerning usual primary care that actually have an impact on HRQoL remains scarce. Therefore, this observational study aimed to identify factors which are associated with HRQoL in usual primary care at practice and patient-level.

Methods

This observational study was conducted in eight European countries. We were able to match data from survey instruments for 3505 patients with coronary heart disease (CHD) in 228 practices. A multilevel analysis was performed to identify associations of EQ-5D scores at patient and practice-level.

Results

After dropping patients with missing information, our cohort consisted of 2656 patients. In this sample, 30.5% were female and the mean age was 67.5 years (SD 10.1). The final model included a total set of 14 potential explanatory variables. At practice-level no variable was associated with EQ-5D. At patient-level, lower education (r = −0.0381, p<0.0001), female gender (r = −0.0543, p<0.0001) and a higher number of other conditions (r = −0.0340, p<0.0001), had a strong negative effect on HRQoL. Strong positive associations with HRQoL were found for a good medication adherence (Morisky) (r = 0.0195, p<0.0001) and more positive evaluations of physicians'' clinical behavior (r = 0.0282, p = 0.002). In terms of HRQoL no differences between single-handed and group practices exist.

Conclusion

The results of our study suggest that a better patient-physician relationship rather than organization of CHD care is associated with higher HRQOL in the primary care setting. The results may imply that interventions to improve HRQoL require a strong patient-centered approach.     

Heart transplantation in the Netherlands: quo vadis?

Heart transplantation is limited by the lack of donor organs. Twenty years after the start of the Dutch transplant programmes in Rotterdam and Utrecht the situation has even worsened, despite efforts to increase the donor pool. The Dutch situation seems to be worse than in other surrounding countries, and several factors that may influence donor organ availability and organ utilisation are discussed. The indications and contraindications for heart transplantation are presented, which are rather restrictive in order to select optimal recipients for the scarce donor hearts. Detailed data on donor hearts, rejected for transplantation, are shown to give some insight into the difficult process of dealing with marginal donor organs. It is concluded that with the current low numbers of acceptable quality donor hearts, there is no lack of capacity in the two transplanting centres nor is the waiting list limiting the number of transplants. The influence of our current legal system on organ donation, which requires (prior) permission from donor and relatives, is probably limited. The most important determinants of donor organ availability are: 1. The potential donor pool, consisting of brain dead victims of (traffic) accidents and CVAs and 2. Lack of consent to a request for donation. The potential donor pool is remarkably small in the Netherlands, due to relatively low numbers of (traffic) accidents, with an almost equal number of CVA-related brain dead patients compared with neighbouring countries. Lack of consent can only be pushed back by improved public awareness of the importance of donation and improved skills of professionals in asking permission in case there is no previous consent.     

Sympatric Speciation: When Is It Possible in Bacteria?

According to theory, sympatric speciation in sexual eukaryotes is favored when relatively few loci in the genome are sufficient for reproductive isolation and adaptation to different niches. Here we show a similar result for clonally reproducing bacteria, but which comes about for different reasons. In simulated microbial populations, there is an evolutionary tradeoff between early and late stages of niche adaptation, which is resolved when relatively few loci are required for adaptation. At early stages, recombination accelerates adaptation to new niches (ecological speciation) by combining multiple adaptive alleles into a single genome. Later on, without assortative mating or other barriers to gene flow, recombination generates unfit intermediate genotypes and homogenizes incipient species. The solution to this tradeoff may be simply to reduce the number of loci required for speciation, or to reduce recombination between species over time. Both solutions appear to be relevant in natural microbial populations, allowing them to diverge into ecological species under similar constraints as sexual eukaryotes, despite differences in their life histories.     

Evidence-Based Laboratory Medicine: Is It Working in Practice?

The principles of Evidence-Based Medicine have been established for about two decades, with the need for evidence-based clinical practice now being accepted in most health systems around the world. These principles can be employed in laboratory medicine. The key steps in evidence-based practice, namely (i) formulating the question; (ii) searching for evidence; (iii) appraising evidence; (iv) applying evidence; and (v) assessing the experience are all accepted but, as yet, translation into daily clinical and laboratory practice has been slow. Furthermore, the demand for evidence-based laboratory medicine (EBLM) has been slow to develop.There are many contrasting observations about laboratory medicine, for example (i) there is too much testing vs insufficient testing; (ii) testing is expensive vs laboratories are expected to generate income; and (iii) test results have little impact on outcomes vs test results are crucial to clinical decision making. However, there is little evidence to support any of these observations. Integrating the principles of EBLM into routine practice will help to resolve some of these issues by identifying (a) where laboratory medicine fits into the care pathway; (b) where testing is appropriate; (c) the nature and quality of evidence required to demonstrate the clinical utility of a test; (d) how the test result impacts on clinical actions; (e) where changes in the care pathway will occur; and (f) where benefit/value can be achieved. These answers will help to establish the culture of EBLM in clinical and laboratory practice.     

Dynamic Scapular Movement Analysis: Is It Feasible and Reliable in Stroke Patients during Arm Elevation?

Knowledge of three-dimensional scapular movements is essential to understand post-stroke shoulder pain. The goal of the present work is to determine the feasibility and the within and between session reliability of a movement protocol for three-dimensional scapular movement analysis in stroke patients with mild to moderate impairment, using an optoelectronic measurement system. Scapular kinematics of 10 stroke patients and 10 healthy controls was recorded on two occasions during active anteflexion and abduction from 0° to 60° and from 0° to 120°. All tasks were executed unilaterally and bilaterally. The protocol’s feasibility was first assessed, followed by within and between session reliability of scapular total range of motion (ROM), joint angles at start position and of angular waveforms. Additionally, measurement errors were calculated for all parameters. Results indicated that the protocol was generally feasible for this group of patients and assessors. Within session reliability was very good for all tasks. Between sessions, scapular angles at start position were measured reliably for most tasks, while scapular ROM was more reliable during the 120° tasks. In general, scapular angles showed higher reliability during anteflexion compared to abduction, especially for protraction. Scapular lateral rotations resulted in smallest measurement errors. This study indicates that scapular kinematics can be measured reliably and with precision within one measurement session. In case of multiple test sessions, further methodological optimization is required for this protocol to be suitable for clinical decision-making and evaluation of treatment efficacy.     

Circulating Level of CTRP1 in Patients with Nonalcoholic Fatty Liver Disease (NAFLD): Is It through Insulin Resistance?

Nonalcoholic fatty liver disease (NAFLD) is considered as one of the most common liver diseases. It is robustly linked to obesity and insulin resistance and is regarded as hepatic manifestation of metabolic syndrome (MetS). Adipokines are involved in the pathophysiology of liver diseases. The aim of this study was to evaluate the plasma concentrations of CTRP1 (complement-C1q TNF-related protein 1) in 22 patients with NAFLD, 22 patients with type 2 diabetes mellitus (T2DM), 22 patients with NAFLD+T2DM and 21 healthy controls, as well as their correlation with the level of metabolic and hepatic parameters. Plasma concentration of CTRP1 was measured with ELISA method. Plasma concentration of CTRP1 in patients with NAFLD, T2DM and NAFLD+T2DM were significantly higher than healthy subjects (p<0.0001). Moreover, we observed significant positive correlations between plasma level of CTRP1 and fasting blood glucose (FBG) (p<0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (p<0.001), body mass index (BMI) (p = 0.001), alanine amino transferase (ALT) (p = 0.002), gamma glutamyl transferase (γ-GT) (p<0.001) and liver stiffness (LS) (p<0.001). Our results indicate the strong association of CTRP1 with insulin resistance in NAFLD. Also, it seems that CTRP1 can be considered as an emerging biomarker for NAFLD, however, more studies are necessary to unravel the role of CTRP1 in NAFLD pathogenesis.     

Refractoriness in Sustained Visuo-Manual Control: Is the Refractory Duration Intrinsic or Does It Depend on External System Properties?

Researchers have previously adopted the double stimulus paradigm to study refractoriness in human neuromotor control. Currently, refractoriness, such as the Psychological Refractory Period (PRP) has only been quantified in discrete movement conditions. Whether refractoriness and the associated serial ballistic hypothesis generalises to sustained control tasks has remained open for more than sixty years. Recently, a method of analysis has been presented that quantifies refractoriness in sustained control tasks and discriminates intermittent (serial ballistic) from continuous control. Following our recent demonstration that continuous control of an unstable second order system (i.e. balancing a ‘virtual’ inverted pendulum through a joystick interface) is unnecessary, we ask whether refractoriness of substantial duration (∼200 ms) is evident in sustained visual-manual control of external systems. We ask whether the refractory duration (i) is physiologically intrinsic, (ii) depends upon system properties like the order (0, 1^st, and 2^nd) or stability, (iii) depends upon target jump direction (reversal, same direction). Thirteen participants used discrete movements (zero order system) as well as more sustained control activity (1^st and 2^nd order systems) to track unpredictable step-sequence targets. Results show a substantial refractory duration that depends upon system order (250, 350 and 550 ms for 0, 1^st and 2^nd order respectively, n = 13, p<0.05), but not stability. In sustained control refractoriness was only found when the target reverses direction. In the presence of time varying actuators, systems and constraints, we propose that central refractoriness is an appropriate control mechanism for accommodating online optimization delays within the neural circuitry including the more variable processing times of higher order (complex) input-output relations.