Isoprenaline increases the slopes of restitution trajectory in the conscious rabbit with ischemic heart failure

Roughly speaking, restitution is the dependence of recovery time of cardiac electrical activity on heart rate. Increased restitution slope is theorized to be predictive of sudden death after heart injury such as from coronary artery occlusion (ischemia). Adrenaline analogs are known to increase restitution slope in normal hearts, but their effects in failing hearts are unknown. Twenty-six rabbits underwent coronary ligation (n = 15) or sham surgery (n = 11) and implantation of a lead in the heart for recording electrocardiograms. Eight weeks later, unanesthetized rabbits were given 0.25–2.0 ml of 1 μmol/L isoprenaline intravenously, which increased heart rate. Heart rate was quantified by time between QRS peaks (RR) and heart activity duration by R to T peak time (QTp). Ligated rabbits (n = 6) had lower ejection fraction than sham rabbits (n = 7, p < 0.0001) indicative of heart failure, but similar baseline RR (269 ± 15 vs 292 ± 23 ms, p = 0.07), QTp (104 ± 17 vs 91 ± 9 ms, p = 0.1), and isoprenaline-induced minimum RR (204 ± 11 vs 208 ± 6 ms, p = 0.4). The trajectory of QTp vs TQ plots displayed hysteresis and regions of negative slope. The slope of the positive slope region was >1 in ligated rabbits (1.27 ± 0.66) and <1 in sham rabbits (0.35 ± 0.14, p = 0.004). The absolute value of the negative slope was greater in ligated rabbits (− 0.81 ± 0.52 vs − 0.35 ± 0.14, p = 0.04). Isoprenaline increased heart rate and slopes of restitution trajectory in failing hearts. The dynamics of restitution trajectory may hold clues for sudden death in heart failure patients.     

Multifactorial approach and superior treatment efficacy in renal patients with the aid of nurse practitioners. Design of The MASTERPLAN Study [ISRCTN73187232]

Background

Patients with chronic kidney disease (CKD) are at a greatly increased risk of developing cardiovascular disease. Recently developed guidelines address multiple risk factors and life-style interventions. However, in current practice few patients reach their targets. A multifactorial approach with the aid of nurse practitioners was effective in achieving treatment goals and reducing vascular events in patients with diabetes mellitus and in patients with heart failure. We propose that this also holds for the CKD population.

Design

MASTERPLAN is a multicenter randomized controlled clinical trial designed to evaluate whether a multifactorial approach with the aid of nurse-practicioners reduces cardiovascular risk in patients with CKD. Approximately 800 patients with a creatinine clearance (estimated by Cockcroft-Gault) between 20 to 70 ml/min, will be included. To all patients the same set of guidelines will be applied and specific cardioprotective medication will be prescribed. In the intervention group the nurse practitioner will provide lifestyle advice and actively address treatment goals. Follow-up will be five years. Primary endpoint is the composite of myocardial infarction, stroke and cardiovascular mortality. Secondary endpoints are cardiovascular morbidity, overall mortality, decline of renal function, change in markers of vascular damage and change in quality of life. Enrollment has started in April 2004 and the study is on track with 700 patients included on October 15th, 2005. This article describes the design of the MASTERPLAN study.     

Guidelines for indications for coronary revascularization in The Netherlands

In 1996 the Minister of Public Health, Welfare and Sports in The Netherlands published a 'Planning Decree Special Interventions in the Heart'. She requested from the professional organizations guidelines for the indications for interventions in the heart. A working group was formed with representatives from the Dutch professional organizations for cardiology and thoracic surgery, to address this issue for patients with coronary artery disease. The working group confirmed the need to discuss all patients who are considered for either elective or emergency revascularization during a multidisciplinary consultation in (or with) one of the specialized Dutch hospitals. During this meeting of the 'heart team', at least one interventional cardiologist and one thoracic surgeon should be present. There are three possible outcomes of the heart team's consultations for each patient: drug therapy only ('conservative management'), coronary surgery or catheter intervention. For each case, the team should indicate the expected benefit, the risk of the intervention, the urgency and the estimated waiting time. The guidelines presented in this paper address these issues for three patient categories: stable angina pectoris, unstable angina pectoris and acute myocardial infarction.     

Bacterial swimming strategies and turbulence

Most bacteria in the ocean can be motile. Chemotaxis allows bacteria to detect nutrient gradients, and hence motility is believed to serve as a method of approaching sources of food. This picture is well established in a stagnant environment. In the ocean a shear microenvironment is associated with turbulence. This shear flow prevents clustering of bacteria around local nutrient sources if they swim in the commonly assumed "run-and-tumble" strategy. Recent observations, however, indicate a "back-and-forth" swimming behavior for marine bacteria. In a theoretical study we compare the two bacterial swimming strategies in a realistic ocean environment. The "back-and-forth" strategy is found to enable the bacteria to stay close to a nutrient source even under high shear. Furthermore, rotational diffusion driven by thermal noise can significantly enhance the efficiency of this strategy. The superiority of the "back-and-forth" strategy suggests that bacterial motility has a control function rather than an approach function under turbulent conditions.     

Imaging synaptic activity in intact brain and slices with FM1-43 in C. elegans, lamprey, and rat

The fluorescent probe FM1-43 has been used extensively for imaging vesicle recycling; however, high nonspecific adsorption resulting in elevated background levels has precluded its use in certain tissues, notably brain slices. We have found that a sulfobutylated derivative of beta-cyclodextrin (ADVASEP-7) has a higher affinity for FM1-43 than the plasma membrane. ADVASEP-7 was used as a carrier to remove FM1-43 nonspecifically bound to the outer leaflet of the plasma membrane or extracellular molecules, significantly reducing background staining. This has enabled us to visualize synaptic vesicle recycling in the nematode C. elegans, intact lamprey spinal cord, and rat brain slices.     

Disparity in allosteric interactions of monastrol with Eg5 in the presence of ADP and ATP: a difference FT-IR investigation

Eg5 is a kinesin-like motor protein required for mitotic progression in higher eukaryotes. It is thought to cross-link antiparallel microtubules, and provides a force required for the formation of a bipolar spindle. Monastrol causes the catastrophic collapse of the mitotic spindle through the allosteric inhibition of Eg5. Utilizing a truncated Eg5 protein, we employ difference infrared spectroscopy to probe structural changes that occur in the motor protein with monastrol in the presence of either ADP or ATP. Difference FT-IR spectra of Eg5-monastrol-nucleotide complexes demonstrate that there are triggered conformational changes corresponding to an interconversion of secondary structural elements in the motor upon interaction with nucleotides. Notably, conformational changes elicited in the presence of ADP are different from those in the presence of ATP. In Eg5-monastrol complexes, exchange of ADP is associated with a decrease in random structure and an increase in alpha-helical content. In contrast, formation of the Eg5-monastrol-ATP complex is associated with a decrease in alpha-helical content and a concomitant increase in beta-sheet content. One or more carboxylic acid residues in Eg5 undergo unique changes when ATP, but not ADP, interacts with the motor domain in the presence of monastrol. This first direct dissection of inhibitor-protein interactions, using these methods, demonstrates a clear disparity in the structural consequences of monastrol in the presence of ADP versus ATP.     

The role of mechanical forces in dextral rotation during cardiac looping in the chick embryo

Cardiac looping is a vital morphogenetic process that transforms the initially straight heart tube into a curved tube normally directed toward the right side of the embryo. While recent work has brought major advances in our understanding of the genetic and molecular pathways involved in looping, the biophysical mechanisms that drive this process have remained poorly understood. This paper examines the role of biomechanical forces in cardiac rotation during the initial stages of looping, when the heart bends and rotates into a c-shaped tube (c-looping). Embryonic chick hearts were subjected to mechanical and chemical perturbations, and tissue stress and strain were studied using dissection and fluorescent labeling, respectively. The results suggest that (1) the heart contains little or no intrinsic ability to rotate, as external forces exerted by the splanchnopleure (SPL) and the omphalomesenteric veins (OVs) drive rotation; (2) unbalanced forces in the omphalomesenteric veins play a role in left-right looping directionality; and (3) in addition to ventral bending and rightward rotation, the heart tube also bends slightly toward the right. The results of this study may help investigators searching for the link between gene expression and the mechanical processes that drive looping.     

The ontogeny of fluctuating asymmetry

We tested seven hypotheses regarding the mechanisms by which fluctuating asymmetry (FA) originates. We did this by analyzing data on four bilateral characters measured repeatedly during the development of individual domestic fowl. Immediately posthatching, there was substantial directional asymmetry, which rapidly decreased. We detected FA at significant levels in all characters in the majority of our measurements over the remainder of development. We also examined the effects of known environmental stressors (food and density stress) on levels of FA. At the levels we examined, changes in these stressors did not alter the degree of asymmetry we found in fowl. Time series of asymmetry for individuals did not exhibit regular oscillations, as much of the relevant literature predicts. Asymmetry levels reflected the combined effects of developmental noise, which was random in degree and direction, and feedback processes, which decreased asymmetry by altering growth rates on both sides of the body. Our findings best fit the predictions of the residual asymmetry and compensatory growth hypotheses, which suggest that levels of asymmetry reflect only recent growth history.     

Skeletal muscle basal AMP-activated protein kinase activity is chronically elevated in alloxan-diabetic dogs: impact of exercise.

The effect of diabetes and exercise on skeletal muscle (SkM) AMP-activated protein kinase (AMPK)alpha1 and -alpha2 activities and site-specific phosphorylation of acetyl-CoA carboxylase was examined in the same six dogs before alloxan (35 mg/kg)-induced diabetes (C) and after 4-5 wk of suboptimally controlled hyperglycemic and hypoinsulinemic diabetes (DHG) in the presence and absence of 300-min phlorizin (50 microg.kg-1.min-1)-induced "normoglycemia" (DNG). In each study, the dog underwent a 150-min [3-3H]glucose infusion period, followed by a 30-min treadmill exercise test (60-70% maximal oxygen capacity) to measure the rate of glucose disposal into peripheral tissues (Rdtissue). SkM biopsies were taken from the thigh (vastus lateralis) before and immediately after exercise. In the C and DHG states, the rise in plasma free fatty acids (FFA) with exercise ( approximately 40%) was similar. In the DNG group, preexercise FFA were significantly higher, but the absolute rise in FFA with exercise was similar. However, the exercise-induced increment in Rdtissue was significantly blunted (by approximately 40-50%) in the DNG group compared with the other states. In SkM, preexercise AMPKalpha1 and -alpha2 activities were significantly elevated (by approximately 60-125%) in both diabetic states, but unlike the C group these activities did not rise further with exercise. Additionally, preexercise acetyl-CoA carboxylase phosphorylation in both diabetic states was elevated by approximately 70-80%, but the increases with exercise were similar to the C group. Preexercise AMPKalpha1 and -alpha2 activities were negatively correlated with Rdtissue during exercise for the combined groups (both P < 0.02). In conclusion, the elevated preexercise SkM AMPKalpha1 and -alpha2 activities contribute to the ongoing basal supply of glucose and fatty acid metabolism in suboptimally controlled hypoinsulinemic diabetic dogs; but whether they also play a permissive role in the metabolic stress response to exercise remains uncertain.