Metaboreceptor activation in heart failure with reduced ejection fraction: Linking cardiac and peripheral vascular haemodynamics.

NEW FINDINGS: What is the central question of this research? Do patients with heart failure with reduced ejection fraction (HFrEF) exhibit a greater dependence on cardiac or peripheral vascular haemodynamics across multiple levels of muscle metaboreflex activation provoked by postexercise circulatory occlusion? What is the main finding and its importance? The metaboreflex-induced pressor response in HFrEF patients is governed almost entirely by the peripheral circulation, which places a substantial haemodynamic load on the failing heart. This maladaptive response exacerbates the disease-related impairment of systolic function that is a hallmark feature of HFrEF and may therefore contribute to exercise intolerance in this patient group. ABSTRACT: We sought to evaluate the muscle metaboreflex in heart failure with reduced ejection fraction (HFrEF) patients, with an emphasis on the interaction between cardiac and peripheral vascular haemodynamics across multiple levels of metaboreceptor activation. In 23 HFrEF patients (63 ± 2 years of age) and 15 healthy control subjects (64 ± 3 years of age), we examined changes in mean arterial pressure, cardiac output, systemic vascular conductance, effective arterial elastance, stroke work and forearm deoxyhaemoglobin concentration during metaboreceptor activation elicited by postexercise circulatory occlusion (PECO) after three levels of static-intermittent handgrip exercise (15, 30 and 45% maximal voluntary contraction). Across workloads, the metaboreflex-induced increase in deoxyhaemoglobin and mean arterial pressure were similar between groups. However, in control subjects, the pressor response was driven by changes (Δ) in cardiac output  (Δ495 ± 155, Δ564 ± 156 and Δ666 ± 217 ml min-1 ), whereas this change was accomplished by intensity-dependent reductions in systemic vascular conductance in patients with HFrEF (Δ-4.9 ± 1.5, Δ-9.1 ± 1.9 and Δ-12.7 ± 1.8 ml min mmHg-1 ). This differential response contributed to the exaggerated increases in effective arterial elastance in HFrEF patients compared with control subjects, coupled with a blunted response in stroke work in the HFrEF patients. Together, these findings indicate a preserved role of the metaboreflex-induced pressor response in HFrEF but suggest that this response is governed by changes in the peripheral circulation. The net effect of this response appears to be maladaptive, as it places a substantial haemodynamic load on the left ventricle that may exacerbate left ventricular systolic dysfunction and contribute to exercise intolerance in this patient population.

Hemodynamic responses to small muscle mass exercise in heart failure patients with reduced ejection fraction.

To better understand the mechanisms responsible for exercise intolerance in heart failure with reduced ejection fraction (HFrEF), the present study sought to evaluate the hemodynamic responses to small muscle mass exercise in this cohort. In 25 HFrEF patients (64 ± 2 yr) and 17 healthy, age-matched control subjects (64 ± 2 yr), mean arterial pressure (MAP), cardiac output (CO), and limb blood flow were examined during graded static-intermittent handgrip (HG) and dynamic single-leg knee-extensor (KE) exercise. During HG exercise, MAP increased similarly between groups. CO increased significantly (+1.3 ± 0.3 l/min) in the control group, but it remained unchanged across workloads in HFrEF patients. At 15% maximum voluntary contraction (MVC), forearm blood flow was similar between groups, while HFrEF patients exhibited an attenuated increase at the two highest intensities compared with controls, with the greatest difference at the highest workload (352 ± 22 vs. 492 ± 48 ml/min, HFrEF vs. control, 45% MVC). During KE exercise, MAP and CO increased similarly across work rates between groups. However, HFrEF patients exhibited a diminished leg hyperemic response across all work rates, with the most substantial decrement at the highest intensity (1,842 ± 64 vs. 2,675 ± 81 ml/min; HFrEF vs. control, 15 W). Together, these findings indicate a marked attenuation in exercising limb perfusion attributable to impairments in peripheral vasodilatory capacity during both arm and leg exercise in patients with HFrEF, which likely plays a role in limiting exercise capacity in this patient population.

PathGen: a transitive gene pathway generator.

SUMMARY: Many online sources of gene interaction networks supply rich visual data regarding gene pathways that can aid in the study of biological processes, disease research and drug discovery. PathGen incorporates data from several sources to create transitive connections that span multiple gene interaction databases. Results are displayed in a comprehensible graphical format, showing gene interaction type and strength, database source and microarray expression data. These features make PathGen a valuable tool for in silico discovery of novel gene interaction pathways, which can be experimentally tested and verified. The usefulness of PathGen interaction analyses was validated using genes connected to the altered facial development related to Down syndrome. AVAILABILITY: http://dna.cs.byu.edu/pathgen. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. Further information is available at http://dna.cs.byu.edu/pathgen/PathGenSupplemental.pdf.

Synergistic effects of secretory phospholipase A2 from the venom of Agkistrodon piscivorus piscivorus with cancer chemotherapeutic agents.

Healthy cells typically resist hydrolysis catalyzed by snake venom secretory phospholipase A2. However, during various forms of programmed cell death, they become vulnerable to attack by the enzyme. This observation raises the question of whether the specificity of the enzyme for dying cells could be used as a strategy to eliminate tumor cells that have been intoxicated but not directly killed by chemotherapeutic agents. This idea was tested with S49 lymphoma cells and a broad range of antineoplastic drugs: methotrexate, daunorubicin, actinomycin D, and paclitaxel. In each case, a substantial population of treated cells was still alive yet vulnerable to attack by the enzyme. Induction of cell death by these agents also perturbed the biophysical properties of the membrane as detected by merocyanine 540 and trimethylammonium-diphenylhexatriene. These results suggest that exposure of lymphoma cells to these drugs universally causes changes to the cell membrane that render it susceptible to enzymatic attack. The data also argue that the snake venom enzyme is not only capable of clearing cell corpses but can aid in the demise of tumor cells that have initiated but not yet completed the death process.