β1-adrenoceptor blockade treatment of right ventricular dysfunction caused by pulmonary hypertension

Failure of the right ventricle (or ventricular) (RV) is the leading cause of death in patients with pulmonary arterial hypertension (PAH), however no treatments specifically target the failing RV. β1-adrenoceptor blockers (β-blockers, BB) reduce mortality in left heart failure but current clinical guidelines caution against their use in PAH. Recent studies suggest β-blockers may be beneficial in PAH however the mechanisms remain unknown. The present study sought to establish whether the β1- blocker metoprolol (10 mg/kg/day) improved survival and function in a rat model of PAH induced by monocrotaline (60 mg/kg, MCT), and to elucidate the mechanisms responsible. Daily metoprolol or placebo was administered 15 days post-monocrotaline injection. PAH resulted in severe RV hypertrophy, dysfunction and heart failure by median day 23 in placebo treated rats (FAIL), whereas metoprolol extended the median survival to day 31 (MCT+BB). RV function measured by echocardiography and catheterisation was severely impaired in FAIL, but was partially restored in MCT+BB on day 23±1. Metoprolol appeared to act primarily on the myocardium and not the vasculature. Contractile abnormalities in isolated FAIL RV cardiomyocytes included increased cell volume, negative force and Ca2+ transient response to faster pacing, increased stiffness to stretch and shorter resting sarcomere length. Reduced creatine kinase activity was found in FAIL; creatine kinase inhibition reproduced characteristics of FAIL in healthy cells, whereas exogeneous creatine kinase reversed the shorter sarcomere length in FAIL cells. Contractile and Ca2+ handling properties of MCT+BB cells were partially or fully restored relative to healthy cells. Capillary density was reduced in FAIL and partially restored in MCT+BB; computer modelling indicated fewer areas of hypoxia in MCT+BB RV. Assessment of FAIL RV mitochondria revealed reduced creatine-coupled respiration but no other detectable defects. Metoprolol improved survival, Ca2+-handling, contractility, oxygen delivery and diastolic properties of PAH rats. β-blockers represent a novel myocardium-specific therapy to target the failing RV in PAH

Molecular, subcellular, and arrhythmogenic mechanisms in genetic RyR2 disease

The ryanodine receptor (RyR2) has a critical role in controlling Ca2+ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure that comprises the functional channel. Numerous mutations in the gene encoding RyR2 protein have been identified and many are linked to a wide spectrum of arrhythmic heart disease. Gain of function mutations (GoF) result in a hyperactive channel that causes excessive spontaneous SR Ca2+ release. This is the predominant cause of the inherited syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, rare hypoactive loss of function (LoF) mutations have been identified that produce atypical effects on cardiac Ca2+ handling that has been termed calcium release deficiency syndrome (CRDS). Aberrant Ca2+ release resulting from both GoF and LoF mutations can result in arrhythmias through the Na+/Ca2+ exchange mechanism. This mini-review discusses recent findings regarding the role of RyR2 domains and endogenous regulators that influence RyR2 gating normally and with GoF/LoF mutations. The arrhythmogenic consequences of GoF/LoF mutations will then be discussed at the macromolecular and cellular level

Intensity-dependence of exercise and active recovery in high-intensity interval training

Background: High-intensity interval training (HIIT) with interspersing active recovery is an effective mode of exercise training in cohorts ranging from athletes to patients. Here, we assessed the intensity-dependence of the intervals and active recovery bouts for permitting a sustainable HIIT protocol. Methods: 14 males completed 4x4-minute HIIT protocols where intensities of intervals ranged 80-100% of maximal oxygen uptake (VO2max) and active recovery ranged 60-100% of lactate (La-) threshold (LT). Blood La- measurements indicated fatigue, while tolerable duration of intervals indicated sustainability. Results: HIIT at 100% of VO2max allowed 44±10% [30-70%] completion, i.e. fatigue occurred after 7minutes:6seconds of the intended 16 minutes of high intensity, whereas HIIT at 95-80% of VO2max was 100% sustainable (p<0.01). Measured intensity did not differ from intended intensity across the protocols (p>0.05). Blood La- concentration [La-] increased to 9.3±1.4mM during HIIT at 100% of VO2max, whereas at 80-95% of VO2max stabilised at 2-6mM in an intensity-dependent manner (p<0.01 vs 100% of VO2max and p<0.05 vs baseline). Active recovery at 60-70% of LT during HIIT associated with steady-state blood [La-] peaking at 6-7mM, whereas at 80-100% of LT, blood [La-] accumulated to 10-13mM (p<0.05). After HIIT, active recovery at 80-90% of LT cleared blood [La-] 90% faster than at 60-70% of LT (p<0.05). Conclusions: To permit highest exercise stress during 4x4-minute HIIT, exercise intensity should be set to 95% of VO2max, whereas active recovery should be set to 60-70% of LT during HIIT and 80-90% of LT after HIIT to most efficiently prevent excess La- and aid recovery

Voluntary exercise delays heart failure onset in rats with pulmonary artery hypertension.

Increased physical activity is recommended for the general population and to patients of many diseases because of its health benefits but can be contraindicated if it is thought a risk for serious cardiovascular events. One such condition is pulmonary artery hypertension (PAH). PAH and right ventricular failure was induced in rats by a single injection of monocrotaline (MCT). MCT rats with voluntary access to a running wheel ran on average 2km per day. The time for half the animals to develop heart failure signs (median survival time) was 28 days (exercise failure (EF) group), significantly longer than sedentary animals (sedentary failure (SF) group), 23 days). The contractility of single failing myocytes in response to increasing demand (stimulation frequency) was significantly impaired compared with both sedentary control (SC) and exercising control (EC) myocytes. However, myocytes from exercising MCT rats, tested at 23 days (EM group) showed responses intermediate to the control (SC, EC) and failing (SF, EF) groups. We conclude that voluntary exercise is beneficial to rats with heart failure induced by PAH and this is evidence to support the consideration of appropriate exercise regimes for potentially vulnerable groups

Inducing Ito,f and phase 1 repolarization of the cardiac action potential with a Kv4.3/KChIP2.1 bicistronic transgene

The fast transient outward potassium current (I(to,f)) plays a key role in phase 1 repolarization of the human cardiac action potential (AP) and its reduction in heart failure (HF) contributes to the loss of contractility. Therefore, restoring I(to,f) might be beneficial for treating HF. The coding sequence of a P2A peptide was cloned, in frame, between Kv4.3 and KChIP2.1 genes and ribosomal skipping was confirmed by Western blotting. Typical I(to,f) properties with slowed inactivation and accelerated recovery from inactivation due to the association of KChIP2.1 with Kv4.3 was seen in transfected HEK293 cells. Both bicistronic components trafficked to the plasmamembrane and in adenovirus transduced rabbit cardiomyocytes both t-tubular and sarcolemmal construct labelling appeared. The resulting current was similar to I(to,f) seen in human ventricular cardiomyocytes and was 50% blocked at ~0.8 mmol/l 4-aminopyridine and increased ~30% by 5 μmol/l NS5806 (an I(to,f) agonist). Variation in the density of the expressed I(to,f), in rabbit cardiomyocytes recapitulated typical species-dependent variations in AP morphology. Simultaneous voltage recording and intracellular Ca(2+) imaging showed that modification of phase 1 to a non-failing human phenotype improved the rate of rise and magnitude of the Ca(2+) transient. I(to,f) expression also reduced AP triangulation but did not affect I(Ca,L) and I(Na) magnitudes. This raises the possibility for a new gene-based therapeutic approach to HF based on selective phase 1 modification

Utility and safety of draining pleural effusions in mechanically ventilated patients: a systematic review and meta-analysis

Abstract Introduction Pleural effusions are frequently drained in mechanically ventilated patients but the benefits and risks of this procedure are not well established. Methods We performed a literature search of multiple databases (MEDLINE, EMBASE, HEALTHSTAR, CINAHL) up to April 2010 to identify studies reporting clinical or physiological outcomes of mechanically ventilated critically ill patients who underwent drainage of pleural effusions. Studies were adjudicated for inclusion independently and in duplicate. Data on duration of ventilation and other clinical outcomes, oxygenation and lung mechanics, and adverse events were abstracted in duplicate independently. Results Nineteen observational studies (N = 1,124) met selection criteria. The mean PaO2:FiO2 ratio improved by 18% (95% confidence interval (CI) 5% to 33%, I 2 = 53.7%, five studies including 118 patients) after effusion drainage. Reported complication rates were low for pneumothorax (20 events in 14 studies including 965 patients; pooled mean 3.4%, 95% CI 1.7 to 6.5%, I 2 = 52.5%) and hemothorax (4 events in 10 studies including 721 patients; pooled mean 1.6%, 95% CI 0.8 to 3.3%, I 2 = 0%). The use of ultrasound guidance (either real-time or for site marking) was not associated with a statistically significant reduction in the risk of pneumothorax (OR = 0.32; 95% CI 0.08 to 1.19). Studies did not report duration of ventilation, length of stay in the intensive care unit or hospital, or mortality. Conclusions Drainage of pleural effusions in mechanically ventilated patients appears to improve oxygenation and is safe. We found no data to either support or refute claims of beneficial effects on clinically important outcomes such as duration of ventilation or length of stay

Arrhythmogenic late Ca2+sparks in failing heart cells and their control by action potential configuration

Sudden death in heart failure patients is a major clinical problem worldwide, but it is unclear how arrhythmogenic early afterdepolarizations (EADs) are triggered in failing heart cells. To examine EAD initiation, high-sensitivity intracellular Ca2+ measurements were combined with action potential voltage clamp techniques in a physiologically relevant heart failure model. In failing cells, the loss of Ca2+ release synchrony at the start of the action potential leads to an increase in number of microscopic intracellular Ca2+ release events (“late” Ca2+ sparks) during phase 2–3 of the action potential. These late Ca2+ sparks prolong the Ca2+ transient that activates contraction and can trigger propagating microscopic Ca2+ ripples, larger macroscopic Ca2+ waves, and EADs. Modification of the action potential to include steps to different potentials revealed the amount of current generated by these late Ca2+ sparks and their (subsequent) spatiotemporal summation into Ca2+ ripples/waves. Comparison of this current to the net current that causes action potential repolarization shows that late Ca2+ sparks provide a mechanism for EAD initiation. Computer simulations confirmed that this forms the basis of a strong oscillatory positive feedback system that can act in parallel with other purely voltage-dependent ionic mechanisms for EAD initiation. In failing heart cells, restoration of the action potential to a nonfailing phase 1 configuration improved the synchrony of excitation–contraction coupling, increased Ca2+ transient amplitude, and suppressed late Ca2+ sparks. Therapeutic control of late Ca2+ spark activity may provide an additional approach for treating heart failure and reduce the risk for sudden cardiac death

In and Beyond the Care Setting : Relationships Between Young People and Care Workers: A Literature Review

This review seeks to identify and summarise findings from literature about the nature of relationships that develop between older children and young people, and those caring for them within and beyond residential and fostering settings. We make particular efforts to include studies that gather the views of young people themselves. We consider the issues and challenges that young people face in moving on from care, the type of support they receive during this process, and focus on the relational elements of this support. The study as a whole focuses on young people in adolescence as they approach the point where they will leave care and undertake the transition towards more independent living. The review will briefly outline the background and policy context, before discussing some of the key themes found in the literature. • Part 1 explores the issues facing young people leaving care and the need for more targeted, specialist support. • Part 2 discusses the importance of relationships for young people leaving care and the growing interest in relationship-based practice. • Part 3 explores various aspects of relationships valued by care leavers. • Part 4 looks at relationships in different types of care settings