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The radial artery is the preferred access site for cardiac catheterization because of patient comfort, early ambulation, and improved survival in acute coronary syndromes, when compared to the femoral artery route. However, it is associated with a high radial artery occlusion (RAO) rate, and patent haemostasis which can reduce this is extremely hard to implement in a busy clinical practice. Smaller sized sheaths are associated with less RAO but are uncommonly used as they could limit procedural prowess and complexity. Alternatively, the distal radial artery (dRA) approach appears to be safer with observed RAO rates of well under 1 percent without compromising benefits offered by the radial artery access. Default dRA can be accessed by palpation alone in most cases with some practice, and this can be improved further with ultrasound guidance. There is a subset of patients, especially in the elderly, where dRA access can be particularly challenging. To mitigate this, we propose a two-step cannulation strategy and illustrate this with a few cases with difficult dRA and radial artery anatomies. [ABSTRACT FROM AUTHOR]

Objective: We tested whether ablation methodology and study design can explain the varying outcomes in terms of atrial fibrillation (AF)‐free survival at 1 year. Background: There have been numerous paroxysmal AF ablation trials, which are heterogeneous in their use of different ablation techniques and study design. A useful approach to understanding how these factors influence outcome is to dismantle the trials into individual arms and reconstitute them as a large meta‐regression. Methods: Data were collected from 66 studies (6941 patients). With freedom from AF as the dependent variable, we performed meta‐regression using the individual study arm as the unit. Results: Success rates did not change regardless of the technique used to produce pulmonary vein isolation (PVI). Neither was adjunctive lesion sets associated with any improvement in outcome. Studies that included more males and fewer hypertensive patients were found more likely to report better outcomes. The electrocardiography method selected to assess outcome also plays an important role. Outcomes were worse in studies that used regular telemonitoring (by 23%; P < 0.001) or in patients who had implantable loop recorders (by 21%; P = 0.006), rather than those with the less thorough periodic Holter monitoring. Conclusions: Outcomes of AF ablation studies involving PVI are not affected by the technologies used to produce PVI. Neither do adjunctive lesion sets change the outcome. Achieving high success rates in these studies appears to be dependent more on patient mix and on the thoroughness of AF detection protocols. These should be carefully considered when quoting the success rates of AF ablation procedures that are derived from such studies. [ABSTRACT FROM AUTHOR]

Although systole was for long considered the core of cardiac function, hemodynamic performance is evenly dependent on appropriate systolic and diastolic functions. The recognition that isolated diastolic dysfunction is the major culprit for approximately fifty percent of all heart failure cases imposes a deeper understanding of its underlying mechanisms so that better diagnostic and therapeutic strategies can be designed. Risk factors leading to diastolic dysfunction affect myocardial relaxation and/or its material properties by disrupting the homeostasis of cardiomyocytes as well as their relation with surrounding matrix and vascular structures. As a consequence, slower ventricular relaxation and higher myocardial stiffness may result in higher ventricular filling pressures and in the risk of hemodynamic decompensation. Thus, determining the mechanisms of diastolic function and their implications in the pathophysiology of heart failure with normal ejection fraction has become a prominent field in basic and clinical research. [ABSTRACT FROM AUTHOR]

Abstract: Diastole plays a central role in cardiovascular homeostasis. Its two main determinants, myocardial relaxation and passive properties of the ventricular wall, are nowadays regarded as physiological mechanisms susceptible of active modulation. Furthermore, diastolic dysfunction and heart failure with normal ejection fraction (previously called diastolic heart failure) are two subjects of major clinical relevance and an intense area of research. The role of several neurohumoral mediators like angiotensin-II and endothelin-1 on the modulation of diastolic function was systematically described as having only chronic deleterious effects such as cardiac hypertrophy and fibrosis. However, over the last years a growing body of evidence described a new role for several peptides on the acute modulation of diastolic function. In the acute setting, some of these mediators may have the potential to induce an adaptive cardiac response. In this review, we describe the role of angiotensin-II, endothelin-1, nitric oxide, urotensin-II and ghrelin on the acute modulation of diastolic function, emphasizing its pathophysiological relevance. Only a thorough understanding of diastolic physiology as well as its active modulation, both in the acute and chronic settings, will improve our knowledge on diastolic dysfunction and allow us to solve the enigmas of heart failure with normal ejection fraction. [Copyright &y& Elsevier]

Today there is an increasing demand for heart transplantations for patients diagnosed with heart failure. Though, shortage of donors as well as the large number of ineligible patients hurdle such treatment option. This, in addition to the considerable number of transplant rejections, has driven the clinical research towards the field of regenerative medicine. Nonetheless, to date, several stem cell therapies tested in animal models fall by the wayside and when they meet the criteria to clinical trials, subjects often exhibit modest improvements. A main issue slowing down the admission of such therapies in the domain of human trials is the lack of protocol standardization between research groups, which hampers comparison between different approaches as well as the lack of thought regarding the clinical translation. In this sense, given the large amount of reports on stem cell therapy studies in animal models reported in the last 3 years, we sought to evaluate their advantages and limitations towards the clinical setting and provide some suggestions for the forthcoming investigations. We expect, with this review, to start a new paradigm on regenerative medicine, by evoking the debate on how to plan novel stem cell therapy studies with animal models in order to achieve more consistent scientific production and accelerate the admission of stem cell therapies in the clinical setting. [ABSTRACT FROM AUTHOR]

Background--Little is known about the function of inositol 1,4,5-trisphosphate receptors (IP3Rs) in the adult heart experimentally. Moreover, whether these Ca2+ release channels are present and play a critical role in human cardiomyocytes remains to be defined. IP3Rs may be activated after Gαq-protein-coupled receptor stimulation, affecting Ca2+ cycling, enhancing myocyte performance, and potentially favoring an increase in the incidence of arrhythmias. Methods and Results--IP3R function was determined in human left ventricular myocytes, and this analysis was integrated with assays in mouse myocytes to identify the mechanisms by which IP3Rs influence the electric and mechanical properties of the myocardium. We report that IP3Rs are expressed and operative in human left ventricular myocytes. After Gαq-protein-coupled receptor activation, Ca2+ mobilized from the sarcoplasmic reticulum via IP3Rs contributes to the decrease in resting membrane potential, prolongation of the action potential, and occurrence of early afterdepolarizations. Ca2+ transient amplitude and cell shortening are enhanced, and extrasystolic and dysregulated Ca2+ elevations and contractions become apparent. These alterations in the electromechanical behavior of human cardiomyocytes are coupled with increased isometric twitch of the myocardium and arrhythmic events, suggesting that Gαq-protein-coupled receptor activation provides inotropic reserve, which is hampered by electric instability and contractile abnormalities. Additionally, our findings support the notion that increases in Ca2+ load by IP3Rs promote Ca2+ extrusion by forward-mode Na+/Ca2+ exchange, an important mechanism of arrhythmic events. Conclusions--The Gαq-protein/coupled receptor/IP3R axis modulates the electromechanical properties of the human myocardium and its propensity to develop arrhythmias. [ABSTRACT FROM AUTHOR]

Aims The heart is constantly challenged with acute bouts of stretching or overload. Systolic adaptations to these challenges are known but adaptations in diastolic stiffness remain unknown. We evaluated adaptations in myocardial stiffness due to acute stretching and characterized the underlying mechanisms. Methods and results Left ventricles (LVs) of intact rat hearts, rabbit papillary muscles and myocardial strips from cardiac surgery patients were stretched. After stretching, there was a sustained >40% decrease in end-diastolic pressure (EDP) or passive tension (PT) for 15 min in all species and experimental preparations. Stretching by volume loading in volunteers and cardiac surgery patients resulted in E/E' and EDP decreases, respectively, after sustained stretching. Stretched samples had increased myocardial cGMP levels, increased phosphorylated vasodilator-stimulated phosphoprotein phosphorylation, as well as, increased titin phosphorylation, which was reduced by prior protein kinase G (PKG) inhibition (PKGi). Skinned cardiomyocytes from stretched and non-stretched myocardia were studied. Skinned cardiomyocytes from stretched hearts showed decreased PT, which was abrogated by protein phosphatase incubation; whereas those from non-stretched hearts decreased PT after PKG incubation. Pharmacological studies assessed the role of nitric oxide (NO) and natriuretic peptides (NPs). PT decay after stretching was significantly reduced by combined NP antagonism, NO synthase inhibition and NO scavenging, or by PKGi. Response to stretching was remarkably reduced in a rat model of LV hypertrophy, which also failed to increase titin phosphorylation. Conclusions We describe and translate to human physiology a novel adaptive mechanism, partly mediated by titin phosphorylation through cGMP-PKG signalling, whereby myocardial compliance increases in response to acute stretching. This mechanism may not function in the hypertrophic heart. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Inositol 1,4,5-Trisphosphate Receptors and Human Left Ventricular Myocytes" is presented.

Spontaneous bacterial peritonitis (SBP) in cirrhotic patients is a serious complication associated with a high mortality rate. A baseline audit of the acute medical take (AMT) at Northwick Park suggested a lack of awareness regarding management. A questionnaire based on contemporary SBP guidelines was circulated to all trainee doctors (FY1 to SpR). Ascitic fluid testing requests were analysed over a six-month period. The electronic requesting system was updated to include prompts and direct links to Trust SBP guidelines, and a one-hour lecture to all members of the AMT, supported by an educational booklet on SBP, was performed. Re-audit was carried out six months post-intervention, the AMT completed a second questionnaire and ascitic flu id testing requests were re-audited. In comparable pre- and post-intervention AMT cohorts, a clinical and educational intervention led to a significant improvement in understanding of when to investigate (p<0.001), samples (p=0.002) and containers (p≤0.001) required, urgency of obtaining results (p≤0.001), and initiation of treatment for suspected SBP (p=0.007). Significantly more ascitic samples were sent, with specific suspicion of SBP more readily documented, crucial to expediting laboratory processing. Targeted education and production of a clinical algorithm has significantly improved the management of patients with SBP. [ABSTRACT FROM AUTHOR]

Highlights: [•] Under normal conditions slow force response is dependent on AT1 receptor activity. [•] Ischemia blunts the Frank–Starling mechanism. [•] Ischemia abolishes the slow force response and induces a progressive force decline. [•] AT1 receptor antagonism rescues the contractility deterioration during ischemia. [•] AT2 receptor antagonism blunts the effects of AT1 antagonism during ischemia. [Copyright &y& Elsevier]

Background: Although progenitor cells have been described in distinct anatomical regions of the lung, description of resident stem cells has remained elusive. Methods: Surgical lung-tissue specimens were studied in situ to identify and characterize human lung stem cells. We defined their phenotype and functional properties in vitro and in vivo. Results: Human lungs contain undifferentiated human lung stem cells nested in niches in the distal airways. These cells are self-renewing, clonogenic, and multipotent in vitro. After injection into damaged mouse lung in vivo, human lung stem cells form human bronchioles, alveoli, and pulmonary vessels integrated structurally and functionally with the damaged organ. The formation of a chimeric lung was confirmed by detection of human transcripts for epithelial and vascular genes. In addition, the self-renewal and long-term proliferation of human lung stem cells was shown in serial-transplantation assays. Conclusions: Human lungs contain identifiable stem cells. In animal models, these cells participate in tissue homeostasis and regeneration. They have the undemonstrated potential to promote tissue restoration in patients with lung disease. (Funded by the National Institutes of Health.) N Engl J Med 2011;364:1795-806. [ABSTRACT FROM AUTHOR]

An analysis of the clonality of cardiac progenitor cells (CPCs) and myocyte turnover in vivo requires genetic tagging of the undifferentiated cells so that the clonal marker of individual mother cells is traced in the specialized progeny. CPC niches in the atria and apex of the mouse heart were infected with a lentivirus carrying EGFP, and the destiny of the tagged cells was determined 1-5 months later. A common integration site was identified in isolated CPCs, cardiomyocytes, endothelial cells (ECs), and fibroblasts, documenting CPC self-renewal and multipotentiality and the clonal origin of the differentiated cell populations. Subsequently, the degree of EGFP-lentiviral infection of CPCs was evaluated 2-4 days after injection, and the number of myocytes expressing the reporter gene was measured 6 months later. A BrdU pulse-chasing protocol was also introduced as an additional assay for the analysis of myocyte turnover. Over a period of 6 months, each EGFP-positive CPC divided approximately eight times generating 230 cardiomyocytes; this value was consistent with the number of newly formed cells labeled by BrdU. To determine whether, human CPCs (hCPCs) are self-renewing and multipotent, these cells were transduced with the EGFP-lentivirus and injected after acute myocardial infarction in immunosuppressed rats. hCPCs, myocytes, ECs, and fibroblasts collected from the regenerated myocardium showed common viral integration sites in the human genome. Thus, our results indicate that the adult heart contains a pool of resident stem cells that regulate cardiac homeostasis and repair. [ABSTRACT FROM AUTHOR]

Acute effects of angiotensin II (AngII) on diastolic properties of the myocardium were investigated.Increasing concentrations of AngII (10−9 to 10−5 M) were added to rabbit papillary muscles in the absence (n=11) or presence of: (i) AT1 receptor antagonists, losartan (10−6 M; n=7) or ZD-7155 (10−7 M; n=8); (ii) ZD-7155 (10−7 M) plus AT2 receptor antagonist PD-123,319 (2 × 10−6 M; n=6); (iii) PKC inhibitor, chelerythrine (10−5 M; n=8); or (iv) Na+/H+ exchanger (NHE) inhibitor, 5-(N-methyl-N-isobutyl)-amiloride (10−6 M; n=10). Passive length–tension relations were constructed before and after a single concentration of AngII (10−5 M, n=6). Effects of AngII infusion (10 μg kg−1 min−1) were evaluated in in situ rabbit hearts.AngII concentration dependently increased inotropy and resting muscle length (RL). At 10−5 M, active tension increased 43.3±6.25% and RL 1.96±0.4%. Correcting RL to its initial value resulted in a 46±4% decrease of resting tension, indicating decreased muscle stiffness, as confirmed by the right and downward shift of the passive length–tension relation promoted by AngII. In the intact heart, at matched systolic pressures of 112 mmHg, AngII decreased end-diastolic pressures from 10.3±0.3 to 5.9±0.5 mmHg, and minimal diastolic pressures from 8.4±0.5 to 4.6±0.6 mmHg.AT1 blockade inhibited AngII effects on myocardial inotropy and stiffness, while PKC or NHE inhibition only significantly attenuated its effects on resting length and tension.In conclusion, AngII decreases myocardial stiffness, an effect that requires AT1 receptor activation and is mediated by PKC and NHE. This represents a novel mechanism of acute neurohumoral modulation of diastolic function, suggesting that AngII is a powerful regulator of cardiac filling.British Journal of Pharmacology (2006) 147, 690–697. doi:10.1038/sj.bjp.0706659; published online 16 January 2006 [ABSTRACT FROM AUTHOR]