The E3 ubiquitin ligase SMURF1 regulates cell-fate specification and outflow tract septation during mammalian heart development.

Smad ubiquitin regulatory factor 1 (SMURF1) is a HECT-type E3 ubiquitin ligase that plays a critical role in vertebrate development by regulating planar cell polarity (PCP) signaling and convergent extension (CE). Here we show that SMURF1 is involved in mammalian heart development. We find that SMURF1 is highly expressed in outflow tract cushion mesenchyme and Smurf1-/- mouse embryos show delayed outflow tract septation. SMURF1 is expressed in smooth muscle cells of the coronary arteries and great vessels. Thickness of the aortic smooth muscle cell layer is reduced in Smurf1-/- mouse embryos. We show that SMURF1 is a negative regulator of cardiomyogenesis and a positive regulator of smooth muscle cell and cardiac fibroblast differentiation, indicating that SMURF1 is important for cell-type specification during heart development. Finally, we provide evidence that SMURF1 localizes at the primary cilium where it may regulate bone morphogenetic protein (BMP) signaling, which controls the initial phase of cardiomyocyte differentiation. In summary, our results demonstrate that SMURF1 is a critical regulator of outflow tract septation and cell-type specification during heart development, and that these effects may in part be mediated via control of cilium-associated BMP signaling.

Asian earthquake: report from the first volunteer British hospital team in Pakistan.

At 8:52 am on 8 October 2005 a massive earthquake wracked northern Pakistan and Kashmir. Various teams were sent to Islamabad and the disaster region from the UK. We discuss the types of injury patterns seen and recommend that a central register of volunteers should be created to deal with similar situations in the future.

Guidelines on the management of secondary prophylaxis of vascular events in stable patients in primary care.

Atherothrombosis, thrombus formation superimposed on an existing atherosclerotic plaque, is an acute process leading to ischaemic events such as myocardial infarction, stroke and critical limb ischaemia. Patients presenting with clinical conditions associated with atherothrombosis are at increased risk of subsequent vascular events. The beneficial effect of antiplatelet therapies for short-term and long-term secondary prevention of atherothrombotic events has been established. These guidelines aim to provide evidence-based recommendations that will assist in the antiplatelet-mediated secondary prophylaxis of vascular events in patients with stable cardiovascular disease treated in the primary healthcare setting. Medline and the Cochrane library were accessed using free-text strategies in the domains of antiplatelet agents and antithrombotics. Development of the guidelines was driven by a series of Steering Committee meetings, in which the quality of relevant studies was assessed and identified using narrative summary. These guidelines present evidence and recommendations for the treatment of numerous atherothrombotic indications depending on individual patient circumstances.

A randomised controlled trial of a self-management plan for patients with newly diagnosed angina.

BACKGROUND: There are approximately 1.8 million patients with angina in the United Kingdom, many of whom report a poor quality of life, including raised levels of anxiety and depression. AIM: To evaluate the effect of a cognitive behavioural disease management programme, the Angina Plan, on psychological adjustment in patients newly diagnosed with angina pectoris. DESIGN OF STUDY: Randomised controlled trial. SETTING: Patients from GP practices in a Northern UK city (York) between April 1999 and May 2000. METHOD: Recruited patients were randomised to receive the Angina Plan or to a routine, practice nurse-led secondary prevention educational session. RESULTS: Twenty of the 25 practices invited to join the study supplied patients' names; 142 patients attended an assessment clinic and were randomised There were no significant differences in any baseline measures. At the six month post-treatment follow-up, 130 (91%) patients were reassessed. When compared with the educational session patients (using analysis of covariance adjusted for baseline scores in an intention-to-treat analysis) Angina Plan patients showed a greater reduction in anxiety (P = 0.05) and depression (P = 0.01), the frequency of angina (reduced by three episodes per week, versus a reduction of 0.4 per week, P = 0.016) the use of glyceryl trinitrate (reduced by 4.19 fewer doses per week versus a reduction of 0.59 per week, P = 0.018), and physical limitations (P<0.001: Seattle Angina Questionnaire). They were also more likely to report having changed their diet (41 versus 21, P<0.001) and increased their daily walking (30 versus 2, P<0.001). There was no significant difference between the groups on the other sub-scales of the Seattle Angina Questionnaire or in any of the medical variables measured. CONCLUSION: The Angina Plan appears to improve the psychological, symptomatic, and functional status of patients newly diagnosed with angina.

FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse.

The node and the anterior visceral endoderm (AVE) are important organizing centers that pattern the mouse embryo by establishing the anterior-posterior (A-P), dorsal-ventral (D-V), and left-right (L-R) axes. Activin/nodal signaling through the Smad2 pathway has been implicated in AVE formation and in morphogenesis of the primitive streak, the anterior end of which gives rise to the node. The forkhead DNA-binding protein, FoxH1 (or Fast), functions as a Smad DNA-binding partner to regulate transcription in response to activin signaling. Here, we show that deletion of FoxH1 in mice results in failure to pattern the anterior primitive streak (APS) and form node, prechordal mesoderm, notochord, and definitive endoderm. In contrast, formation of the AVE can occur in the absence of FoxH1. The FoxH1 mutant phenotype is remarkably similar to that of mice deficient in the forkhead protein Foxa2 (HNF3beta), and we show that Foxa2 expression is dependent on FoxH1 function. These results show that FoxH1 functions in an activin/nodal-Smad signaling pathway that acts upstream of Foxa2 and is required specifically for patterning the APS and node in the mouse.

Unruptured aneurysm of the left sinus of Valsalva extending into the left ventricular outflow tract: presentation and imaging.

The symptomatic presentation of an unruptured sinus of Valsalva aneurysm is rare. A 48 year old man with a history of treated hypothyroidism, and a five year history of ileocolonic Crohn's disease of chronic low grade activity presented with a profound left hemiplegia. He was in sinus rhythm and normotensive. Cardiac auscultation was repeatedly normal. Computed tomography of the head performed early in the course of the illness was reported as normal. Duplex Doppler examination of the carotid arteries performed six months later revealed no significant atheroma. There was complete resolution of the neurological deficit over a period of months. A year later he presented with chest pain suggestive of myocardial ischaemia. Computed tomography, magnetic resonance imaging, transthoracic and transoesophageal echocardiography, and cardiac catheterisation pointed to a sinus of Valsalva aneurysm protruding into the left ventricular outflow tract. In view of the previous neurological event and ongoing chest pain suggestive of myocardial ischaemia, the lesion was resected. The patient made a good recovery and postoperative transoesophageal echocardiography showed normal aortic valve function with no residual regurgitation. This is the first reported case of pure left ventricular outflow tract extension of an unruptured left sinus aneurysm. The presentation with ischaemic cardiac pain does not seem to be explained by conventional mechanisms.

Arrhythmogenesis in experimental models of heart failure: the role of increased load.

OBJECTIVES: To assess the effects of cardiac failure due to doxorubicin cardiotoxicity or chronic myocardial infarction on arrhythmia induction, ventricular repolarization and refractoriness in isolated perfused rabbit hearts under different loading conditions. METHODS: Cardiac failure was induced by doxorubicin injection (1-1.25 mg.kg-1 twice weekly for 8 weeks, n = 16) or coronary ligation (n = 12), with 12 controls. Cardiac failure was defined by an echocardiographic ejection fraction < or = 0.40. Arrhythmia susceptibility was assessed by programmed ventricular stimulation and fibrillation threshold measurement during Langendorff and during working heart perfusion under baseline conditions and at maximum tolerated preload and afterload. Monophasic action potential duration, dispersion of refractoriness, conduction time and effective refractory period were measured at each level of load. RESULTS: During unloaded (Langendorff) perfusion, there was a low incidence of arrhythmia induction in all hearts. Increasing load did not alter arrhythmogenesis significantly in normal hearts, but led to increases in arrhythmia inducibility and falls in fibrillation threshold which were significantly greater in failing than in non-failing hearts. Monophasic action potential duration was significantly (P < 0.05) shorter in failing than in non-failing hearts in the doxorubicin-treated [mean (s.e.m.) 140(2) vs. 147(2) ms] and post-infarction groups [146(2) vs. 154 (3) ms] during working heart perfusion. The shortening in action potential duration and effective refractory period during increased preload tended to be greater in failing than in non-failing hearts. There were no changes in conduction times in response to changes in loading. CONCLUSIONS: The inducibility of ventricular arrhythmias is greater in failing than in non-failing hearts and is further enhanced by increases in preload. Shortening of repolarization and refractoriness due to increased preload may contribute to the increased risk of ventricular tachyarrhythmias and sudden death in cardiac failure.

Comparison of in vivo and in vitro haemodynamic function in experimental heart failure: use of echocardiography.

OBJECTIVE: To compare in vivo and in vitro haemodynamic performance in two models of experimental cardiac failure. To validate echocardiography as a means of non-invasive assessment of left ventricular dysfunction in rabbits. METHODS: Cardiac failure was induced by doxorubicin injection (1-1.25 mg.kg-1 twice weekly for 8 weeks (n = 16)) or coronary ligation (n = 12), with 12 controls. Left ventricular diastolic dimension and ejection fraction were assessed in vivo by echocardiography. The doxorubicin-treated and ligation hearts were subdivided by ejection fraction > 0.40 or < or = 0.40 into non-failing and failing groups. Thermodilution cardiac output was measured in vivo at baseline and after a fluid load. Basal cardiac output and peak cardiac output achieved by increased preload were measured in vitro in the working heart mode. RESULTS: The mean ejection fractions in the doxorubicin-treated and ligation groups were significantly (P < 0.001) lower than in controls, but there was wide inter-individual variability ranging from normal to severely impaired function [mean +/- s.d. (range) controls 0.65 +/- 0.03 (0.59-0.72), doxorubicin 0.45 +/- 0.11 (0.30-0.67), ligation 0.42 +/- 0.12 (0.25-0.65)]. Basal and peak cardiac outputs in vivo and in vitro were significantly lower in the doxorubicin and coronary ligation groups than in controls, although there was a wider scatter of values in the pathological groups. Among the doxorubicin and coronary ligation groups, hearts with ejection fractions < or = 0.40 demonstrated significantly impaired haemodynamic function compared with those with ejection fractions > 0.40. There were significant correlations between ejection fraction and all indices of haemodynamic function in vivo and in vitro. CONCLUSIONS: Simple non-invasive measurement of ejection fraction allowed improved characterization of haemodynamic responses in vivo and in vitro. Individual assessment of animals by echocardiography will improve interpretation of cellular or molecular studies in experimental heart failure by relating observed abnormalities to the degree of global cardiac dysfunction.

Do radionuclide and echocardiographic techniques give a universal cut off value for left ventricular ejection fraction that can be used to select patients for treatment with ACE inhibitors after myocardial infarction?

OBJECTIVE: To determine whether echocardiography and radionuclide angiography give comparable results when the left ventricular ejection fraction is measured early after myocardial infarction and thus whether, irrespective of the method used, a single value for the ejection fraction could be used as a guide for starting treatment with an angiotensin converting enzyme inhibitor. DESIGN: Prospective comparison of measurement of left ventricular ejection fraction by echocardiography and radionuclide angiography. SETTING: Coronary care units of two university teaching hospitals in Glasgow. PATIENTS: 99 patients studied within 36 hours of acute myocardial infarction. OUTCOME MEASURES: Left ventricular ejection fraction assessed by echocardiography and radionuclide angiography. RESULTS: 70 (77%) of the 99 patients had ejection fraction measured by both echocardiographic and radionuclide techniques, 30 in centre 1 and 40 in centre 2. In centre 1 the mean difference (SD) in ejection fraction (radionuclide angiography--echocardiography) was -8 (10%); 95% CI -12 to -4%. In centre 2 the mean difference was -14 (11%); 95% CI -17 to -11%. If patients had been treated with an ACE inhibitor on the basis of a radionuclide ejection fraction of < 40% then 93% in centre 1 (28 of 30) and 98% in centre 2 (39 of 40) would have been treated. This compares with 63% (19 of 30) and 50% (20 of 40), respectively if echocardiography had been used as a guide. CONCLUSION: Measurement of ejection fraction is highly dependent on the method used and it is therefore impossible to quote a universally applicable figure for left ventricular ejection fraction below which an ACE inhibitor should be used after myocardial infarction.

A clinical and in vitro study on the possible interaction of intravenous nitrates with heparin anticoagulation.

It has been reported that intravenous nitrates inhibit the anticoagulant effect of heparin. This possible interaction has potentially serious implications for the management of patients with acute coronary ischemic syndromes. This possible interaction was assessed prospectively in a clinical and in an in vitro study involving 24 patients receiving both drugs for the management of unstable angina pectoris. There was a small inhibitory effect of intravenous glyceryl trinitrate or isosorbide dinitrate on the anticoagulant effect of heparin in 3 of 24 cases in vivo, as assessed by activated partial thromboplastin time measurements. Nitrates or propylene glycol had no effect on heparin activity in vitro. It was concluded that there may be an inhibitory effect of nitrates on anticoagulation in a small minority of patients, but close attention to detail in monitoring heparin anticoagulation is far more important.

Comparison of two strategies for myocardial management during coronary artery operations.

Despite the current trend for using blood cardioplegia, ventricular fibrillation with intermittent ischemia is still used as a strategy to manage the myocardium with impressive results. These two methods of myocardial management were compared in 40 patients undergoing elective coronary artery operations using creatine kinase MB isoforms and troponin T assays. Each patient was randomized to have either cold blood cardioplegia (n = 20) or ventricular fibrillation with intermittent ischemia (n = 20) for myocardial management during the construction of distal anastomoses. Until recently, the comparison of different methods of myocardial management has been hindered by the lack of a specific and sensitive marker of myocardial damage. Analysis of creatine kinase MB isoforms (MB2, cardiac tissue form; MB1, plasma-modified form) and cardiac-specific troponin T (a structural protein) has been shown to improve the sensitivity for the detection of myocardial damage. There were no significant differences between the two groups in age, sex ratio, extent of disease, or left ventricular function. Blood samples for analysis were collected before cross-clamp application and at time intervals up to 48 hours after. Median peak creatine kinase MB2 activity was found to be significantly higher in the blood cardioplegia group compared with ventricular fibrillation (26.5 U/L versus 19.5 U/L, respectively, p = 0.04). Although median peak troponin T concentration was higher in the blood cardioplegia group, the difference failed to reach significance (2.2 ng/mL versus 1.6 ng/mL, p = 0.15).(ABSTRACT TRUNCATED AT 250 WORDS)

QT interval dispersion: a non-invasive marker of susceptibility to arrhythmia in patients with sustained ventricular arrhythmias?

OBJECTIVE: To assess QT interval dispersion on the surface electrocardiogram in patients with sustained ventricular arrhythmias. DESIGN: A retrospective and prospective blinded controlled study of patients referred for investigation of ventricular arrhythmias at a tertiary cardiac centre. PATIENTS AND METHODS: 89 consecutive patients with sustained ventricular arrhythmias due to chronic ischaemic heart disease, cardiomyopathy, or ventricular tachycardia (VT) in a normal heart. 32 patients did not meet the inclusion criteria; therefore 57 patients were compared with a control group of 40 patients with myocardial disease but no history of arrhythmias and 12 normal controls with no myocardial disease. Standard 12 lead electrocardiograms were enlarged, the QT intervals for each lead measured, and QT dispersion calculated. RESULTS: There was a significantly greater mean QT dispersion (77 ms) in patients with sustained ventricular arrhythmias compared with the control group (38 ms, p < 0.01). This held for all groups; after myocardial infarction VT (82 (22) ms v control 38 (10) ms; p < 0.01), dilated cardiomyopathy VT (76 (18) ms v control 40 (11) ms, p < 0.01), and normal heart VT (65 (7) ms v control 32 (8), p < 0.05). There was also a greater QT dispersion in patients with impaired left ventricular function and VT, with a correlation between left ventricular function and QT dispersion in patients with VT (r = 0.56, p < 0.01). CONCLUSION: QT interval dispersion may be a further non-invasive marker of susceptibility to ventricular arrhythmias.

Early treatment with captopril after acute myocardial infarction.

OBJECTIVES: To determine the effects of early treatment with captopril on haemodynamic function, neuroendocrine biochemistry, left ventricular structure, clinical outcome, and exercise capacity over one year from acute myocardial infarction. DESIGN: Randomised, double blind, placebo controlled comparison of captopril and placebo. SETTING: Coronary care units and cardiology departments of two university teaching hospitals in Glasgow. PATIENTS: 99 haemodynamically stable patients with acute myocardial infarction, selected on clinical grounds as being at risk of late ventricular dilatation. INTERVENTION: Captopril or identical placebo started between six and 24 hours after start of symptoms and continued for 12 months. Target maintenance dose was 25 mg three times a day. MAIN OUTCOME MEASURES: (a) Acute haemodynamic effects of treatment; (b) neuroendocrine biochemistry from admission to two months; and (c) change in echocardiographic measures of left ventricular size, clinical outcome, and exercise capacity after 12 months of treatment with a separate analysis of the effects of one month of treatment withdrawal on left ventricular volumes. RESULTS: Captopril caused acute reductions in mean (SEM) pulmonary artery pressure (2.48 (0.69) mm Hg) and systemic vascular resistance (260 (103)) dyn.s.cm-5). Over the first 10 hours captopril reduced mean arterial pressure by 12.1 (2.4) mm Hg compared with 3.8 (1.9) mm Hg in the placebo group. No patient had to be withdrawn from the captopril group because of hypotension. From day 1 onwards systolic and diastolic arterial pressures in the captopril treated group were slightly but not significantly lower than on placebo. There was no difference in the incidence of ventricular or supraventricular arrhythmia with treatment. Captopril prevented the day 3 peak in angiotensin II that occurred in the placebo group (peak concentration (interquartile range): 10.1 (4.8-19.4) pg/ml v 16.8 (4.3-46.3) pg/ml)) but had no effect on atrial natriuretic factor, arginine vasopressin, or catecholamines. Plasma atrial natriuretic factor remained above normal in both groups at two months after infarction. After one year left ventricular volume indices had increased less on captopril than on placebo: left ventricular end systolic volume index 5.4 ml/m2 v 14.7 ml/m2 (95% confidence interval (95% CI) of difference -14.6 to -3.9; p = 0.0011); left ventricular end diastolic volume index 8.4 ml/m2 v 19.0 ml/m2 (95% CI of difference, -17.0 to -4.2; p = 0.0016). Withdrawal of captopril for one month did not affect ventricular volumes. There was no difference in exercise capacity. CONCLUSIONS: Captopril started between six and 24 hours after acute myocardial infarction is not associated with significant hypotension. It suppresses activation of the renin angiotensin system but has no effect on plasma concentrations of other neurohormones. Atrial natriuretic factor remains raised at two months after myocardial infarction. Captopril significantly decreases left ventricular dilatation. This effect is not lost after one month of treatment withdrawal and is thus due to an alteration of left ventricular structure and not to a short lived haemodynamic action of captopril. Long-term treatment with captopril does not result in improved aerobic exercise capacity after acute myocardial infarction.

Approaches to experimental arrhythmias in heart failure.

Sudden cardiac death accounts for at least 50% of the mortality of patients with heart failure. Available clinical evidence suggests that lethal ventricular arrhythmias are responsible for the vast majority of cases of sudden death in heart failure. However, despite extensive clinical investigation over the last decade, there has been relatively little experimental study of the mechanisms underlying the development of lethal ventricular arrhythmias in heart failure. In addition to the original process leading to myocardium alterations, the role of other arrhythmogenic mechanisms such as ventricular overload and neuro endocrine activation remains to be elucidated. In ventricular hypertrophy both reentry and triggered activity may induce arrhythmias. Some studies on experimental models of heart failure did not provide consistent results concerning electrophysiological modifications and their relations with arrhythmias. Few studies in man in vivo are in favor of prolongation as well as increased dispersion of repolarisation in patients undergoing heart transplantation for idiopathic dilated cardio-myopathy. Further studies will need to be undertaken to clarify mechanisms underlying arrhythmias in heart failure.

Effects of early captopril administration on infarct expansion, left ventricular remodeling and exercise capacity after acute myocardial infarction.

In a double-blind study, 99 patients (82 men, age range 40 to 75 years) with acute myocardial infarction (AMI) were randomly assigned to receive captopril or placebo. Treatment began within 24 hours of admission. Serial echocardiographic measurements of endocardial segment lengths and left ventricular (LV) volumes, and ejection fractions were obtained. The 2 groups were matched at baseline except for an excess of previous AMI in the placebo group (13 of 50 vs 2 of 49 patients, p = 0.002). The increase in anterior segment length, from baseline to 2 months, was significantly less in the captopril than in the placebo group (2.8 +/- 1.6 vs 10.4 +/- 2.4mm, 95% confidence interval [CI] -13.5 to -1.7, p = 0.01). The increase in posterior segment length was also less in the captopril group, but the difference was not significant (3.2 +/- 1.2 vs 7.0 +/- 1.8mm, 95% CI -8.0 to 0.5, p = 0.08). Fewer patients in the captopril group demonstrated increases in segment length greater than 2 standard deviations of the measurement error (14 of 70 [20%] vs 29 of 72 [40%] patients, p = 0.009). In patients with anterior AMI, the infarct-containing anterior segment length increased by 4.5 +/- 2.3 mm in the captopril versus 12.4 +/- 3.1 mm in the placebo group (95% CI -15.7 to -0.2, p = 0.046), and fewer patients in the captopril group demonstrated infarct expansion (6 of 20 [30%] vs 13 of 21 [62%] patients, p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)