Biomedical subjects
Publications and source records attributed to John McMurray.
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AIMS: To evaluate the effect of the angiotensin receptor blocker candesartan on New York Heart Association (NYHA) functional class in a broad spectrum of patients with chronic heart failure (CHF). METHODS AND RESULTS: Patients in the CHARM Programme with symptomatic CHF were randomized to placebo (n=3796) or candesartan (n=3803) and followed for a median of 38 months. NYHA class was assessed at baseline, at two weekly intervals during dose titration and 4 monthly thereafter. Patients were classified as "better", "unchanged" or "worse" at the end of the study compared to baseline. Both a simple "last visit carried forward" (LVCF) analysis and "worst rank carried forward" (WRCF) analysis (where patients who died were allocated NYHA class V) were used. In the LVCF analysis, compared to placebo, more candesartan patients improved (35.4% versus 32.5%) and fewer worsened (9.0% versus 10.3%) in NYHA class (p=0.003). The WRCF analysis also showed a better overall change in NYHA class with candesartan compared to placebo. There was no heterogeneity in the response to candesartan between the CHARM component trials. CONCLUSIONS: Candesartan improves NYHA functional class to a similar extent to other proven treatments for CHF when added to these other treatments.
UNLABELLED: In the last decennia heart failure has become one of the most important diseases worldwide in terms of prevalence, morbidity, life expectancy, and in health care management and costs. Despite significant improvements in prevention and treatment, heart failure remains a frequently occurring disorder with increasing incidence and a high hospitalisation and death rate. As major health care problem it deserves full attention of health care authorities. Unfortunately, the seriousness of heart failure and the therapeutic possibilities are often not recognised by those directly involved, i.e. the doctor, the patient or his relatives, let alone that they are known to the general public and health care authorities. The SHAPE study aims at improving heart failure care by increasing awareness and perception of the disease in Europe. Firstly, awareness and perception of heart failure will be documented in the general public, primary care physicians and specialists (cardiologists, internists and geriatricians) in 9 European countries: France, Germany, Italy, the Netherlands, Poland, Romania, Spain, Sweden and the UK. Subsequently, the results will be used to design and carry out suitable awareness and educational programmes in these groups, aimed at improving heart failure care and research. Finally, the results of these programmes will be tested in a second documentation phase and adaptations made where needed. This manuscript describes the rationale and design of the first phase, the Documentation Phase.During the first documentation phase, 800 participants per country selected based on sex, two age groups and urban vs. rural location (100/cell) will be surveyed using a 32-question interview. Questions for the general public focus on recognition, incidence and prevalence, severity and prognosis of the disease in comparison to other disease areas, like cancer, on quality of life, therapeutic possibilities and availability of care. The primary care physician (PCP) survey aims at receiving a minimum of 300 responses. A questionnaire with 33 closed questions will be used covering the PCP's knowledge of heart failure, including prevalence, aetiology, new diagnostic and therapeutic developments and health care costs. Questions concerning diagnostic procedures and various treatments carried out by the PCP in his own practice, as well as referral patterns for diagnostic procedures and for specialist care. Questions relating to the type of practice and number of patients in each PCP's clinical practice. A minimum of 150 cardiologists and 150 internists + geriatricians will be surveyed per country. The specialist's questionnaire contains 31 questions focusing on identification of heart failure patients, patients at risk, use and availability of diagnostic tools, importance of therapies and order of treatment, perceived risks of treatment, relevance of counselling and advice, use of paramedical personnel, and questions concerning practice size, type of practice and number of patients with heart failure. CONCLUSION: This first part of the SHAPE study will provide important information about the level of knowledge and understanding of heart failure of the general public, as well as the perception of the relevance of heart failure and appropriate diagnostic and therapeutic approaches by both the primary care physician and the medical specialist. This knowledge will be extremely valuable when it comes to defining optimal educational programmes in the different target groups studied in SHAPE necessary to implement appropriate heart failure care in Europe and to obtain the means to do so.
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Csk is a soluble protein tyrosine kinase that phosphorylates and negatively regulates protein tyrosine kinases of the Src family. The spectral properties of the intrinsic Trp fluorescence of Csk and their underlying structural features were investigated in combination with urea denaturation and site-specific mutagenesis. It was found that W352 contributed approximately 35% of the total Trp fluorescence of Csk even though seven other Trp residues were present. The enhanced contribution by W352 to Csk fluorescence was due to an interaction between its indole ring and the positively charged guanidino group of R318. W352 is located on the peptide substrate binding P+1 loop, and R318 is located on the catalytic loop. The W352-R318 interaction, called a cation-pi interaction, uniquely couples the two loops in the active site. Mutations that disrupted this coupling resulted in varying levels of decreases in Csk activity, and consistent and significant increases in K(m) values for its physiological substrate, Src protein tyrosine kinase. These results indicated that structural coupling between the two loops by the cation-pi interaction played an important role in Csk substrate binding. Since both R318 and W352 are highly conserved among protein tyrosine kinases, this cation-pi interaction is likely a signature structural feature of most, if not all, PTKs. These studies elucidated the roles of two conserved signature residues in Csk and formed a baseline for further structure-function studies of Csk and other PTKs.
BACKGROUND: It has been shown recently that the pregnancy and parturition hormone, relaxin, is secreted by the heart. This study examined the effects of relaxin in small human resistance arteries from the systemic and pulmonary circulations. METHODS AND RESULTS: Arteries were obtained from gluteal biopsies and resected lung tissue and studied with the use of wire myography. Cumulative concentration relaxation curves were constructed in systemic arteries with substance P, epoprostenol, atrial natriuretic peptide, and relaxin (concentration range 10(-13) -10(-7)M). The maximal responses were 88(+/-5)%, 67(+/-10)%, 52(+/-16)% and 66(+/-16)%, respectively. Endothelium removal virtually abolished the action of relaxin. Relaxin had no vasodilator effect in pulmonary arteries. CONCLUSIONS: Relaxin is a powerful dilator of systemic resistance arteries secreted by the heart that may contribute to cardiovascular regulation.
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The function of autophosphorylation in Src family protein tyrosine kinases is not fully understood. In this paper we compared the catalytic and ligand-binding properties of autophosphorylated and nonautophosphorylated (control) Src. The following are the main differences we found. First, while both forms had the same K(m) for ATP-Mg, autophosphorylated Src had significantly higher K(m) values for the phosphate-accepting substrates, polyE(4)Y, and RCM-lysozyme. The autophosphorylated form also had significantly higher V(max) values than the control. The substrate specificity, as measured by V(max)/K(m) ratio, was altered by autophosphorylation and was dependent on the phosphate-accepting substrate. Second, while autophosphorylation did not affect Src activation by free Mg(2+), Zn(2+), which inhibited Src by competing against an essential Mg(2+) activator, inhibited the control threefold more potently than the autophosphorylated form. Third, autophosphorylation significantly reduced the ability of its SH2 domain to bind phosphotyrosine. Fourth, a Pro-rich Src SH3 domain binding peptide activated the control, but not the autophosphorylated Src even though the apparent binding affinity was not significantly affected by autophosphorylation. These differences indicated that autophosphorylation induced significant and widespread changes in the catalytic and regulatory properties of Src. The implications of these findings relative to Src biological regulation are discussed.
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Other than natriuretic peptides, neurohumoral markers have not been studied adequately in heart failure with preserved systolic function. There is little evidence of chronic activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, as in heart failure with reduced systolic function. These and other neurohumoral pathways may, however, become excessively stimulated by exercise and during episodes of acute decompensation. Blood natriuretic peptide concentrations are chronically elevated in patients with heart failure and preserved systolic function but not to the same extent as in patients with reduced systolic function. The role of neurohumoral antagonists in the treatment of heart failure and preserved systolic function has yet to be fully investigated.
BACKGROUND: Endothelin-receptor blockade provides haemodynamic benefit in experimental and clinical heart failure. We aimed to measure the effects of long-term endothelin-blockade on left-ventricular (LV) remodelling and clinical outcomes in patients with chronic heart failure. METHODS: 642 patients with chronic heart failure were assigned the oral endothelin(A)-antagonist darusentan at 10, 25, 50, 100, or 300 mg daily or placebo for 24 weeks in addition to standard therapy in a randomised, double-blind, placebo-controlled trial. In the 50-300 mg groups, darusentan was uptitrated over 6 weeks. Primary endpoint was change in LV end-systolic volume (LVESV) at 24 weeks from baseline, measured by MRI. All patients for whom assessable MRI scans were available at baseline and follow-up were included in the analysis. FINDINGS: Darusentan was well tolerated. LVESV could be assessed in 485 (76%) patients with paired MRI data at baseline and 6 months. The change in LVESV was not significantly different from that with placebo at any dose (mean difference from placebo 1.27 mL [95% CI -9.9 to 12.4] with 10 mg dose, -1.84 mL [-13.0 to 9.3] with 25 mg, -5.68 mL [-16.9 to 5.6] with 50 mg, -4.05 mL [-15.5 to 7.4] with 100 mg, and -4.34 mL [-15.7 to 7.0] with 300 mg). Heart failure worsened in 71 (11.1%) patients, and 30 (4.7%) died during the study with no difference between groups. INTERPRETATION: Endothelin(A) blockade with darusentan did not improve cardiac remodelling or clinical symptoms or outcomes in patients with chronic heart failure receiving an angiotensin-converting-enzyme inhibitor, beta blocker, or aldosterone antagonist. Thus, endothelin(A) blockade is unlikely to be useful as an add-on treatment in such patients.