Exercise in hypertrophic cardiomyopathy is associated with sympatho-adrenal imbalance.
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Cardiomyopathy, Hypertrophic↗
Biomedical subjects
R Donnelly
Publications and source records attributed to R Donnelly.
B-type natriuretic peptide as a screening test for patients undergoing echocardiography to determine left ventricular dysfunction.
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Adolescent↗
Effects of metformin and oleic acid on adipocyte expression of resistin.
AIM: The adipocyte-secreted hormone resistin has been implicated in obesity-induced insulin resistance and type 2 diabetes, but pharmacological and dietary factors that regulate resistin gene expression and the effects of resistin on cellular glucose uptake in muscle have not been clearly defined. METHODS: Expression of resistin mRNA was studied in differentiated 3T3-L1 adipocytes by using real-time semiquantitative reverse transcription-polymerase chain reaction. The effects of resistin on insulin-stimulated and insulin-independent 2-deoxyglucose uptake were evaluated in L6 muscle cells. RESULTS: Insulin 1 microm and rosiglitazone 10 microm markedly reduced resistin mRNA expression (relative to the control gene TF2D) by 4.7-fold (p < 0.05) and 5.3-fold (p < 0.02), respectively. Similar reductions in resistin mRNA were demonstrated with metformin 100 microm (6.2-fold reduction, p < 0.02) and oleic acid 100 microm (3.9-fold reduction, p < 0.03). Resistin 1 microm significantly reduced maximum insulin-stimulated 2-deoxyglucose uptake in L6 cells from 634 to 383% (relative to 100% for control, p < 0.001), and co-administration of rosiglitazone had no effect on resistin-induced insulin resistance. In the absence of insulin, however, resistin increased glucose uptake dose-dependently (e.g., 1.75-fold at 5 microm, p < 0.001) via a mitogen-activated protein kinase-dependent pathway. CONCLUSIONS: These results demonstrate that various glucose-lowering therapies and oleic acid reduce resistin gene expression in isolated adipocytes, and that resistin impairs insulin-stimulated glucose uptake in skeletal muscle-derived cells.
3T3-L1 Cells↗
Contrasting effects of varicose vein surgery on endothelial-dependent and -independent cutaneous vasodilation in the perimalleolar region.
OBJECTIVES: To evaluate the effects of varicose vein surgery on cutaneous microvascular perfusion and vasodilator responses to acetylcholine (Ach) and sodium nitroprusside (SNP) in the gaiter area of patients with great saphenous vein insufficiency. METHODS: Twenty-nine patients with isolated great saphenous vein incompetence attended three study mornings (before surgery, and 6-8 weeks and 6 months after sapheno-femoral ligation+partial stripping) during which cutaneous microvascular responses were measured in the supine and standing positions using laser Doppler fluximetry (LDF) combined with incremental-dose iontophoretic administration of endothelial-dependent (Ach) and -independent (SNP) vasodilators. RESULTS: Varicose vein surgery had no significant effect on baseline cutaneous perfusion or the microvascular response to Ach: e.g. peak vasodilator responses to the 1000 microC stimulus were mean 58 SEM 7, 64 SEM 6 and 65 SEM 7PU on the pre-operative, 6-8 weeks and 6 months assessments. In contrast, the corresponding responses to SNP were significantly increased following surgery: e.g. at 2000 microC, mean 63 SEM 9, 142 SEM 4 and 157 SEM 9PU (p<0.0001) in the upright position. CONCLUSIONS: Sapheno-femoral ligation and partial stripping in patients with great saphenous vein insufficiency improves endothelial-independent cutaneous vasodilator function at the gaiter area, which may at least partly explain the benefits of surgery in reducing the risk of venous ulceration.
Acetylcholine↗
Does temporal artery biopsy influence the management of temporal arteritis?
BACKGROUND: Temporal arteritis (TA) is the commonest form of primary vasculitis. Symptoms are variable, and therefore the diagnosis (or exclusion) of TA is often difficult. Surgeons are frequently asked to perform a temporal artery biopsy (TAB), but whether the histological result actually influences clinical management is unclear. AIM: To assess whether, in routine clinical practice, a TAB affects clinical decision-making in patients with suspected TA. DESIGN: Retrospective audit. METHODS: All patients who underwent a TAB in a single hospital over a 2-year period were identified. This included patients referred from different specialist departments. Individual patient records were examined to document the TAB result, and in particular, the timings of commencement and discontinuation of corticosteroid therapy. RESULTS: A total of 44 patients were included. TAB was positive in seven patients and negative in 37. In 31, there was no change in their clinical management despite a negative biopsy result: 18 continued with corticosteroids for >6 months with a clinical diagnosis of TA, and in 13 patients a decision to stop steroids, or an alternative diagnosis, was made before the biopsy result was known. DISCUSSION: In this retrospective study, only a small number of TABs provided positive histological confirmation of TA, and in most patients undergoing TAB, there was little evidence that clinical decision-making with respect to corticosteroid therapy was influenced by the TAB result.
Adrenal Cortex Hormones↗
Therapeutic angiogenesis in peripheral arterial disease: can biotechnology produce an effective collateral circulation?
The physiological processes of angiogenesis, vasculogenesis and arteriogenesis contribute to the growth of collateral vessels in response to obstructive arterial disease causing lower limb or myocardial ischaemia, but in clinical practice the endogenous angiogenic response is often suboptimal or impaired, e.g. by factors such as ageing, diabetes or drug therapies. Therapeutic angiogenesis is an application of biotechnology to stimulate new vessel formation via local administration of pro-angiogenic growth factors in the form of recombinant protein or gene therapy, or by implantation of endothelial progenitor cells that will synthesize multiple angiogenic cytokines. Numerous experimental and clinical studies have sought to establish 'proof of concept' for therapeutic angiogenesis in PAD and myocardial ischaemia using different treatment modalities, but the results have been inconsistent. This review summarises the mechanisms of angiogenesis and the results of recent trials evaluating the efficacy and safety of different gene therapy, recombinant protein and cellular-based treatment approaches to enhance collateral vessel formation.
Animals↗
Occupational asthma after exposure to plaster casts containing methylene diphenyl diisocyanate.
BACKGROUND: The case of a 34-year-old female nurse is presented. She worked in an accident and emergency department in a district general hospital, with methylene diphenyl diisocyanate (MDI)-containing synthetic plaster casts. She worked with MDI on a daily basis for 4 years. She was out of the department for 1 year and on her return developed cough, wheeze and dyspnoea within 5 min of exposure to MDI- containing synthetic casts. METHOD: A bronchial provocation test was performed and confirmed an early asthmatic response. RESULTS: There was a 39% decrease in the forced expiratory volume in 1 s 15 min after exposure, which required the administration of a bronchodilator on two occasions. The patient has subsequently avoided MDI-containing synthetic plaster casts and has experienced no further respiratory symptoms. CONCLUSION: This case illustrates that respiratory sensitization can occur as a result of exposure to MDI-containing synthetic casts and highlights the need for vigilance when health care workers are using isocyanate-containing synthetic casts.
Adult↗
Protein kinase C inhibition and diabetic retinopathy: a shot in the dark at translational research.
TRANSLATIONAL RESEARCH IN PRACTICE: a PKC-beta inhibitor for diabetic retinopathy
Diabetic Retinopathy↗
The role of cilostazol in the treatment of intermittent claudication.
This paper represents a review, by experts, of current opinion and information on intermittent claudication (IC) and the role that cilostazol plays in its treatment. IC is a common and debilitating condition that has a significant adverse impact on health-related quality of life (HR-QoL). It is currently under-recognised as a powerful marker of increased cardiovascular (CV) risk. The clinical priority is secondary prevention -- sometimes referred to as best medical therapy aimed at reducing CV risk. However, the priority for most patients (often overlooked by clinicians) is symptom relief: an increase in walking distance leading to an improvement in HR-QoL. The symptoms of IC may be improved by exercise, pharmacotherapy, and when these are unsuitable or unsuccessful, endovascular or surgical intervention. Cilostazol is indicated for the improvement of maximal and pain-free walking distance in patients with IC who do not have rest pain or tissue necrosis. In clinical trials, cilostazol improved symptoms both objectively and subjectively, and also improved HR-QoL. Cilostazol is usually well tolerated, with adverse events being generally mild to moderate in intensity, and transient or resolved after symptomatic treatment (e.g. non-prescription analgesics). Such events only infrequently require permanent drug withdrawal. There are no interactions with other drugs commonly prescribed in patients with IC, such as statins and anti-platelet agents. Cilostazol also has a range of potentially beneficial effects that may in the future be proven to decrease CV risk and modify the underlying process of atherosclerosis. Cilostazol represents the best evidence-based pharmacological therapy available for the symptoms of IC and should be the first-line treatment for symptom improvement in appropriate patients. Based on the available treatment strategies, the paper presents a suggested algorithm for the management of IC highlighting the role of cilostazol.
Algorithms↗
Rosiglitazone and pulmonary oedema: an acute dose-dependent effect on human endothelial cell permeability.
AIMS/HYPOTHESIS: Peripheral and pulmonary oedema has emerged as the most common drug-related side effect of rosiglitazone in clinical practice, but the underlying mechanisms are not clear. Fluid retention and changes in vascular tone could contribute to oedema formation, but the interpretation of clinical and in vivo studies is particularly difficult and the direct effects of thiazolidinediones on endothelial barrier function have not been previously reported. METHODS: Human pulmonary artery endothelial cells were seeded and grown on 0.4 microm collagen-coated filters to form a tight monolayer (transendothelial electrical resistance 9-11 ohms.cm(-2) after 2-3 days). Transendothelial albumin flux (expressed as the percentage clearance of albumin relative to control) was measured using Evans blue-labelled albumin after exposure to rosiglitazone 1-100 micromol/l for 1 h to 48 h, and after removal of drug from the monolayer. RESULTS: Incubation of pulmonary artery endothelial cells with rosiglitazone for 4 h produced immediate concentration-dependent increases in transendothelial albumin flux: e.g., relative to control (100%), 113%+/-13% (1 micromol/l), 215%+/-37% (10 micromol/l, p=0.01) and 461%+/-96% (100 micromol/l, p=0.002) (n=12). There was no effect after 1 h. The acute hyperpermeability response to rosiglitazone, maximal after 4 h, was fully reversible after washing the monolayer. After incubation for 24 to 48 h the effect of rosiglitazone on pulmonary endothelial permeability tended to subside: e.g., 210%+/-59% (24 h) for rosiglitazone 100 micromol/l (p=0.06). CONCLUSION/INTERPRETATION: Exposure to high-therapeutic concentrations of rosiglitazone causes a reversible fourfold increase in pulmonary endothelial permeability which could be clinically relevant especially at higher doses and at times of peak plasma drug concentration.
Albumins↗
Increased skeletal muscle expression of PKC-theta but not PKC-alpha mRNA in type 2 diabetes: inverse relationship with in-vivo insulin sensitivity.
BACKGROUND: Increases in PKC-theta (the major isoenzymic form of PKC in skeletal muscle) protein and isozyme activity have been reported in skeletal muscle from patients with type 2 diabetes mellitus (T2DM) and dietary-induced rodent models of insulin resistance, but the underlying biochemical mechanism is unclear and muscle PKC-theta mRNA expression has not been previously reported in patients with T2DM or in relation to in-vivo measurements of insulin sensitivity. METHODS: Diet-only treated patients with T2DM (n=7) and healthy nondiabetic controls (n=7) of similar BMI attended the clinical research unit on two occasions, 1 week apart, for a skeletal muscle biopsy 2 h after a 75-g oral glucose load and measurement of whole-body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. RESULTS: Type 2 DM patients were insulin resistant (M-value 3.0 +/- 0.4 vs. 8.6 +/- 0.8 mg glucose kg(-1) min(-1)) with fasting hyperinsulinaemia (306 +/- 116 vs. 34 +/- 9 pmol L(-1), P<0.001) and hypertriglyceridaemia (3.6 +/- 0.7 vs. 1.3 +/- 0.3 mmol L(-1), P<0.01) relative to controls. Semi-quantitative RT-PCR showed that expression of PKC-theta mRNA (relative to GAPDH mRNA) was 6-fold higher in T2DM subjects (0.63 + 0.25% vs. 0.09 + 0.07%, P<0.001), whereas there was no difference in expression of PKC-alpha mRNA between the two groups. Expression of PKC-theta mRNA was inversely correlated with insulin sensitivity (M) and positively correlated with fasting serum insulin concentration (P<0.02). CONCLUSIONS: This is the first clinical study of PKC-theta mRNA expression in human diabetic skeletal muscle. The results indicate that transcriptional up-regulation of PKC-theta may at least partly contribute to the increased muscle PKC-theta signalling in T2DM, and that PKC-theta mRNA may be inversely related to in-vivo insulin sensitivity.
Adult↗
Effects of rosiglitazone and oleic acid on UCP-3 expression in L6 myotubes.
AIMS: The regulation of uncoupling protein-3 (UCP-3) expression in muscle remains unclear, specifically in relation to dietary and drug treatments. The present study evaluated the effects of oleic acid and rosiglitazone on UCP-3 mRNA expression in differentiated L6 myotubes. METHODS: L6 myocytes were cultured and differentiated prior to exposure to rosiglitazone 10 micro mol/l, oleic acid 100 micro mol/l, or the combination, for 24 h, prior to semiquantitative evaluation of UCP-3 mRNA relative to GAPDH mRNA by RT-PCR. RESULTS: Exposure to oleic acid produced a significant increase in UCP-3 mRNA (0.012 +/- 0.007 vs. 0.0011 +/- 0.0006 for untreated cells, relative to GAPDH mRNA, p < 0.001). Rosiglitazone alone had no effect on UCP-3 expression and nor did the glitazone affect oleic-acid-induced upregulation of UCP-3. CONCLUSIONS: In L6 myotubes, 24-h exposure to oleic acid produced a 10-fold increase in UCP-3 mRNA expression, but rosiglitazone had no effect. Oleic-acid-induced upregulation of UCP-3 was not affected (positively or negatively) by glitazone exposure.
Animals↗
Metabolic and cardiovascular effects of very-low-calorie diet therapy in obese patients with Type 2 diabetes in secondary failure: outcomes after 1 year.
AIMS: To evaluate the short-term and 1-year outcomes of an intensive very-low-calorie diet (VLCD) on metabolic and cardiovascular variables in obese patients with Type 2 diabetes (T2DM) and symptomatic hyperglycaemia despite combination oral anti-diabetic therapy +/- insulin, and to assess patient acceptability and the feasibility of administering VLCD treatment to this subgroup of patients in a routine practice setting. METHODS: Forty obese patients with T2DM (22 M, mean age 52 years, body mass index (BMI) 40 kg/m2, duration of T2DM 6.1 years) and symptomatic hyperglycaemia despite combination oral therapy (n = 26) or insulin + metformin (n = 14) received 8 weeks of VLCD therapy (750 kcal/day) followed by standard diet and exercise advice at 2-3-month intervals up to 1 year. Insulin was discontinued at the start of the VLCD, and anti-diabetic therapy was adjusted individually throughout the study, including (re)commencement of insulin as required. RESULTS: Immediate improvements in symptoms and early weight loss reinforced good compliance and patient satisfaction. After 8 weeks of VLCD, body weight and BMI had fallen significantly: 119 +/- 19-107 +/- 18 kg and 40.6-36.6 kg/m2, respectively, with favourable reductions in serum total cholesterol (5.9-4.9 mm), blood pressure (10/6 mmHg) and fructosamine (386 +/- 73-346 +/- 49 microm) (equates to an HbA1c reduction of approximately 1%). Sustained improvements were evident after 1 year, with minimal weight regain, e.g. mean body weight 109 +/- 18 kg and BMI 37 +/- 4 kg/m2. Glycaemic control tended to deteriorate after 1 year. CONCLUSIONS: The absence of a control group is a major limitation, but the results indicate that 8 weeks of VLCD treatment may be effective and well tolerated in symptomatic obese patients with T2DM in secondary failure, producing sustained cardiovascular and metabolic improvements after 1 year. VLCD therapy is a treatment option that deserves greater consideration in this difficult-to-treat patient population.
Adult↗
Effects of posture and venous insufficiency on endothelial-dependent and -independent cutaneous vasodilation in the perimalleolar region.
OBJECTIVES: To assess the effects of posture, endothelial function and venous insufficiency on cutaneous microvascular vasodilator function in the gaiter area, in particular defining factors which may affect microangiopathy and ulcer formation. METHODS: Endothelial-dependent and -independent vasodilator responses to incremental-doses of acetylcholine (Ach) and sodium nitroprusside (SNP) were evaluated in the perimalleolar region in the supine and standing positions in middle-aged patients with isolated superficial venous insufficiency (ISVI) (n = 25) and healthy controls (n = 28) using laser Doppler fluximetry (LDF) and iontophoresis of vasodilators. RESULTS: The venoarteriolar reflex (vasoconstriction on standing) was equally present in both groups, and reduced the vasodilator responses to SNP in the upright position (e.g., for patients with ISVI, peak SNP response was 82 +/- 11 PU [standing] vs 123 +/- 15 PU [supine]). The presence of ISVI had no effect on endothelial vasodilator function in the supine position, but on standing cutaneous reactivity to Ach was significantly reduced (e.g., peak Ach response 69 +/- 8 PU [ISVI] vs 109 +/- 11 PU [controls], p < 0.003). CONCLUSIONS: Upright posture impairs cutaneous endothelial-dependent vasodilation in the gaiter area of patients with ISVI. This may be of clinical and prognostic utility in identifying which patients with uncomplicated ISVI are at highest risk of tissue breakdown and ulcer formation in the gaiter area.
Acetylcholine↗
Losartan attenuates endothelial hyperpermeability responses to VPF and high glucose but not angiotensin II.
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Angiotensin II↗
Management of intermittent claudication: the importance of secondary prevention.
Atherosclerotic peripheral arterial disease (PAD) is a common disorder usually associated with silent or symptomatic arterial disease elsewhere in the circulation and a cluster of cardiovascular risk factors inducing atheroma progression and/or thrombotic complications. Because of these strong clinical associations, especially with coronary heart disease, the ankle-brachial pressure index (ABPI) is of prognostic significance. The clinical management of IC should include relief of symptoms combined with prevention of secondary cardiovascular complications, e.g. acute thrombotic events causing limb- or life-threatening ischaemia, which are often due to atherosclerotic plaque rupture leading to thrombotic vessel occlusion. Many patients with PAD do not receive an optimum package of secondary prevention, tailored to include maximum cholesterol reduction, BP and glycaemic control, ACE inhibition and single or combination anti-platelet therapy. This review considers recent information from large secondary prevention trials, e.g. the PAD subgroups within the HOPE, CAPRIE and statin studies. Slowing progression of atherosclerosis, and inducing stabilisation and regression of atheromatous plaques, is now feasible using long-term combination drug therapy. The phrase angle quotation mark, leftangle quotation mark, leftconservative therapyangle quotation mark, rightangle quotation mark, right, popular among vascular surgeons, implies a passive minimal-intervention strategy of surveillance and lifestyle advice; such terminology is perhaps no longer appropriate since considerable improvements in survival are likely to accrue if all patients with PAD, especially those with low ABPI, receive vigorous, titrated medical therapies, tailored to individual patients, as part of an evidence-based secondary prevention regime.
Angiotensin-Converting Enzyme Inhibitors↗
Does the angiotensin-converting enzyme (ACE) gene polymorphism affect rate of abdominal aortic aneurysm expansion?
OBJECTIVES: the tissue renin-angiotensin system (RAS), which plays an important role in vascular structure and function, is regulated in part by an insertion-deletion polymorphism of the angiotensin converting enzyme (ACE) gene. We hypothesised that ACE genotype might affect rate of AAA expansion via modulating long-term structural changes associated with RAS activation. METHODS: fifty-eight patients (50 M, mean age 70 years, mean initial aneurysm size 4.3 cm) with current or previous AAA and serial (>3) annual ultrasound measurements of antero-posterior AAA size provided a sample of leucocyte DNA for ACE genotyping. AAA expansion rate (cm per year) for individual subjects was calculated by linear regression. RESULTS: median AAA expansion rate was 0.28 cm/year (range 0-1.8 cm/year), and the genotype distribution included DD (n=14), DI (n=29) and II (n=15). Corresponding median AAA expansion rates for each of the three genetic subgroups were 0.22, 0.32 and 0.30 cm/year, respectively (p=0.6, nonparametric). CONCLUSIONS: the wide inter-individual variability in AAA expansion rate is likely to reflect complex genetic and environmental interactions, but the lack of any relationship with ACE genotype suggests that differences in vascular ACE activity in aortic tissue are not major determinants of the variability in rate of AAA dilatation.
Aged↗
Improvements in total mortality and lipid levels after acute myocardial infarction in an English health district (1995-1999).
OBJECTIVES: To quantify changes in 30 day and one year mortality among patients with acute myocardial infarction in southern Derbyshire (population 560 000) in each of five consecutive years (1995-1999) before the publication of the National Service Framework for coronary heart disease, and to assess the proportion of one year survivors in whom serum lipids were measured and were below target values. DESIGN: All hospital admissions coded on the patient administration system (PAS) as "AMI" (ICD codes I-21, I-22, and I-23) and with a creatine kinase measurement in the pathology database were identified over a five year period (n = 4912). All deaths in the district are automatically notified to the PAS. Total mortality after acute myocardial infarction (30 days and one year) and lipid levels were analysed by year of admission, age group (35-74 years v > or = 75 years), and sex using unconditional logistic regression analysis. SETTING: An acute hospitals trust and pathology laboratory, as sole service providers for a catchment population of 560 000. RESULTS: The number of admissions for acute myocardial infarction was similar in each of the five years (n = 4912, 62% male, 63% < 75 years old). Overall, among patients aged 35-74 years there were 396 deaths (13%) at 30 days and 585 (19%) at one year; mortality was higher in women (1.28-fold at 30 days, p = 0.02) and in subjects aged 75 years or more (3.26-fold at 30 days, p < 0.0001). There was a progressive reduction in 30 day mortality of 9%/year over the five year period (95% confidence interval, 4% to 13%, p = 0.012). The proportion of one year survivors (35-74 years) in whom serum lipids were measured at least once increased from 74% in 1995 to 88% in 1999; of these, 27% of men and 23% of women had a total serum cholesterol of < 5 mmol/l in 1995, increasing to 65% and 74%, respectively, in 1998 and 1999 (p < 0.0001). CONCLUSIONS: In the five year period 1995-1999, there was a significant year on year decline in 30 day and one year mortality after admission for acute myocardial infarction, and progressively more patients achieved cholesterol levels below 5 mmol/l. Men were more likely than women to have their lipids measured after myocardial infarction. Mortality at one year was 1.32-fold higher among women than among men.
Adult↗