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Biomedical subjects

A M Shah

Publications and source records attributed to A M Shah.

At least 19 recordsLinked to original sources
PubMed2006

Redox signalling involving NADPH oxidase-derived reactive oxygen species.

Increased oxidative stress plays an important role in the pathophysiology of many diseases such as atherosclerosis, diabetes mellitus, myocardial infarction and heart failure. In addition to the well-known damaging effects of oxygen-free radicals, ROS (reactive oxygen species) also have signalling roles, acting as second messengers that modulate the activity of diverse intracellular signalling pathways and transcription factors, thereby inducing changes in cell phenotype. NADPH oxidases appear to be especially important sources of ROS involved in redox signalling. Seven NADPH oxidase isoforms, known as Noxs (NAPDH oxidases), are expressed in a cell- and tissue-specific fashion. These oxidases are thought to subserve distinct functions as a result of their tightly regulated activation (e.g. by neurohormonal and growth factors and mechanical stimuli) and their specific coupling with distinct downstream signalling pathways. In the present paper, we review the structure and mechanisms of activation of NADPH oxidases and consider their involvement in redox signalling, focusing mainly on the cardiovascular system.

Atherosclerosis↗
PubMed2006

Effect of fat distribution on endothelial-dependent and endothelial-independent vasodilatation in healthy humans.

AIM: The present study aims to explore the relationship between inflammatory cytokines, plasma lipids, insulin, blood pressure (BP), total adiposity/markers of fat distribution and endothelial function in healthy people across a wide range of body fatness. METHODS: Seventy-three healthy people (44 women; age range: 24-64 years) with body mass index (BMI) range of 18.6-73.1 kg/m2 were recruited. All participants underwent assessment of conduit artery endothelial-dependent vasodilatation by using flow-mediated vasodilatation (FMD) of the brachial artery and endothelial-independent vasodilatation to sublingual GTN. They had blood taken for measurement of plasma markers of glucose homeostasis (fasting insulin and glucose), systemic inflammation (interleukin-6 (IL-6), C-reactive protein (CRP) and tumour necrosis factor-alpha receptor 2 (TNF-alpha R2)) and lipids (low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides). Morphometric assessment (waist circumference, BMI and waist-to-hip ratio (WHR)) and systolic and diastolic arterial pressure were also measured. RESULTS: Markers of total body fat/fat distribution (waist circumference, BMI and WHR), inflammation (IL-6, CRP and TNF-alpha R2), metabolism (fasting insulin, HDL, LDL and triglycerides) and BP (systolic and diastolic) correlated with FMD. Among these measurements, WHR was the only independent predictor of FMD (r2 = 0.30; p = 0.0001). CONCLUSIONS: WHR is an important marker of endothelial dysfunction in healthy people across a wide range of body fatness.

Adult↗
PubMed2005

Moderate mitral stenosis in pregnancy: the haemodynamic impact of diuresis.

A case of asymptomatic, newly diagnosed, moderate mitral stenosis in a 27 year old pregnant woman is described. A conservative management strategy with regular cardiac assessment was adopted and the patient remained well. Routine transthoracic echocardiography at 36 weeks' gestation showed the development of severe pulmonary hypertension with right ventricular pressure overload, which was successfully treated with oral diuretics resulting in rapid normalisation of pulmonary pressure. Mitral stenosis in pregnancy and its management in pregnancy are briefly discussed.

Adult↗
PubMed2004

Predicting sudden death in patients with mild to moderate chronic heart failure.

OBJECTIVES: To explore the relation between non-invasive measures of cardiac function and sudden cardiac death, as well as the development and utility of an index integrating these variables to identify patients at increased risk of this mode of death. DESIGN: UK-HEART (United Kingdom-heart failure evaluation and assessment of risk trial) was a prospective study conducted between December 1993 and April 2000. The study was specifically designed to identify non-invasive markers of death and mode of death among patients with chronic heart failure. SETTING: 8 UK general hospitals. MAIN OUTCOME MEASURES: Death and mode of death. RESULTS: 553 patients aged a mean (SD) of 63 (10) years, in New York Heart Association functional class 2.3 (0.02), recruited prospectively. After 2365 patient-years' follow up, 201 patients had died (67 suddenly). Predictors of sudden death were greater cardiothoracic ratio, QRS dispersion, QT dispersion corrected for rate (QTc) across leads V1-V6 on the 12 lead ECG, and the presence of non-sustained ventricular tachycardia. The hazard ratio and 95% confidence intervals (CI) of sudden death for a 10% increase in cardiothoracic ratio was 1.43 (95% CI 1.20 to 1.71), for a 10% increase in QRS dispersion 1.11 (95% CI 1.04 to 1.19), for the presence of non-sustained ventricular tachycardia 2.03 (95% CI 1.27 to 3.25), and for a 10% increase in QTc dispersion across leads V1-V6 1.03 (95% CI 1.00 to 1.07) (all p < 0.04). An index derived from these four factors performed well in identifying patients specifically at increased risk of sudden death. CONCLUSIONS: Results show that an index derived from three widely available non-invasive investigations has the potential to identify ambulant patients with chronic heart failure at increased risk of sudden death. This predictive tool could be used to target more sophisticated investigations or interventions aimed at preventing sudden death.

Aged↗
PubMed2004

Inspiratory muscle load and capacity in chronic heart failure.

BACKGROUND: Although breathlessness is common in chronic heart failure (CHF), the role of inspiratory muscle dysfunction remains unclear. We hypothesised that inspiratory muscle endurance, expressed as a function of endurance time (Tlim) adjusted for inspiratory muscle load and inspiratory muscle capacity, would be reduced in CHF. METHODS: Endurance was measured in 10 healthy controls and 10 patients with CHF using threshold loading at 40% maximal oesophageal pressure (Poes(max)). Oesophageal pressure-time product (PTPoes per cycle) and Poes(max) were used as indices of inspiratory muscle load and capacity, respectively. RESULTS: Although Poes(max) was slightly less in the CHF group (-117.7 (23.6) v -100.0 (18.3) cm H(2)O; 95% CI -37.5 to 2.2 cm H(2)O, p = 0.1), Tlim was greatly reduced (1800 v 306 (190) s; 95% CI 1368 to 1620 s, p<0.0001) and the observed PTPoes per cycle/Poes(max) was increased (0.13 (0.05) v 0.21 (0.04); 95% CI -0.11 to -0.03, p = 0.001). Most of this increased inspiratory muscle load was due to a maladaptive breathing pattern, with a reduction in expiratory time (3.0 (5.8) v 1.1 (0.3) s; 95% CI 0.3 to 3.5 s, p = 0.03) accompanied by an increased inspiratory time relative to total respiratory cycle (Ti/Ttot) (0.43 (0.14) v 0.62 (0.07); 95% CI -0.3 to -0.1, p = 0.001). However, log Tlim, which incorporates the higher inspiratory muscle load to capacity ratio caused by this altered breathing pattern, was >/=85% predicted in seven of 10 patients. CONCLUSIONS: Although a marked reduction in endurance time was observed in CHF, much of this reduction was explained by the increased inspiratory muscle load to capacity ratio, suggesting that the major contributor to task failure was a maladaptive breathing pattern rather than impaired inspiratory muscle endurance.

Aged↗
PubMed2004

Bronchoscopic closure of bronchopleural fistula using gelfoam.

Management of a persistent bronchopleural fistula (BPF) can be a therapeutic challenge. The etiological factors responsible for BPF include pulmonary tuberculosis, post-thoracic resection surgeries, trauma, malignancy, necrotising infections and rupture of lung abscess. The immediate management of BPF is drainage of the pleural cavity with insertion of an intercostal drainage tube. Patients with BPF may also require surgical intervention in the form of a wedge resection or lobectomy or muscle flap surgery. We report a case of a peripheral BPF secondary to a bacterial infection, which was successfully managed by the instillation of gelfoam via flexible bronchoscopy.

Bronchial Fistula↗
PubMed2003

Pathophysiological implications of insulin resistance on vascular endothelial function.

BACKGROUND: Insulin resistance is a key component of the insulin resistance syndrome and is a crucially important metabolic abnormality in Type 2 diabetes. Insulin-resistant individuals are at significantly increased risk of cardiovascular disease, although the underlying mechanisms remain incompletely understood. The endothelium is thought to play a critical role in maintaining vascular homeostasis, a process dependent on the balance between the production of nitric oxide, superoxide and other vasoactive substances. Endothelial dysfunction has been demonstrated in insulin-resistant states in animals and humans and may represent an important early event in the development of atherosclerosis. Insulin resistance may be linked to endothelial dysfunction by a number of mechanisms, including disturbances of subcellular signalling pathways common to both insulin action and nitric oxide production. Other potential unifying links include the roles of oxidant stress, endothelin, the renin angiotensin system and the secretion of hormones and cytokines by adipose tissue. Lifestyle measures and drug therapies which improve insulin sensitivity and ameliorate endothelial dysfunction may be important in delaying the progression to overt cardiovascular disease in at risk individuals. METHODS: We conducted a literature search using Medline, restricted to articles published in the English language between 1966 and the present, and reviewed bibliographies of relevant articles. An initial search strategy employing combinations of the MeSH terms: insulin resistance; endothelium, vascular; insulin; nitric oxide or hyperinsulinaemia produced over 300 references. Focused searches using keywords relevant to the molecular aspects of endothelial function and insulin signalling, and lifestyle or pharmacological interventions relevant to insulin resistance or endothelial function, produced over 300 further references. Abstracts of all references were screened before selecting those relevant to this review.

Arteriosclerosis↗
PubMed2003

Oxidative stress and heart failure.

Despite advances in treatment, chronic congestive heart failure carries a poor prognosis and remains a leading cause of cardiovascular death. Accumulating evidence suggests that reactive oxygen species (ROS) play an important role in the development and progression of heart failure, regardless of the etiology. Under pathophysiological conditions, ROS have the potential to cause cellular damage and dysfunction. Whether the effects are beneficial or harmful will depend upon site, source and amount of ROS produced, and the overall redox status of the cell. All cardiovascular cell types are capable of producing ROS, and the major enzymatic sources in heart failure are mitochondria, xanthine oxidases and the nonphagocytic NADPH oxidases (Noxs). As well as direct effects on cellular enzymatic and protein function, ROS have been implicated in the development of agonist-induced cardiac hypertrophy, cardiomyocyte apoptosis and remodelling of the failing myocardium. These alterations in phenotype are driven by redox-sensitive gene expression, and in this way ROS may act a potent intracellular second messengers. Recent experimental studies have suggested a possible causal role for increased ROS in the development of contractile dysfunction following myocardial infarction and pressure overload, however the precise contribution of different cellular and enzymatic sources involved remain under investigation.

Apoptosis↗
PubMed2002

Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans.

It is now well established that obesity is an independent risk factor for the development of coronary artery atherosclerosis. The maintenance of vascular homeostasis is critically dependent on the continued integrity of vascular endothelial cell function. A key early event in the development of atherosclerosis is thought to be endothelial cell dysfunction. A primary feature of endothelial cell dysfunction is the reduced bioavailability of the signalling molecule nitric oxide (NO), which has important anti atherogenic properties. Recent studies have produced persuasive evidence showing the presence of endothelial dysfunction in obese humans NO bioavailability is dependent on the balance between its production by a family of enzymes, the nitric oxide synthases, and its reaction with reactive oxygen species. The endothelial isoform (eNOS) is responsible for a significant amount of the NO produced in the vascular wall. NO production can be modulated in both physiological and pathophysiological settings, by regulation of the activity of eNOS at a transcriptional and post-transcriptional level, by substrate and co-factor provision and through calcium dependent and independent signalling pathways. The present review discusses general mechanisms of reduced NO bioavailability including factors determining production of both NO and reactive oxygen species. We then focus on the potential factors responsible for endothelial dysfunction in obesity and possible therapeutic interventions targetted at these abnormalities.

Arteriosclerosis↗
PubMed2002

Coronary artery perforation during percutaneous intervention: incidence and outcome.

OBJECTIVE: To examine the clinical outcome of percutaneous coronary intervention where the procedure was complicated by vessel perforation. SETTING: Tertiary referral centre. METHODS: The procedural records of 6245 patients undergoing coronary intervention were reviewed. In 52 patients (0.8%) the procedure was complicated by vessel perforation, ranging from wire exit to free flow of contrast into the pericardial space. The majority of lesions treated were complex (37% type B, 59% type C) and 9 of 52 (17%) were chronic occlusions. Ten patients (19%) received abciximab. Four underwent rotational atherectomy (8%). RESULTS: In 28 of 52 patients (54%) the perforation was benign and managed conservatively without the development of haemodynamically significant sequelae. In 24 of 52 (46%) a significant pericardial effusion ensued requiring drainage. Of these 24 procedures 6 had involved the treatment of a chronic occlusion (25%). Eight of the 24 patients were referred for emergency bypass surgery (33%), 3 of whom died. Of the remaining 16 not referred for surgery, 3 died. Of the 10 procedures complicated by vessel perforation where abciximab had been administered, 9 (90%) led to pericardial tamponade. Latterly 2 vessel perforations were successfully treated by the deployment of a covered stent. CONCLUSIONS: Coronary artery perforation with sequelae during intervention is rare--26 of 6245 (0.4%). This complication was seen in the treatment of chronic occlusions, which are therefore not risk-free procedures. The development of pericardial tamponade carries a high mortality. While prompt surgical intervention may be life saving, expertise in the use of covered stents may provide a valuable rescue option for this serious complication. Caution should be exercised where coronary perforation occurs and abciximab has been used.

Abciximab↗
PubMed2001

Impaired endothelial regulation of ventricular relaxation in cardiac hypertrophy: role of reactive oxygen species and NADPH oxidase.

BACKGROUND: Endothelium-derived nitric oxide (NO) selectively enhances myocardial relaxation. In experimental left ventricular hypertrophy (LVH), this endothelium-dependent LV relaxant response is impaired despite a preserved response to exogenous NO. We investigated the potential role of reactive oxygen species (ROS) in this defect. METHODS AND RESULTS: Short-term treatment with the antioxidants vitamin C (10 micromol/L) or deferoxamine (500 micromol/L) restored LV relaxant responses to the NO agonists bradykinin (10 nmol/L) and substance P (100 nmol/L) in isolated ejecting hearts of aortic-banded guinea pigs. Substance P decreased the time to onset of LV relaxation (tdP/dt(min)) by -6.8+/-1.7 ms in the presence of vitamin C and by -8.9+/-2.2 ms in the presence of deferoxamine compared with -0.8+/-2.2 ms in the absence of antioxidants (P<0.05 either antioxidant versus control). A similar restoration of relaxant response to substance P was observed in the presence of the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (10 micromol/L), but not with tetrahydrobiopterin or L-arginine. Protein expression of the NADPH oxidase subunits gp91-phox and p67-phox and myocardial NADPH oxidase activity were significantly increased (P<0.05) in the banded group compared with shams. CONCLUSIONS: An increase in ROS, most likely derived at least in part from NADPH oxidase, is responsible for the impaired endothelial regulation of LV relaxation in LVH. These are the first data to potentially link increased NADPH oxidase-derived ROS with a defect in cardiac contractile function in a pathological setting.

Animals↗
PubMed2001

Effects of nitric oxide synthase inhibition on Basal function and the force-frequency relationship in the normal and failing human heart in vivo.

BACKGROUND: Nitric oxide (NO) exerts autocrine/paracrine effects on cardiac function, including alterations of the inotropic state. In vitro studies suggest that NO modulates the myocardial force-frequency relationship. Basal left ventricular (LV) contractility is depressed and the force-frequency relationship is blunted in human heart failure, and it is speculated that an increase in NO production is involved. METHODS AND RESULTS: We compared the effects of intracoronary NO synthase inhibition with N(G)-monomethyl-L-arginine (L-NMMA; 25 micromol/min) on basal LV function and the response to incremental atrial pacing in patients with dilated cardiomyopathy (n=11; mean age, 51 years) and in control subjects with atypical chest pain and normal cardiac function (n=7; mean age, 54 years). In controls, L-NMMA significantly reduced basal LV dP/dt(max) (from 1826 to 1578 mm Hg/s; P<0.002), but had no effect on heart rate, mean aortic pressure, or right atrial pressure. Pacing-induced increases in LV dP/dt(max) were unaltered by L-NMMA. In patients with dilated cardiomyopathy, L-NMMA had no effect on baseline LV dP/dt(max) (from 1313 to 1337 mm Hg/s; P=NS). The blunted pacing-induced rise in LV dP/dt(max) in these patients was unaltered by L-NMMA. CONCLUSION: Endogenous NO has a small baseline positive inotropic effect in the normal human heart, which is lost in heart failure patients. NO does not significantly influence the force-frequency relationship in either the normal or failing human heart in vivo. Because this study was performed in patients with moderate heart failure, whether the findings apply to subjects with more severe heart failure requires further investigation.

Adult↗
PubMed2001

A DNA polymerase beta mutator mutant with reduced nucleotide discrimination and increased protein stability.

DNA polymerase beta (pol beta) offers a simple system to examine the role of polymerase structure in the fidelity of DNA synthesis. In this study, the M282L variant of pol beta (M282Lbeta) was identified using an in vivo genetic screen. Met282, which does not contact the DNA template or the incoming deoxynucleoside triphosphate (dNTP) substrate, is located on alpha-helix N of pol beta. This mutant enzyme demonstrates increased mutagenesis in both in vivo and in vitro assays. M282Lbeta has a 7.5-fold higher mutation frequency than wild-type pol beta; M282Lbeta commits a variety of base substitution and frameshift errors. Transient-state kinetic methods were used to investigate the mechanism of intrinsic mutator activity of M282Lbeta. Results show an 11-fold decrease in dNTP substrate discrimination at the level of ground-state binding. However, during the protein conformational change and/or phosphodiester bond formation, the nucleotide discrimination is improved. X-ray crystallography was utilized to gain insights into the structural basis of the decreased DNA synthesis fidelity. Most of the structural changes are localized to site 282 and the surrounding region in the C-terminal part of the 31-kDa domain. Repositioning of mostly hydrophobic amino acid residues in the core of the C-terminal portion generates a protein with enhanced stability. The combination of structural and equilibrium unfolding data suggests that the mechanism of nucleotide discrimination is possibly affected by the compacting of the hydrophobic core around residue Leu282. Subsequent movement of an adjacent surface residue, Arg283, produces a slight increase in volume of the pocket that may accommodate the incoming correct base pair. The structural changes of M282Lbeta ultimately lead to an overall reduction in polymerase fidelity.

Amino Acid Substitution↗
PubMed2001

Y265H mutator mutant of DNA polymerase beta. Proper teometric alignment is critical for fidelity.

DNA polymerases have the unique ability to select a specific deoxynucleoside triphosphate from a pool of similarly structured substrates. One of these enzymes, DNA polymerase beta, offers a simple system to relate polymerase structure to the fidelity of DNA synthesis. In this study, a mutator DNA polymerase beta, Y265H, was identified using an in vivo genetic screen. Purified Y265H produced errors at a 40-fold higher frequency than the wild-type protein in a forward mutation assay. At 37 degrees C, transient kinetic analysis demonstrated that the alteration caused a 111-fold decrease in the maximum rate of polymerization and a 117-fold loss in fidelity for G misincorporation opposite template A. Our data suggest that the maximum rate of polymerization was reduced, because Y265H was dramatically impaired in its ability to perform nucleotidyl transfer in the presence of the correct nucleotide substrate. In contrast, at 20 degrees C, the mutant protein had a fidelity similar to wild-type enzyme. Both proteins at 20 degrees C demonstrate a rapid change in protein conformation, followed by a slow chemical step. These data suggest that proper geometric alignment of template, 3'-OH of the primer, magnesium ions, dNTP substrates, and the active site residues of DNA polymerase beta are important factors in polymerase fidelity and provide the first evidence that Tyr-265 is important for this alignment to occur properly in DNA polymerase beta.

Bacterial Proteins↗