Biomedical subjects
Patrick Vallance
Publications and source records attributed to Patrick Vallance.
Risk of myocardial infarction and stroke after acute infection or vaccination.
BACKGROUND: There is evidence that chronic inflammation may promote atherosclerotic disease. We tested the hypothesis that acute infection and vaccination increase the short-term risk of vascular events. METHODS: We undertook within-person comparisons, using the case-series method, to study the risks of myocardial infarction and stroke after common vaccinations and naturally occurring infections. The study was based on the United Kingdom General Practice Research Database, which contains computerized medical records of more than 5 million patients. RESULTS: A total of 20,486 persons with a first myocardial infarction and 19,063 persons with a first stroke who received influenza vaccine were included in the analysis. There was no increase in the risk of myocardial infarction or stroke in the period after influenza, tetanus, or pneumococcal vaccination. However, the risks of both events were substantially higher after a diagnosis of systemic respiratory tract infection and were highest during the first three days (incidence ratio for myocardial infarction, 4.95; 95 percent confidence interval, 4.43 to 5.53; incidence ratio for stroke, 3.19; 95 percent confidence interval, 2.81 to 3.62). The risks then gradually fell during the following weeks. The risks were raised significantly but to a lesser degree after a diagnosis of urinary tract infection. The findings for recurrent myocardial infarctions and stroke were similar to those for first events. CONCLUSIONS: Our findings provide support for the concept that acute infections are associated with a transient increase in the risk of vascular events. By contrast, influenza, tetanus, and pneumococcal vaccinations do not produce a detectable increase in the risk of vascular events.
Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress.
OBJECTIVES: Our aim was to investigate mechanisms of inflammation-induced endothelial dysfunction in humans. METHODS: Endothelial function in twenty-one healthy human volunteers was measured using forearm venous plethysmography before and 8 h after administration of typhoid vaccination to generate an inflammatory response. Basal and stimulated endothelial nitric oxide (NO) bioavailability was assessed by measurement of the responses to intra-arterial N(G)-monomethyl-l-arginine (l-NMMA) and bradykinin, respectively. The effects of supplementation with l-arginine or ascorbic acid were assessed to probe the effects of substrate deficiency and oxidative stress, respectively. Systemic effects were determined by measuring cytokine response, total anti-oxidant status (TAOS) and urinary protein excretion. RESULTS: Vaccination induced a cytokine response, a fall in total anti-oxidant status and increased urinary albumin excretion (UAE). There was a reduction in the response to bradykinin (BK, P<0.005) and l-NMMA (P<0.0001) with no effect on the response to glyceryl trinitrate (GTN) and norepinephrine (NE). Following vaccination blood flow response to BK (but not GTN) was partially returned to pre-vaccine levels by infusion of ascorbic acid (P=0.01). Supplementation with l-arginine had no effect. CONCLUSION: Inflammation causes widespread endothelial dysfunction, reduces vascular NO bioavailability and increases oxidative stress. These actions are partially reversible with local anti-oxidants. These findings suggest a role for reactive oxygen species in inflammation-induced endothelial dysfunction.
Endothelial NO synthase genotype and risk of preeclampsia: a multicenter case-control study.
Polymorphisms in the endothelial NO synthase (eNOS) gene have been evaluated as risk factors for preeclampsia. However, data from small studies are conflicting. We assessed whether eNOS genotypes alter the risk of preeclampsia in a population in which the incidence of this disorder is high. A total of 844 young pregnant women (322 preeclamptic and 522 controls) were recruited from 5 cities. Genotyping for the Glu298Asp, intron-4 and -786T-->C polymorphisms in the eNOS gene was conducted. Multivariate odds ratios (ORs) were obtained to estimate the association of individual polymorphisms and haplotypes with preeclampsia risk. No increase in the risk of preeclampsia for the intron-4 or -786T-->C polymorphisms was observed under any model of inheritance. In contrast, in women homozygous for the Asp298 allele, the adjusted OR for preeclampsia was 4.60 (95% confidence interval [CI], 1.73 to 12.22) compared with carriers of the Glu298 allele. After a multivariate analysis, carriage of the "Asp298-786C-4b" haplotype was also associated with increased risk of preeclampsia (OR, 2.11 [95% CI, 1.33 to 3.34]) compared with carriers of the "Glu298-786T-4b" haplotype. The eNOS Glu298Asp polymorphism and the Asp298-786C-4b haplotype are risk factors for preeclampsia.
Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway.
An increasing number of reports indicate that endogenously produced inhibitors of nitric oxide synthase, particularly asymmetric dimethylarginine (ADMA), regulate nitric oxide generation in disease states. This article describes the biology of ADMA and the implications for cardiovascular physiology and pathophysiology.
ESH/ESC guidelines.
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Cardiovascular risk and diabetes. Are the methods of risk prediction satisfactory?
BACKGROUND: Methods available to predict cardiovascular disease (CVD) and coronary heart disease (CHD) risk include the Joint British Societies Risk Chart (JBSRC), the CardioRisk Manager (CRM) calculator, the PROCAM calculation and specific to diabetes, the UKPDS risk engine. Our aim was to examine their efficacy in a clinic-based population of diabetic patients. DESIGN: Patients were identified who attended clinic at baseline (1990-1991) and categorised by the presence/absence of CHD/CVD at follow-up (2000-2001). Ten-year risk was calculated using JBSRC, CRM, PROCAM and the UKPDS risk engine. METHODS: A total of 798 patients were identified under follow-up (2000-2001), with sufficient data for risk prediction. Risk prediction methods were assessed by: (1) the Hosmer-Lemeshow test (calibration test); (2) the C-index, derived from the ROC curve [a discriminatory measure ranging from 0.5 (no discrimination) to 1.0 (perfect discrimination)]; and (3) Spearman correlation of the observed and predicted risk. RESULTS: All tests (except PROCAM) demonstrated acceptable discrimination with respect to CHD/CVD, however, all underestimated the risk of future events. With respect to CVD, the JBSRC had a C-index of 0.80, CRM: 0.76, UKPDS: 0.74 and PROCAM: 0.67. With respect to CHD the C-indexes were 0.77, 0.73, 0.65 and 0.76 respectively. Risk prediction by CRM had a stronger relationship with observed events than UKPDS and PROCAM (r=0.97, 0.86, 0.81 respectively). CONCLUSIONS: All scores have reasonable discrimination, but underestimate future events. The CRM showed the strongest correlation between observed and predicted risk with the least amount of scatter from the line of best fit. The CRM, when adjusted by the calibration factor, provides the most accurate method of risk prediction.
Training in paediatric clinical pharmacology in the UK.
AIMS: To produce a training programme in paediatric clinical pharmacology. METHODS: A working group, consisting of clinical pharmacologists (paediatric and adult), general paediatricians and the pharmaceutical industry was established to produce the training programme. RESULTS: Following a two year training programme in general paediatrics, a three year training programme in clinical pharmacology has been established. This includes one year of research in clinical pharmacology (paediatric or adult). The other two years involve training in different aspects of paediatric clinical pharmacology and general paediatrics. CONCLUSION: The existence of a formal training programme should result in a significant increase in the number of paediatric clinical pharmacologists.
Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence.
BACKGROUND: NO is a major regulator of cardiovascular physiology that reduces vascular and cardiac contractility. Accumulating evidence indicates that endogenous inhibitors may regulate NOS. The NOS inhibitors asymmetric dimethylarginine (ADMA) and N-monomethylarginine are metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). This study was designed to determine if increased expression of DDAH could reduce tissue and plasma levels of the NOS inhibitors and thereby increase NO synthesis. METHODS AND RESULTS: We used gene transfer and transgenic approaches to overexpress human DDAH I in vitro and in vivo. The overexpression of DDAH in cultured endothelial cells in vitro induced a 2-fold increase in NOS activity and NO production. In the hDDAH-1 transgenic mice, we observed approximately 2-fold increases in tissue NOS activity and urinary nitrogen oxides, associated with a 2-fold reduction in plasma ADMA. The systolic blood pressure of transgenic mice was 13 mm Hg lower than that of wild-type controls (P<0.05). The systemic vascular resistance and cardiac contractility were decreased in response to the increase in NO production. CONCLUSIONS: DDAH I overexpression increases NOS activity in vitro and in vivo. The hDDAH-1 transgenic animal exhibits a reduced systolic blood pressure, systemic vascular resistance, and cardiac stroke volume. This study provides compelling evidence that the elaboration and metabolism of endogenous ADMA plays an important role in regulation of NOS activity.
Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype.
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and is metabolised by dimethylarginine dimethylaminohydrolase (DDAH). Elevated levels of circulating ADMA correlate with various cardiovascular pathologies less is known about the cellular effects of altered DDAH activity. We modified DDAH activity in cells and measured the changes in ADMA levels, morphological phenotypes on Matrigel, and expression of vascular endothelial growth factor (VEGF). DDAH over-expressing ECV304 cells secreted less ADMA and when grown on Matrigel had enhanced tube formation compared to untransfected cells. VEGF mRNA levels were 2.1-fold higher in both ECV304 and murine endothelial cells (sEnd.1) over-expressing DDAH. In addition the DDAH inhibitor, S-2-amino-4(3-methylguanidino)butanoic acid (4124W 1mM), markedly reduced human umbilical vein endothelial cell tube formation in vitro. We have found that upregulating DDAH activity lowers ADMA levels, increases the levels of VEGF mRNA in endothelial cells, and enhances tube formation in an in vitro model, whilst blockade of DDAH reduces tube formation.
Human cytomegalovirus seropositivity is associated with impaired vascular function.
BACKGROUND: Herpesvirus infection is a possible risk factor for atherogenesis, and diabetics may be at particular risk. Endothelial dysfunction is an early marker for atherosclerosis, and the present study tests the hypotheses that (1) prior infection with cytomegalovirus (CMV) and herpes simplex virus (HSV) is associated with endothelial dysfunction and (2) this may be more marked in diabetics. METHODS AND RESULTS: Serum samples were tested for anti-IgG antibodies to CMV and HSV from 400 subjects (mean age for diabetics and nondiabetics, 37.8+/-4.3 and 37.9+/-3.7 [SD]). We also assessed Helicobacter pylori and Chlamydia pneumoniae serology. Coronary atheroma was quantified by means of electron beam computed tomography. Subjects (n=157) underwent venous occlusion plethysmography with acetylcholine, bradykinin, glyceryl trinitrate, norepinephrine, and l-NG-monomethyl-l-arginine. Individuals who were seropositive for CMV had reduced responses to bradykinin (P=0.005) and glyceryl trinitrate (P=0.006). The reduced response to bradykinin remained significant (P=0.045) after adjusting for the response to glyceryl trinitrate and was independent of conventional risk factors. Positive serology for the other organisms did not have an independent effect on reactivity. There was a weaker association between CMV and coronary artery calcification (P=0.09). Positive serology for each of the other pathogens did not affect reactivity, but there was a relation between total pathogen burden and impaired vascular reactivity. No significant differences were found between diabetics and nondiabetics. CONCLUSIONS: This study shows that CMV-seropositive individuals have endothelial dysfunction and impaired responses to NO. This association was independent of conventional risk factors and may be associated with increased atherosclerosis burden.
Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase.
OBJECTIVE: Plasma levels of an endogenous nitric oxide (NO) synthase inhibitor, asymmetric dimethylarginine (ADMA), are elevated in chronic renal failure, hypertension, and chronic heart failure. In patients with renal failure, plasma ADMA levels are an independent correlate of left ventricular ejection fraction. However, the cardiovascular effects of a systemic increase in ADMA in humans are not known. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled study in 12 healthy male volunteers, we compared the effects of intravenous low-dose ADMA and placebo on heart rate, blood pressure, cardiac output, and systemic vascular resistance at rest and during exercise. We also tested the hypothesis that ADMA is metabolized in humans in vivo by dimethylarginine dimethylaminohydrolase (DDAH) enzymes. Low-dose ADMA reduced heart rate by 9.2+/-1.4% from 58.9+/-2.0 bpm (P<0.001) and cardiac output by 14.8+/-1.2% from 4.4+/-0.3 L/min (P<0.001). ADMA also increased mean blood pressure by 6.0+/-1.2% from 88.6+/-3.4 mm Hg (P<0.005) and SVR by 23.7+/-2.1% from 1639.0+/-91.6 dyne. s. cm-5 (P<0.001). Handgrip exercise increased cardiac output in control subjects by 96.8+/-23.3%, but in subjects given ADMA, cardiac output increased by only 35.3+/-10.6% (P<0.05). DDAHs metabolize ADMA to citrulline and dimethylamine. Urinary dimethylamine to creatinine ratios significantly increased from 1.26+/-0.32 to 2.73+/-0.59 after ADMA injection (P<0.01). We estimate that humans generate approximately 300 micromol of ADMA per day, of which approximately 250 micromol is metabolized by DDAHs. CONCLUSIONS: This study defines the cardiovascular effects of a systemic increase in ADMA in humans. These are similar to changes seen in diseases associated with ADMA accumulation. Finally, our data also indicate that ADMA is metabolized by DDAHs extensively in humans in vivo.
Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia.
BACKGROUND: Maternal endothelial dysfunction is a feature of established pre-eclampsia but whether this is a cause or consequence of the disorder is not clear. We tested the hypothesis that endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine (ADMA), the endogenous inhibitor of endothelial nitric oxide synthase, precede and contribute to the development of pre-eclampsia. METHODS: We assessed uterine artery doppler waveforms in 86 women at 23-25 weeks' gestation. We tested endothelial function in all women using flow-mediated dilation of the brachial artery at 23-25 weeks' gestation. Plasma concentrations of ADMA were also measured. FINDINGS: 43 women had normal uterine artery doppler waveforms and subsequently had a normal outcome. The second group of 43 had evidence of impaired placental perfusion and of these, 19 (44%) had normal outcome, 14 (33%) developed intrauterine growth restriction of the fetus (IUGR), and pre-eclampsia arose in ten (23%). Women who developed pre-eclampsia had significantly lower flow-mediated dilation than did women who had normal outcome (3.58% [SD 2.76] vs 8.59% [2.76]; p<0.0001). Irrespective of pregnancy outcome, women with evidence of impaired placental perfusion had significantly higher levels of ADMA than did women with normal doppler waveforms (2.4 micromol/L [IQR 1.97-3.14] vs 0.81 micromol/L [0.49-1.08]; p<0.0001). There was a strong inverse correlation between ADMA and flow-mediated dilation but only in the group of women who eventually developed pre-eclampsia (r=-0.8, p=0.005). INTERPRETATION: Maternal endothelial function is impaired in women who eventually develop pre-eclampsia and it occurs before the development of the clinical syndrome. Furthermore, women with high resistance placental circulation at risk of pre-eclampsia, IUGR, or both have raised concentrations of ADMA, which is a potential contributory factor for pre-eclampsia, and is associated with endothelial dysfunction in some women.
Endothelium-dependent and -independent vascular dysfunction in type 1 diabetes: role of conventional risk factors, sex, and glycemic control.
OBJECTIVE: Defective NO release/response may contribute to increased coronary risk and the loss of sex difference in coronary heart disease in diabetes. We aimed to determine whether NO release/response is impaired in type 1 diabetes and whether any defects are greater in women than men. METHODS AND RESULTS: Forearm blood flow response to vasoactive drugs was assessed by venous plethysmography in 88 diabetic and 69 control subjects aged 30 to 53 years. In diabetic patients, response was 18% lower for acetylcholine (ACh) (P=0.002), 6% lower for bradykinin (P=0.14), and 17% lower for glyceryl trinitrate (GTN) (P<0.001). Women had a higher response to ACh than men (17%, P=0.006). The diabetes-associated defect in ACh was greater in women (25% lower, P=0.01) than men (13% lower, P=0.08), although not significantly (P=0.26 for the interaction). Poorer glycemic control was associated with ACh response (P=0.003) and contributed to the greater defect in diabetic women than men. CONCLUSIONS: The diabetes-associated defect in GTN response was similar in men and women. Established coronary heart disease risk factors did not explain any of the defects in ACh or GTN response associated with diabetes. Type 1 diabetes is associated with impaired responsiveness to NO and with an impairment in ACh-stimulated NO release.
Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia.
BACKGROUND: Nitric oxide (NO) plays an important part in lowering pulmonary vascular resistance after birth, and in persistent pulmonary hypertension of the newborn (PPHN), NO-mediated dilation is dysfunctional. The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) circulates in plasma, and its concentrations are elevated in certain cardiovascular diseases, including pulmonary hypertension. ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the activity of which regulates ADMA concentrations and provides a mechanism for modulating NO synthase in vivo. We investigated the changes in expression and activity of the 2 isoforms of DDAH in lungs from newborn piglets both during normal development and in PPHN. METHODS AND RESULTS: Using Western blotting, we showed that DDAHI expression did not change in the normal developing lung; however, DDAHII increased after birth and reached a peak at 1 day. This was reflected in an increase in total DDAH activity according to an L-citrulline assay. With pulmonary hypertension, no changes in DDAHI expression were observed, but DDAHII expression was markedly decreased compared with age-matched controls. Total DDAH activity was similarly reduced. CONCLUSIONS: These results indicate that each DDAH isoform is differentially regulated during both lung development and PPHN. Suppression of DDAHII isoform expression may be a mechanism underlying PPHN.
Protease-activated receptor 2-mediated vasodilatation in humans in vivo: role of nitric oxide and prostanoids.
BACKGROUND: Systemic hypotension as a consequence of vascular dysfunction is a well-recognized and important feature of critical illness. Although serine protease activation has been implicated as a cause of vascular dysfunction in systemic inflammation, the mechanism is unknown. Recently, a class of receptors with an entirely novel mechanism of action, protease-activated receptors (PARs), has been identified that would explain the link between protease activation and systemic hypotension. Our aim was to test the hypothesis that in vivo activation of protease-activated receptor 2 (PAR-2) in humans would mediate vasodilatation. METHODS AND RESULTS: For these first-in-human studies, an activating peptide for the human PAR-2 receptor was synthesized and administered to healthy volunteers. Using both the dorsal hand vein technique and forearm plethysmography, we studied the effects of PAR-2 activation in human blood vessels and investigated the mechanism of vasodilation. Activation of PAR-2 receptors in vivo dilated human blood vessels in a dose-dependent manner, and the effects were reduced by inhibition of both nitric oxide and prostanoid synthesis CONCLUSIONS: These findings demonstrate that serine protease activity can cause human vasodilation and provide a possible explanation of why serine protease activation in critical illness is associated with vascular dysfunction.
Asymmetric dimethylarginine (ADMA): a key regulator of nitric oxide synthase.
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