Pulmonary arterial hypertension in hereditary hemorrhagic telangiectasia associated with ACVRL1 mutation: a case report.

INTRODUCTION: Hereditary hemorrhagic telangiectasia is an autosomal dominant condition with an estimated prevalence of 1 in 5000. It is characterized by the presence of abnormalities of vascular structures, and may affect many organ systems, including the lungs, brain, spinal cord, gastrointestinal tract, and liver. A causative mutation is identified in approximately 97% of patients with definite hereditary hemorrhagic telangiectasia in one of three genes including a mutation in endoglin, a mutation in a locus mapped to chromosome 5, and an activin receptor-like kinase-1 (ACVRL1) mutation that is associated with an increased incidence of primary pulmonary hypertension. Pulmonary arterial hypertension is a rare (15-25 cases per million people) but severe vascular disorder. Heritable pulmonary arterial hypertension is associated with several gene mutations, with 75% having a mutation in the bone morphogenetic protein receptor 2 (BMPR2). However, the remaining 25% of patients have other associated genetic mutations including ACVLR1, which is also associated with hereditary hemorrhagic telangiectasia. Pulmonary arterial hypertension is a rare complication in patients with hereditary hemorrhagic telangiectasia (< 1% of the hereditary hemorrhagic telangiectasia population). We describe a case report with this rare occurrence. CASE PRESENTATION: A 70-year-old white/caucasian Irish male presented for screening for hereditary hemorrhagic telangiectasia due to a history of recurrent epistaxis (once/week) and a family history suggestive of pulmonary hypertension. Genetic testing confirmed an ACVRL1 mutation, while an echocardiogram and right heart catheterization confirmed pulmonary arterial hypertension. On examination, he had several mucocutaneous telangiectasia across his face. He was commenced on tadalafil and macitentan. However, this led to increased iron deficiency anemia and pedal edema. Selexipag was also added to his drug regime. He continues to require intermittent admissions for diuresis and blood transfusions. CONCLUSION: The association of hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension is rare (< 1%). Here we describe a case of hereditary hemorrhagic telangiectasia complicated with pulmonary arterial hypertension as a result of an ACVRL1 mutation. We also describe the clinical challenges of treating these two conditions together, as treatment options for pulmonary arterial hypertension tend to worsen hereditary hemorrhagic telangiectasia symptoms.

Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV.

Recent studies from this laboratory have demonstrated that angiotensin II (Ang II) stimulates the expression of plasminogen activator inhibitor 1 (PAI-1) in cultured endothelial cells. This response does not appear to be mediated via an interaction with either the AT1 or the AT2 receptor subtype. Since a novel angiotensin receptor has been identified in a variety of tissues that specifically binds the hexapeptide Ang IV (Ang II, [3-8]), we therefore examined the effects of Ang IV on the expression of PAI-1 mRNA in bovine aortic endothelial cells. Ang IV stimulated dose- and time-dependent increases in the expression of PAI-1 mRNA. The effect of Ang IV (10 nM) was not inhibited by Dup 753 (1.0 microM), a highly specific antagonist of the AT1 receptor, or by PD123177 (1.0 microM), a highly specific antagonist of the AT2 receptor. In contrast, the AT4 receptor antagonist, WSU1291 (1.0 microM), effectively prevented PAI-1 expression. Although larger forms of angiotensin (i.e., Ang I, Ang II, and Ang III) are capable of inducing PAI-1 expression, this property is lost in the presence of converting enzyme or aminopeptidase inhibitors. These results indicate that the hexapeptide Ang IV is the form of angiotensin that stimulates endothelial expression of PAI-1. This effect appears to be mediated via the stimulation of an endothelial receptor that is specific for Ang IV.

Trial of a novel plasma gas disinfection system (Radica) to reduce mattress residual bacterial contamination in the acute hospital setting: a preliminary study.

BACKGROUND: In routine clinical practice, mattresses are manually cleaned using specialised cleaning and high-level disinfecting fluids. While effective against a wide range of organisms, the success of this approach is dependent on a thorough and complete application and is likely to be susceptible to human error and thus variable. The efficacy of available infection control measures to reduce such mattress contamination is unknown as it is not subject to quality control measures. There is a pressing need to identify more effective methods to prevent cross contamination within the medical environment, given the lack of available treatment strategies. AIM: The purpose of this study is to investigate the ability of a new technology, gaseous technology, to reduce colonization levels, compared to standard cleaning, and so attenuate superficial nosocomial infections. METHODS: We conducted a prospective, single-centre, open-label, non-randomized trial with blinded outcome assessments, comparing the standard cleaning of hospital mattresses with a novel plasma based disinfection system Radica™, followed by a standard post-cleaning culturing protocol (five swabs/mattress). RESULTS: The median (interquartile range) maximal colony count per mattress for the 20 Radica versus 7 routinely cleaned mattresses was 1 (1-2.7) versus Too-Numerous-to-Count (TNTC) (32-TNTC), respectively, p = 0.002. Of the 20 Radica™ treated mattresses, 12 (60 %) had no positive culture result while all of the standard cleaned mattresses had at least two positive cultures. CONCLUSION: The plasma based Radica disinfection system reduces mattress bacterial colonization levels as compared to routine cleaning. This is a potentially important technology in the health care system to reduce surface colonisation and hence nosocomial infections.

Cardiovascular safety of anti-diabetic drugs.

Cardiovascular disease is the leading cause of morbidity and mortality among patients with diabetes, underscoring the importance of choosing anti-diabetic drugs that do not increase cardiovascular risk but might reduce the risk of cardiovascular events. Most type 2 diabetic patients die from cardiovascular causes despite the beneficial effects of blood pressure (BP) and lipid-lowering medications. The prevalence of patients with cardiovascular disease and diabetes mellitus is growing exponentially. Approximately 40% of patients hospitalized with heart failure and reduced ejection fraction have diabetes mellitus. The recent trials conducted in patients with heart failure who had diabetes showed a different response to standard medication, with these patients being more prone to develop side effects than patients with the same degree of heart failure but without diabetes mellitus. Therefore, careful selection of drug therapy paying particular attention to cardiovascular safety is important in optimizing diabetic therapy. This review discusses the efficacy and safety of the most commonly prescribed anti-diabetic drugs in the context of cardiovascular impact.

Plasma S-adenosylhomocysteine is a more sensitive indicator of cardiovascular disease than plasma homocysteine.

BACKGROUND: Although plasma total homocysteine has been identified as an independent risk factor for vascular disease in a multitude of studies, there is a considerable overlap in values between patients at risk and control subjects. The difference in values can be used to distinguish statistically between the 2 groups, provided each group is large enough; however, discriminating between individual patients at risk and control subjects is difficult. OBJECTIVE: We investigated whether the precursor of homocysteine, S-adenosylhomocysteine, is a more sensitive indicator of risk. DESIGN: We measured plasma total homocysteine, S-adenosylhomocysteine, S-adenosylmethionine, creatinine, folate, and vitamin B-12 in 30 patients with proven cardiovascular disease and 29 age- and sex-matched control subjects. RESULTS: The homocysteine values (+/-SD) were 12.8 +/- 4.9 (95% CI: 11.0, 14.7) micromol/L for patients and 11.0 +/- 3.2 (9.8, 12.2) micromol/L for control subjects. The S-adenosylhomocysteine values were 40.0 +/- 20.6 (32.3, 47.7) nmol/L for patients and 27.0 +/- 6.7 (24.5, 30.0) nmol/L for control subjects (P = 0.0021). The S-adenosylmethionine values were 121.8 +/- 42.9 (105.8, 137.8) nmol/L for patients and 103.9 +/- 21.8 (95.6, 112.2) nmol/L for control subjects (P = 0.0493). The creatinine values were 110 +/- 27 (97, 120) micromol/L for patients and 97 +/- 9 (80, 100) micromol/L for control subjects (P = 0.0025). Values for folate and vitamin B-12 did not differ significantly between groups. CONCLUSIONS: Plasma S-adenosylhomocysteine appears to be a much more sensitive indicator of the difference between patients with cardiovascular disease and control subjects than is homocysteine. Both plasma total homocysteine and S-adenosylhomocysteine are significantly correlated with plasma creatinine in patients.

Optimal Albunex dosing for enhancement of Doppler tricuspid regurgitation spectra.

Intravenous albunex was more effective than agitated saline in enhancing incomplete Doppler echocardiography spectra for tricuspid regurgitation without a significant alteration in the maximal detected velocity. The optimal dose was 1 to 4 ml in most patients, using an initial dose of 1 ml and titrating further dosing on the basis of the initial contrast effect.

Diagnosing left ventricular dysfunction after myocardial infarction: the Dundee algorithm.

Large-scale trials of angiotensin converting enzyme (ACE) inhibitors after acute myocardial infarction (AMI) suggest that the benefits are greatest in patients with left ventricular (LV) dysfunction. However, early evaluation of LV function in all patients after AMI by current methods can be difficult due to a lack of resources and skilled personnel. Thus a clinical algorithm that could be used at the bedside to reliably identify patients with a left ventricular ejection fraction (LVEF) < or = 40% would be helpful as an occasional alternative to echocardiography. We have devised such an algorithm based on the presence of one of: (i) clinical signs of heart failure; (ii) an index Q-wave anterior myocardial infarction; (iii) lack of thrombolytic therapy when there is a history of two or more previous myocardial infarctions and a CK rise > 1000 U/l. We tested this new algorithm prospectively in the coronary care units of two hospitals (one UK and one USA). In the UK centre, the sensitivity and specificity of the algorithm at identifying patients with a LVEF < or = 40% were 82% and 72%, respectively. In the US centre, the sensitivity of the algorithm was 91% and the specificity 78% at identifying patients with LV dysfunction. We have validated a simple clinical algorithm which can be used at the bedside for identifying patients who would benefit from an ACE inhibitor after AMI.

QT dispersion is reduced after valve replacement in patients with aortic stenosis.

OBJECTIVE: To investigate whether QT dispersion is a reliable index of the severity of aortic stenosis and left ventricular hypertrophy in the setting of aortic stenosis. DESIGN: A retrospective analysis of the results of echocardiography and electrocardiography before and after aortic valve replacement. SETTING: Tertiary centre. PATIENTS: 36 men (30 white and six black) with symptomatic aortic stenosis requiring valve replacement. RESULTS: All patients had significant aortic stenosis (mean (SD) aortic valve area 0.68 (0.18) cm2) and evidence of left ventricular hypertrophy (left ventricular mass index (LVMI): 267 (90) g/m2). Before aortic valve replacement, QT dispersion was correlated with mean aortic valve area and LVMI (r = 0.697, p < 0.001, and r = 0.59, p < 2.4 x 10(-6), respectively). QT dispersion and QT corrected for heart rate dispersion decreased from 133 (54) to 71 (33) ms and from 151 (64) to 94 (76) ms, respectively (p < 0.001 for both). LVMI regressed after aortic valve replacement to 190 (79) g/m2, p < 0.01. CONCLUSIONS: QT dispersion is increased in association with LVMI in patients with significant symptomatic aortic stenosis. Aortic valve replacement reduces QT dispersion and LVMI. QT dispersion could be a useful indicator of risk and risk reduction in patients with significant symptomatic aortic stenosis.

Doppler echocardiography in cardiac tamponade and constrictive pericarditis.

Doppler echocardiography has greatly facilitated the assessment of patients with compressive cardiac disease. Patients in whom cardiac tamponade or pericardial constriction are suspected should undergo a complete echocardiographic examination including careful Doppler analysis of transmitral flow and inflow through the hepatic vein or superior vena cava (SVC). Monitoring of both the electrocardiogram and the phase of respiration are an integral part of this examination. Patients with cardiac tamponade exhibit a > 25% reduction in E wave velocity during the first inspiratory cardiac cycle; they exhibit predominant systolic inflow through the hepatic vein or SVC (with a predominant X descent with little or no Y descent). In constrictive pericarditis the pattern of transmitral flow variation is comparable to that observed in cardiac tamponade, however, a prominent Y descent is often observed on hepatic vein or SVC Doppler study. Similar changes with respiration may be observed in mitral inflow in obese patients or in those with chronic obstructive pulmonary disease, however, in these conditions the nadir of E wave velocity is observed 2-3 cardiac cycles after the first inspiratory beat. Restrictive cardiomyopathy may produce a similar systemic venous flow pattern, but increased inspiratory flow reversals and lack of respiratory variation in transmitral flow velocity distinguish it from constrictive pericarditis.

A prostacyclin analog impairs the response to tissue-type plasminogen activator during coronary thrombolysis: evidence for a pharmacokinetic interaction.

Inhibition of thromboxane (TX) A2 with aspirin enhances the response to coronary thrombolysis. However, experimental evidence suggests that platelet activation during coronary thrombolysis is mediated by a number of agonists, in addition to TXA2. As a consequence, greater benefit would be expected with antiplatelet agents that have a broader spectrum of activity. However, a recent clinical trial, combining tissue plasminogen activator (t-PA) with the prostacyclin analog, iloprost, did not detect such a benefit. To address the mechanism of this response, we compared the effect of iloprost, a stable analog of prostacyclin, with GR32191, a TXA2/prostaglandin endoperoxide receptor antagonist, on the response to i.v. t-PA in a closed chest, canine model of coronary thrombosis. GR32191 reduced the time to reperfusion by 47% (n = 6, P less than .05), consistent with a role for TXA2-mediated platelet activation in impairing thrombolysis. In contrast, iloprost increased the time to reperfusion by 50% (n = 5, P = NS) and in four of nine animals reperfusion failed to occur despite inhibition of platelet aggregation. In a separate series of experiments, steady-state plasma t-PA clearance increased by 38% (407 +/- 49 vs. 294 +/- 42 ml/min; n = 8, P less than .02) during infusion of iloprost and recovered after its withdrawal. This appeared to be a specific effect, as infusion of nitroglycerin at a dose which induced a similar fall in blood pressure altered neither the time to reperfusion nor plasma t-PA. Iloprost impairs the thrombolytic response to t-PA via an increase in the clearance of this agent.

Platelet and vascular function during coronary thrombolysis with tissue-type plasminogen activator.

Platelet activation may limit the response to tissue-type plasminogen activator (t-PA) during coronary thrombolysis in humans. As an index of platelet activation, we assessed thromboxane A2 biosynthesis during coronary thrombolysis with intravenous t-PA in patients with acute myocardial infarction. Urinary 2,3-dinor-thromboxane B2, a metabolite of thromboxane A2, was increased to a peak of 3,327 +/- 511 pg/mg creatinine (n = 12) following administration of intravenous t-PA and remained elevated for 48 hours. This increase was abolished by pretreatment with aspirin 325 mg orally (n = 6), indicating de novo biosynthesis of thromboxane A2 rather than washout of preformed metabolites during reperfusion. Prostacyclin (PGI2) biosynthesis, determined by excretion of 2,3-dinor-6-keto-PGF1 alpha, also increased after t-PA administration. However, this increase was less pronounced in patients who reperfused (28 +/- 3.3 ng.hr/mg creatinine) than in patients who failed to reperfuse (118 +/- 30 ng.hr/mg creatinine, p less than 0.05). These data provide evidence of platelet activation during coronary thrombolysis with t-PA. In patients who reperfuse, the reduction in PGI2 biosynthesis may be a marker of reperfusion injury to the vasculature and may further amplify platelet activation.

The urokinase-type plasminogen activator receptor mediates tyrosine phosphorylation of focal adhesion proteins and activation of mitogen-activated protein kinase in cultured endothelial cells.

Urokinase-type plasminogen activator (uPA) binds to cells via a specific glycosylphosphatidylinositol-anchored receptor. Although occupancy of the uPA receptor (uPAR) has been shown to alter cellular function and to induce gene expression, the signaling mechanism has not been characterized. Urokinase induced an increase in the tyrosine phosphorylation of multiple proteins in bovine aortic endothelial cells. In contrast, low molecular weight uPA did not induce this response. Analysis by immunoblotting demonstrated tyrosine phosphorylation of focal adhesion kinase (FAK), the focal adhesion-associated proteins paxillin and p130(cas), and mitogen-activated protein kinase (MAPK) following the occupancy of the uPAR by uPA. Treatment of cells with phosphatidylinositol-specific phospholipase C, which cleaves glycosylphosphatidylinositol-linked proteins from the cell surface, blocked the uPA-induced tyrosine phosphorylation of FAK, indicating the requirement of an intact uPAR on the cell surface. The uPA-induced activation of MAPK was completely inhibited by genistein, but not by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3, 4-d]pyrimidine, a specific inhibitor of Src family kinases. Thus, this study demonstrates a novel role for the uPAR in endothelial cell signal transduction that involves the activation of FAK and MAPK, which are mediated by the receptor-binding domain of uPA. This may have important implications for the mechanism through which uPA influences cell migration and differentiation.

Pharmacokinetics of tissue-type plasminogen activator during acute myocardial infarction in men. Effect of a prostacyclin analogue.

BACKGROUND: Coronary reocclusion complicates the thrombolytic therapy of acute myocardial infarction despite the routine use of aspirin. This is consistent with experimental studies demonstrating that multiple agonists, in addition to thromboxane A2, mediate the platelet activation underlying reocclusion. Consequently, a more potent antiplatelet therapy with a broader spectrum of activity than aspirin may be required in this setting. Prostacyclin and its more stable analogue, iloprost, inhibit platelet aggregation to all known agonists and exert an additional effect over aspirin alone. Experiments in animal models have demonstrated, however, that iloprost increases the clearance of tissue-type plasminogen activator (t-PA) and impairs thrombolysis in vivo. This study examines whether a similar interaction occurs in humans. METHODS AND RESULTS: Twelve patients with acute myocardial infarction received t-PA intravenously, 60 mg in the first hour and a maintenance infusion of 13.3 mg/hr for 3 hours. Patients were assigned in a double-blind fashion to iloprost (2 ng/kg/min) or placebo following the initial 90 minutes of the maintenance infusion of t-PA. Iloprost decreased mean arterial blood pressure (-10 +/- 2.9 mm Hg, p less than 0.05) but did not alter heart rate. Steady-state plasma iloprost concentration was 591 +/- 64 pmol/l. At this concentration, iloprost markedly inhibited platelet aggregation in vitro, particularly in the presence of aspirin. Steady-state clearance of t-PA was unchanged by iloprost (454 +/- 65 versus 443 +/- 136 ml/min in controls, p = NS). Furthermore, neither elimination kinetics nor plasma protein binding of t-PA was altered by iloprost. CONCLUSIONS: At plasma levels that exert a potent antiplatelet effect, iloprost did not alter the pharmacokinetics of t-PA in men. Prostacyclin analogues may prove useful as an adjunct to plasminogen activators, particularly in patients at high risk for thrombotic reocclusion.

Liver regeneration is transiently impaired in urokinase-deficient mice.

To test the hypothesis that urokinase-type plasminogen activator (uPA) plays an important role in liver regeneration in vivo, partial hepatectomy was performed on wild-type and uPA-deficient (uPA-/-) mice. Mice were studied at 24, 44, and 96 h and at 8 days and 4 wk post-partial hepatectomy for evidence of regeneration, as measured by mitotic indexes and [3H]thymidine incorporation. In wild-type mice, thymidine incorporation peaked at 44 h and this index was reduced by 47% in uPA-/- mice (P = 0.02). By 8 days, however, liver mass was comparable in both groups. Histological analysis revealed the presence of focal areas of fibrin deposition and cellular loss by 24 h that were more severe and prevalent in uPA-/- mice than in wild-type mice (62 and 23%, respectively; chi2 = 3.939, P = 0.047). In contrast, regeneration was not impaired in uPA receptor (uPAR)-deficient mice at 24 and 44 h. Taken together, these data indicate that uPA, independent of its interaction with the uPAR, plays an important role in liver regeneration in vivo.