Serena Bergerone

Exhaled Nitric Oxide and Impaired Oxygenation in Cirrhotic Patients before and after Liver Transplantation

Abnormalities of arterial oxygenation are common in patients with cirrhosis [1], and a widened alveolar-arterial oxygen gradient is reported in more than half of these patients at pretransplantation assessment of pulmonary function [2, 3]. Increasing evidence suggests that the abnormal gas exchange in cirrhotic patients is primarily due to intrapulmonary vasodilatations, which cause ventilation-perfusion mismatch and impaired diffusion [4]. Increased circulation of a pulmonary vasodilator seems to be the favored mechanism for intrapulmonary vasodilatations, and recent evidence points to nitric oxide as the most important vasodilating substance [5]. Increased nitric oxide output in exhaled air has been reported in patients with advanced cirrhosis [6], and a correlation between exhaled nitric oxide concentrations and alveolar-arterial oxygen gradient was recently shown in 45 patients with cirrhosis [7]. After successful liver transplantation, oxygenation has been reported to improve in most patients [3]. In a limited series of three patients with full-blown hepatopulmonary syndrome characterized by severe hypoxemia and evidence of intrapulmonary shunting, the increased amount of exhaled nitric oxide reportedly decreased to within the normal range in one patient after successful liver transplantation [8]. To further investigate the association between nitric oxide produced in the lung and oxygenation abnormalities in patients with cirrhosis, we sought to determine exhaled nitric oxide and oxygenation measures before and after liver transplantation in a selected group of patients with cirrhosis who did not have obvious cardiorespiratory diseases. Methods Patients Twenty patients who underwent successful orthotopic liver transplantation at our hospital from August 1995 to February 1997 were recruited for our study. These patients came from a group of 45 patients who were evaluated at the Outpatient Clinic for Liver Cirrhosis during a scheduled visit [7]. All patients gave their informed consent to participate in the study, which was approved by the ethical committee. Included patients had to have been evaluated within 8 weeks before transplantation. Exclusion criteria were respiratory and cardiovascular disease, including clinically significant pleural effusion (larger than costophrenic angle on chest radiography); tense ascites; inability to perform lung function tests; current smoking habit or a smoking history of more than 10 packs per year (1 pack per year = 20 cigarettes per day for 1 year); forced vital capacity (FVC) and FEV (1) less than 80% of predicted; FEV1/FVC 100 less than 70%; and an airway infection in the previous 4 weeks. All patients were reevaluated 3 to 12 months after transplantation. Laboratory Testing Patients underwent the following studies: pulmonary function tests, arterial blood gas analysis done while patients were breathing room air in a seated position, contrast-enhanced echocardiography, and measurement of nitric oxide in exhaled air. The hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient greater than 15 mm Hg and echocardiographic evidence of intrapulmonary vasodilatations [4]. Lung volumes and carbon monoxide diffusing capacity were obtained according to standardized procedures [9, 10]. The reference values of Quanjer were used [11]. Arterial blood gas samples were obtained by percutaneous radial artery puncture while patients were seated and breathing room air. The alveolar oxygen tension was calculated by using the ideal air Equation and assuming a respiratory exchange ratio of 0.8. The alveolar-arterial oxygen difference was then derived. A gradient less than 15 mm Hg was considered normal. Exhaled nitric oxide was measured on a chemiluminescence analyzer (Dasibi Environmental Corp., Glendale, California) that is sensitive to nitric oxide from 1 to 4000 parts per billion (ppb) by volume, adapted for on-line recording of nitric oxide concentration, at a sample gas flow of 250 mL/min according to European Respiratory Society recommendations [12]. The analyzer was calibrated daily against standard gas mixtures. While seated and wearing a noseclip, patients were asked to inhale nitric oxide-free air (<5 ppb) and to perform a slow expiratory vital capacity test over 20 to 30 seconds with a flow of 5 to 15 L/min against a low resistance (5 to 20 cm H2O). Exhaled air was sampled for nitric oxide analysis by way of a Teflon tubing side arm attached to the mouthpiece. Nitric oxide concentration, flow, and pressure were simultaneously displayed against time on a computer screen. Three successive reproducible recordings were made at 2-minute intervals, and the mean values of the plateau (the last part of expiration) of nitric oxide concentration (expressed in ppb) were recorded. Because of flow dependence of exhaled nitric oxide concentration [13], flow rates at which nitric oxide measurements were performed in each patient before and after transplantation were compared and found to not be statistically significantly different (10.2 2.37 L/min compared with 10.6 2.28 L/min). Twenty nonsmoking healthy persons (mean age, 44.6 11.2 years; 12 men) served as normal controls for exhaled nitric oxide concentrations. Saline contrast-enhanced echocardiography was done by use of a peripheral intravenous line, as reported elsewhere [14]. A positive result on contrast-enhanced echocardiography (that is, indicating intrapulmonary right-to-left shunt) was defined as the delayed appearance (three to six beats after the initial appearance of contrast in the right side of the heart) of microbubbles in the left side of the heart. Statistical Analysis The variability of the outcomes (decrease in alveolar-arterial oxygen gradient and exhaled nitric oxide concentration after transplantation) was estimated from previous studies [3, 8]. The sample size was calculated on the basis of an expected 50% decrease in the outcomes after transplantation compared with pretransplantation values, for a two-tailed value of 0.05 and a value of 0.20. Means and SDs were calculated for each variable. The Student t-test for paired data was used to compare data before and after transplantation; the McNemar test was used when appropriate. Regression analysis was performed by using the least-squares method. A P value of 0.05 or less was considered statistically significant. Role of the Funding Source Our funding source had no role in the collection, analysis, or interpretation of the data or in the submission of the paper for publication. Results Eighteen patients (mean age, 48.3 7 years; 14 men) completed the study. Two patients died after surgery (1 of pneumonia and 1 of stroke) 72 and 85 days after transplantation. Cirrhosis was alcoholic in 7 patients; viral in 8 patients; and autoimmune, cryptogenic, and associated with Wilson disease in 1 patient each. According to the Child-Pugh classification [15], 4 patients had class A cirrhosis, 4 had class B cirrhosis, and 10 had class C cirrhosis. Fifteen patients (83.3%) had esophageal varices. Patients were reevaluated 8.5 3.5 months (range, 3 to 12 months) after transplantation. Post-transplantation lung volumes and diffusion did not significantly differ from pretransplantation values: Total lung capacity increased from 95.4% 9.6% of predicted to 96.7% 10.4% of predicted, FEV1 increased from 100.3% 13.3% of predicted to 103% 13.2% of predicted, FEV1/FVC 100 decreased from 80.5% 4.5% of predicted to 79.5% 4.2% of predicted, and the diffusing capacity of the lung for carbon monoxide divided by alveolar volume decreased from 76.5% 20.9% of predicted to 71.6% 17.2% of predicted. Arterial blood gas data, exhaled nitric oxide concentrations, and findings on echocardiographic evaluation of intrapulmonary shunts before and after transplantation are given in Table 1. Before transplantation, the mean exhaled nitric oxide concentration was significantly higher in patients than in controls (13 4.9 ppb compared with 5.75 1.9 ppb; P < 0.001). Table 1. Arterial Blood Gas Analyses, Exhaled Nitric Oxide Concentrations, and Patients with the Hepatopulmonary Syndrome before and after Liver Transplantation* After transplantation, the alveolar-arterial oxygen gradient significantly decreased (from 17.3 7.1 mm Hg before transplantation to 9 5.2 mm Hg; P < 0.001), as did the exhaled nitric oxide concentration (from 13 4.9 ppb to 6.2 2.8 ppb; P < 0.001). The decrease in exhaled nitric oxide concentration after liver transplantation was significantly correlated with the decrease in alveolar-arterial oxygen gradient (r = 0.56; P = 0.014) (Figure 1). Figure 1. Correlation between the differences in alveolar-arterial oxygen gradient and exhaled nitric oxide concentrations before and after liver transplantation. Before transplantation, intrapulmonary shunts were detected by contrast-enhanced echocardiography in five patients, all of whom met the criteria for the hepatopulmonary syndrome and had an alveolar-arterial oxygen gradient greater than 15 mm Hg. In these patients, the pretransplantation exhaled nitric oxide concentration was significantly higher than that in patients without the hepatopulmonary syndrome (18 5.48 ppb compared with 11.07 3.2 ppb; P < 0.005). After transplantation, the hepatopulmonary syndrome was no longer evident; the alveolar-arterial oxygen gradient returned to normal in all affected patients, even the two patients in whom contrast-enhanced echocardiography still showed intrapulmonary vasodilatations. Discussion We found a highly significant decrease in exhaled nitric oxide concentrations after liver transplantation that was correlated with the decrease in alveolar-arterial oxygen gradient. As in other investigations [1-3], respiratory function assessment done before liver transplantation revealed a high prevalence of widened alveolar-arterial oxygen gradient in our patients with advanced liver disease. The high concentration of exhaled nitric oxide in our pati

Hospital at Home for Elderly Patients With Acute Decompensation of Chronic Heart Failure A Prospective Randomized Controlled Trial

BACKGROUND Although the hospital is the standard venue for short-term medical care, it may be hazardous for older persons. This study was performed to evaluate the feasibility and effectiveness of a physician-led hospital-at-home service for selected elderly patients with acute decompensation of chronic heart failure (CHF). METHODS Prospective, single-blind, randomized controlled trial with 6-month follow-up for patients 75 years or older admitted to the hospital from April 1, 2004, through April 31, 2005, for acute decompensation of CHF. Patients were randomly assigned to the general medical ward (n = 53) or to the Geriatric Home Hospitalization Service (GHHS; n = 48). The GHHS provides diagnostic and therapeutic treatments by hospital health care professionals in the home of the patient. RESULTS Patient mortality at 6 months was 15% in the total sample, without significant differences between the 2 settings of care. The number of subsequent hospital admissions was not statistically different in the 2 groups, but the mean (SD) time to first additional admission was longer for the GHHS patients (84.3 [22.2] days vs 69.8 [36.2] days, P = .02). Only the GHHS patients experienced improvements in depression, nutritional status, and quality-of-life scores. CONCLUSIONS Substitutive hospital-at-home care is a viable alternative to traditional hospital inpatient care for elderly patients with acutely decompensated CHF. This type of care demonstrated clinical feasibility and efficacy in comparison with its alternative. Trial Registration clinicaltrials.gov Identifier: NCT00623571.

Association among oral health, apical periodontitis, CD14 polymorphisms, and coronary heart disease in middle-aged adults.

INTRODUCTION There is evidence to suggest that an association exists between oral infections and coronary heart disease (CHD). Subjects presenting lesions of endodontic origin (LEOs) or pulpal inflammation had an increased risk of developing CHD. However, findings concerning systemic manifestations of apical periodontitis (AP) remain controversial. An association between CD14 gene polymorphisms and atherosclerosis-associated diseases has been shown, but there are no data regarding an association between CD14 polymorphism and AP. This study evaluated associations between clinical oral health status, CD14 polymorphisms, and CHD. METHODS A case-controlled clinical trial was designed to compare middle-aged adults with acute myocardial infarction or unstable angina (n = 51) within 12 months of the acute event defined as first manifestation with healthy controls (n = 49). Participants were matched for age, sex, and socioeconomic status. Indicators of oral disease and compliance were evaluated. CD14 polymorphisms were analyzed by restriction fragment length polymorphism-polymerase chain reaction. RESULTS CHD subjects had a higher prevalence of oral diseases and lower compliance to oral preventive strategies than healthy controls. Multivariate analysis showed a positive association between missing teeth (odds ratio [OR] = 1.37; 95% confidence interval [CI], 1.02-1.85), the number of LEOs (OR = 4.37; 95% CI, 1.69-11.28), chronic periodontitis (OR = 5.87; 95% CI, 1.17-29.4), and CHD. No statistically significant association emerged between the CD14 C(-260)T and the CD14 C(-159)T polymorphism, endodontic or periodontal disease, and CHD. CONCLUSIONS Chronic oral diseases may increase the risk of CHD and may be an unconventional risk factor for CHD.

Role of TGF-β1 haplotypes in the occurrence of myocardial infarction in young Italian patients

BackgroundTransforming growth factor beta 1 (TGF-β1) gene play an important role in the acute myocardial infarction (AMI), however no investigation has been conducted so far in young AMI patients.In this study, we evaluated the influence of TGF-β1 polymorphisms/haplotypes on the onset and progression of AMI in young Italian population.Methods201 cases and 201 controls were genotyped for three TGF-β1 polymorphisms (G-800A, C-509T and Leu10Pro). The main follow-up end-points (mean follow-up, 107 ± 49 months) were death, myocardial infarction or revascularization procedures.ResultsSignificant risk factors were smoking (p < 10-4), family history for coronary artery disease (p < 10-4), hypercholesterolemia (p = 0.001) and hypertension (p = 0.002). The C-509T and Leu10Pro polymorphisms showed significant differences (p = 0.026 and p = 0.004) between cases and controls.The most common haplotypes revealed a possible protective effect (GCT, OR 0.75, 95% CI 0.57–0.99, p = 0.042) and an increased risk of AMI (GTC, OR 1.51, 95% CI 1.13–2.02, p = 0.005), respectively.No statistical differences were observed in genotype distribution in the follow-up study between the two groups: 61 patients with subsequent events (13 deaths) and 108 without events.ConclusionEven though our results need to be further confirmed in larger studies, this is the first study reporting on a possible role of TGFβ1 common haplotypes in the onset of AMI in young patients.

Prognostic incremental role of right ventricular function in acute decompensation of advanced chronic heart failure

The purpose of this study was to evaluate the additional prognostic value of echocardiography in acute decompensation of advanced chronic heart failure (CHF), focusing on right ventricular (RV) dysfunction and its interaction with loading conditions. Few data are available on the prognostic role of echocardiography in acute HF and on the significance of pulmonary hypertension in patients with severe RV failure.

Renin-angiotensin-aldosterone system polymorphisms: a role or a hole in occurrence and long-term prognosis of acute myocardial infarction at young age

BackgroundThe renin-angiotensin-aldosterone system (RAAS) is involved in the cardiovascular homeostasis as shown by previous studies reporting a positive association between specific RAAS genotypes and an increased risk of myocardial infarction. Anyhow the prognostic role in a long-term follow-up has not been yet investigated.Aim of the study was to evaluate the influence of the most studied RAAS genetic Single Nucleotide Polymorphisms (SNPs) on the occurrence and the long-term prognosis of acute myocardial infarction (AMI) at young age in an Italian population.MethodsThe study population consisted of 201 patients and 201 controls, matched for age and sex (mean age 40 ± 4 years; 90.5% males). The most frequent conventional risk factors were smoke (p < 0.001), family history for coronary artery diseases (p < 0.001), hypercholesterolemia (p = 0.001) and hypertension (p = 0.002). The tested genetic polymorphisms were angiotensin converting enzyme insertion/deletion (ACE I/D), angiotensin II type 1 receptor (AGTR1) A1166C and aldosterone synthase (CYP11B2) C-344T. Considering a long-term follow-up (9 ± 4 years) we compared genetic polymorphisms of patients with and without events (cardiac death, myocardial infarction, revascularization procedures).ResultsWe found a borderline significant association of occurrence of AMI with the ACE D/I polymorphism (DD genotype, 42% in cases vs 31% in controls; p = 0.056). DD genotype remained statistically involved in the incidence of AMI also after adjustment for clinical confounders.On the other hand, during the 9-year follow-up (65 events, including 13 deaths) we found a role concerning the AGTR1: the AC heterozygous resulted more represented in the event group (p = 0.016) even if not independent from clinical confounders. Anyhow the Kaplan-Meier event free curves seem to confirm the unfavourable role of this polymorphism.ConclusionPolymorphisms in RAAS genes can be important in the onset of a first AMI in young patients (ACE, CYP11B2 polymorphisms), but not in the disease progression after a long follow-up period. Larger collaborative studies are needed to confirm these results.

Prognostic implications of detection of troponin I in patients with unstable angina pectoris.

In our study, troponin I was not a predictor of cardiac events and a negative troponin I test did not exclude the presence of severe coronary artery disease. A positive troponin I test in patients with unstable angina identified a subgroup with probable, more active coronary disease (with higher levels of C-reactive protein).

The membrane attack complex of complement contributes to plasmin‐induced synthesis of platelet‐activating factor by endothelial cells and neutrophils

Thrombolytic agents, used to restore blood flow to ischaemic tissues, activate several enzymatic systems with pro‐inflammatory effects, thus potentially contributing to the pathogenesis of ischaemia–reperfusion injury. Platelet‐activating factor (PAF), a phospholipid mediator of inflammation, has been implicated in the pathogenesis of this process. We previously showed that the infusion of streptokinase (SK) induces the intravascular release of PAF in patients with acute myocardial infarction (AMI), and that cultured human endothelial cells (EC) synthesized PAF in response to SK and plasmin (PLN). In the present study, we investigated the role of the membrane attack complex (MAC) of complement in the PLN‐induced synthesis of PAF. In vivo, we showed a correlation between the levels of soluble terminal complement components (sC5b‐9) and the concentrations of PAF detected in blood of patients with AMI infused with SK. In vitro both EC and polymorphonuclear neutrophils (PMN), incubated in the presence of PLN and normal human serum, showed an intense staining for the MAC neoepitope, while no staining was detected when they were incubated with PLN in the presence of heat‐inactivated normal human serum. Moreover, the insertion of MAC on EC and PMN plasmamembrane elicited the synthesis of PAF. In conclusion, our results elucidate the mechanisms involved in PAF production during the activation of the fibrinolytic system, showing a role for complement products in this setting. The release of PAF may increase the inflammatory response, thus limiting the beneficial effects of thrombolytic therapy. Moreover, it may have a pathogenic role in other pathological conditions, such as transplant rejection, tumoral angiogenesis, and septic shock, where fibrinolysis is activated.

THE STORM (acute coronary Syndrome in paTients end Of life and Risk assesMent) study

Introduction Elderly patients with coexisting frailty and multiple comorbidities frequently present to the emergency department (ED). Because non-cardiovascular comorbidities and declining health status may affect their life expectancy, management of these patients should start in the ED. This study evaluated the role of Gold Standards Framework (GSF) criteria for identifying patients with acute coronary syndromes (ACS) approaching end of life. Methods All consecutive patients admitted to the ED and hospitalised with a diagnosis of ACS between May 2012 and July 2012 were included. According to GSF criteria, patients were labelled as positive GSF status when they met at least one general criterion and two heart disease criteria; furthermore, traditional cardiovascular risk scores (the Global Registry for Acute Coronary Events (GRACE) score and the Age, Creatinine and Ejection Fraction (ACEF) score) were calculated and WHOQOL-BREF was assessed. Mortality and repeat hospitalisation due to cardiovascular and non-cardiovascular causes were evaluated at 3-month and 12-month follow-up. Results From a total of 156 patients with ACS enrolled, 22 (14%) had a positive GSF. A positive GSF was associated with higher rate of non-cardiovascular events (22.7% vs 6.7%; p=0.03) at 3 months and higher rates of both cardiovascular and non-cardiovascular events (36% vs 16.4%; p=0.04 and 27.3% vs 6.7%; p=0.009, respectively) at 12 months. In multivariate analysis, an in-hospital GRACE score was a predictor of cardiovascular events, while a positive GSF independently predicted non-cardiovascular events. Conclusions The GSF score independently predicts non-cardiovascular events in patients presenting with ACS and may be used along with traditional cardiovascular risk scores in choosing wisely the most appropriate treatment. The present results need to be externally validated on larger samples.

Atrial natriuretic factor and concomitant hormonal, hemodynamic and renal function changes after slow continuous ultrafiltration

We treated a patient with refractory biventricular heart failure, dilutional hyponatremia and prerenal azotemia, by means of ultrafiltration. After ultrafiltration, gas exchange and cardiac output improved, with concomitant reduction of systemic and pulmonary vascular resistances. Despite a decrease of right atrial and wedge pressure, atrial natriuretic factor rose and plasma renin activity decreased.