Mara Morello

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

Ablation of atrial fibrillation: does the addition of three-dimensional magnetic resonance imaging of the left atrium to electroanatomic mapping improve the clinical outcome?A randomized comparison of Carto-Merge vs. Carto-XP three-dimensional mapping ablation in patients with paroxysmal and persistent atrial fibrillation

AIMS To compare in a randomized and prospective fashion the outcome of atrial fibrillation (AF) ablation either after one procedure or after two procedures using the Carto-XP vs. the Carto-Merge mapping system in two different AF populations. METHODS AND RESULTS Two hundred and ninety-nine patients with paroxysmal and persistent AF were enrolled in the study. One hundred and fifty patients with paroxysmal or persistent AF were randomly assigned to the Carto-Merge group and 149 patients to the Carto-XP group. The Carto-Merge patients underwent magnetic resonance imaging (MRI) of left atrium (LA) the day before the ablation. The ablation scheme included electrical disconnection of the pulmonary veins plus linear lesions. In the Carto-Merge patients, the three-dimensional MRI of the LA reconstruction merged with the electroanatomical map, and in the Carto-XP patients, the electroanatomical map guided the procedure. Considering the overall population with paroxysmal AF, 54% maintained sinus rhythm (SR), whereas in the persistent AF population, SR was present in 43% of the patients at the 12-month follow-up. In patients with paroxysmal AF, 52% in the Carto-XP group and 55% in the Carto-Merge group maintained SR without drugs. Procedure durations and exposure to X-ray in the Carto-XP group were 94.6 +/- 17.5 and 40.4 +/- 13.5 min, respectively. In the Carto-Merge group, duration and X-ray exposure were 89 +/- 41.6 and 22.1 +/- 11.4 min, respectively. Considering the patients with persistent AF at the12-month follow-up, 44% in the Carto-XP group and 42% in the Carto-Merge group maintained SR without drugs. Procedure durations and X-ray exposure in the Carto-XP group were 102.9 +/- 22.9 and 58 +/- 8.7 min, respectively. In the Carto-Merge group, both duration and X-ray exposure were 114.4 +/- 50.9 and 28.8 +/- 14.3 min, respectively. CONCLUSION Image integration using Carto-Merge in patients undergoing catheter ablation for paroxysmal and persistent AF does not significantly improve the clinical outcome, but shortens the X-ray exposure.

Activity of GH/IGF-I axis in patients with dilated cardiomyopathy.

There is evidence showing that GH and IGF‐I have specific receptors in the heart and that these hormones are able to promote cardiac remodelling and inotropism. It has been reported that patients with dilated cardiomyopathy (DCM) benefit from treatment with rhGH showing a striking increase in cardiac contractility. However, until now, the activity of GH/IGF‐I axis in DCM has never been clearly assessed.

Impact of TAVI on mitral regurgitation: a prospective echocardiographic study.

Objective: This study aims to assess changes in mitral regurgitation (MR) severity after transcatheter aortic valve implantation (TAVI). Background: Existing data on MR after TAVI are contradictory. Methods: Thirty‐five patients with MR graded ≥ 2+ were followed after undergoing TAVI with either the Edwards Sapien or CoreValve device. Echocardiography was performed the week before and 3 months after the procedure. MR was graded on a scale of 0 to 4+, classified as organic or functional, and the effective regurgitant orifice area (EROA) and MR index were calculated. Results: At baseline, MR was graded 4+ in 4 (11.4%) patients, 3+ in 10 (28.6%), and 2+ in 21 (60%). At follow‐up, MR was graded at 3+ in 4 (11.4%) patients, 2+ in 8 (22.9%), and 1+ in 19 (54.3%); 4 (11.4%) exhibited no MR. EROA (24.4 ± 11.5 mm2 pre‐TAVI vs. 11.2 ± 10.3 mm2 post‐TAVI, P < 0.001) and MR index (1.9 ± 0.3 pre‐TAVI vs. 1.3 ± 0.7 post‐TAVI, P < 0.001) were reduced with TAVI, independent of the etiology. MR decreased by at least 1 grade in 28 (80%) patients, with a reduction ≥2 grades in 10 (28.6%) patients; no patient showed a worsened condition. Subgroup analyses showed that the reduction in MR was significant in patients treated with the Edwards Sapien device but not in patients treated with the CoreValve device. Conclusions: This multiparametric echocardiographic evaluation showed that MR improved significantly after TAVI and that this result may be related to the type of valve implanted.

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.

Lead vegetations in patients with local and systemic cardiac device infections: prevalence, risk factors, and therapeutic effects

AIMS Actual rates of lead vegetations (LVs) in cardiovascular device infections (CDI) are debated in this study. The aim of this study is to characterize prevalence and risk factors of LV in patients with CDI treated with lead extraction (LE). METHODS AND RESULTS Between 2003 and 2011, 293 leads were extracted from 136 patients (age 70.5 ± 14.5 years, 109 male) with infective indications: 39.2% chronic draining sinus, 20.9% pocket infections, and 28.8% systemic infections/sepsis. All patients underwent transesophageal echocardiography (TEE) before LE. Lead vegetation prevalence was 40.4%: 62.2% in systemic infection, but noteworthy in local infection/chronic draining sinus (21.9/36.4%). Younger age, renal disease, ad dialysis were associated with systemic infection. Fever after last intervention, revision, previous reparative procedure, infection at wound/device site and infection >6 months were associated with local infection/chronic draining sinus. Cardiac resynchronization therapy device, fever after last intervention, infection <6 months, renal disease, dialysis, abnormal chest X-ray, fever at admission, pulmonary symptoms, white blood cell (WBC) count, erythrocyte sedimentation rate, C-reactive protein increase and positive blood samples were related to LV. Risk of vegetations was reduced by antibiotic prophylaxis. Multivariate analysis indicated that renal failure and increased WBC count were related to LV. CONCLUSION Lead vegetations were frequently observed in patients with only local symptoms. Therefore, TEE should be mandatory in all patients undergoing LE for infective indications.

New echocardiographic insights in short QT syndrome: More than a channelopathy?

BACKGROUND Short QT syndrome (SQTS) is a congenital ion channel disease characterized by an increased risk of sudden cardiac death. Little is known about the possibility that accelerated repolarization alters mechanical function in SQTS. OBJECTIVES The study investigated the presence of left ventricular dysfunction and mechanical dispersion, assessed by tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE), and their correlation with QT interval duration and genetics. METHODS Fifteen SQTS patients (7 with HERG and 3 with KCNQ1 mutation) were studied. Electrocardiographic and echocardiographic parameters were compared with age- and sex-matched healthy controls. RESULTS When compared to the control group, SQTS patients showed reduced left ventricular contraction (global longitudinal strain: -16.0% ± 3.4% vs -22.6% ± 1.7%, P < .001; myocardial performance index 0.59 ± 0.17 vs 0.34 ± 0.08, P < .001) and a higher incidence of ejection fraction <55% (odds ratio 11, 95% confidence interval 1.045-374, P = .04). Mechanical dispersion assessed by TDI (P < .01) and STE (P < .001) was higher in the SQTS group than in controls; each parameter showed a significant inverse correlation with QT interval but not with QT dispersion. CONCLUSION This study showed that in SQTS systolic function may also be affected. SQTS patients presented a significant dispersion of myocardial contraction. TDI and STE could become part of the evaluation of this rare disease.

STAT3 activity is necessary and sufficient for the development of immune-mediated myocarditis in mice and promotes progression to dilated cardiomyopathy

Myocarditis, often triggered by viral infection, may lead to heart auto‐immunity and dilated cardiomyopathy. What determines the switch between disease resolution and progression is however incompletely understood. We show that pharmacological inhibition of STAT3, the main mediator of IL‐6 signalling and of Th17‐cell differentiation, protects mice from the development of Experimental Auto‐immune Myocarditis reducing liver production of the complement component C3, and can act therapeutically when administered at disease peak. Further, we demonstrate that STAT3 is sufficient when constitutively active for triggering the onset of immune‐mediated myocarditis, involving enhanced complement C3 production and IL‐6 signalling amplification in the liver. Disease development can be prevented by C3 depletion and IL‐6 receptor neutralization. This appears to be relevant to disease pathogenesis in humans, since acute myocarditis patients display significantly elevated circulating IL‐6 and C3 levels and activated heart STAT3. Thus, aberrant IL‐6/STAT3‐mediated induction of liver acute phase response genes including C3, which occurs as a consequence of pre‐existing inflammatory conditions, might represent an important factor determining the degree of myocarditis and its clinical outcome.

Echo Doppler predictors of pulmonary artery hypertension in patients with systemic sclerosis.

Objectives: Evaluate echocardiographic predictors of pulmonary artery hypertension (PAH) in a prospective cohort of patients with systemic sclerosis (SSc). Methods: 38 patients with SSc who did not have PAH and significant left heart disease, with peak tricuspid regurgitant velocity (TRV) ≤ 2.8 m/sec and systolic pulmonary artery pressure (sPAP) < 40 mmHg on echo Doppler were enrolled. Patients underwent: clinical assessment, NT‐proBNP, and DLco measurements. Echo Doppler evaluation included right ventricular (RV) dimensions, tricuspid annular plan systolic excursion, fractional area change, tricuspid DTI systolic velocity, Tei index, pulmonary flow acceleration time (AcT), ratio of TRV to RV outflow tract time–velocity integral (TVI) and a parameter of disturbed RV ejection (TRV/AcT). After a planned 12‐month follow‐up we evaluated the predictive value of these parameters for the development of PAH, as demonstrated by right heart catheterization (RHC). Criteria for RHC were TRV ≥ 3 m/sec or sPAP ≥ 40 mmHg. Results: Four patients developed PAH. Only TRV/TVI and TRV/AcT ratios significantly predicted PAH development (TRV/TVI ratio ≥ 0.16 [predefined and ROC confirmed]: OR 99, CI 95%: 4.865–2015, P = 0.004; TRV/AcT ratio ≥ 0.022 [predefined and ROC confirmed]: OR 12.68, CI 95% 1.163–379.3, P = 0.036). Both parameters showed a good diagnostic power (TRV/TVI ratio: ROC area 79%, sensitivity 75%, specificity 97% and diagnostic accuracy 94.74% for cutoff value of 0.16; TRV/AcT ratio: ROC area 75%, sensitivity 75%, specificity 71% and diagnostic accuracy 72% for cutoff value of 0.022). Conclusions: This prospective study identified increased values of the two ratios TRV/TVI and TRV/AcT as predictors of PAH in SSc. (Echocardiography 2011;28:860‐869)

Activated Met signalling in the developing mouse heart leads to cardiac disease.

BACKGROUND The Hepatocyte Growth Factor (HGF) is a pleiotropic cytokine involved in many physiological processes, including skeletal muscle, placenta and liver development. Little is known about its role and that of Met tyrosine kinase receptor in cardiac development. METHODOLOGY/PRINCIPAL FINDINGS In this study, we generated two transgenic mice with cardiac-specific, tetracycline-suppressible expression of either Hepatocyte Growth Factor (HGF) or the constitutively activated Tpr-Met kinase to explore: i) the effect of stimulation of the endogenous Met receptor by autocrine production of HGF and ii) the consequence of sustained activation of Met signalling in the heart. We first showed that Met is present in the neonatal cardiomyocytes and is responsive to exogenous HGF. Exogenous HGF starting from prenatal stage enhanced cardiac proliferation and reduced sarcomeric proteins and Connexin43 (Cx43) in newborn mice. As adults, these transgenics developed systolic contractile dysfunction. Conversely, prenatal Tpr-Met expression was lethal after birth. Inducing Tpr-Met expression during postnatal life caused early-onset heart failure, characterized by decreased Cx43, upregulation of fetal genes and hypertrophy. CONCLUSIONS/SIGNIFICANCE Taken together, our data show that excessive activation of the HGF/Met system in development may result in cardiac damage and suggest that Met signalling may be implicated in the pathogenesis of cardiac disease.