Increased microvolt T-wave alternans in children and adolescents with Eisenmenger syndrome.

OBJECTIVE: To determine the values of microvolt T-wave alternans (MTWA) in children and adolescents with Eisenmenger syndrome (ES) and controls. METHODS: Thirteen were included in the study. After analyzing the 24-h ECG recordings, MTWA was considered using three leads (V5, V1, and aVF). Right heart catheterization and 6-minute walk test (6-MWD) were applied to the patients and pro-brain natriuretic peptide levels were assessed; echocardiographic parameters were obtained from both the groups and the results were compared. RESULTS: The MTWA value in lead V5 was 81.08±10.73 µV in the patient group (63.50±18.78 µV in the control group), in lead V1 was 75.00±16.86 µV (73.94±16.77 µV in the control group), and in lead aVF was 73.77±17.81 µV (72.61±16.21 µV in the control group). Comparison of MTWA values between patients and controls revealed that only lead V5 values were statistically different in the ES group. The 6-MWD scores significantly correlated with lead V5. Right atrial volume and right ventricular fractional area change were significantly correlated with lead V1. The Tei index was significantly correlated with lead aVF. CONCLUSION: The MTWA lead V5 value was significantly higher in children with ES than in controls and was also correlated with decreased exercise tolerance.

Platelet count and mean platelet volume predict outcome in adults with Eisenmenger syndrome.

OBJECTIVES: Although a significant proportion of patients with cyanotic congenital heart disease are thrombocytopaenic, its prevalence and clinical significance in adults with Eisenmenger syndrome (ES) is not well studied. Accordingly, we examined the relationship of thrombocytopaenia and mean platelet volume (MPV) to bleeding or thrombotic complications and survival in a contemporary cohort of patients with ES, including patients with Down syndrome. METHODS: Demographics, laboratory and clinical data were analysed from 226 patients with ES under active follow-up over 11 years. RESULTS: Age at baseline was 34.6±11.4 years and 34.1% were men. Mean platelet count and MPV were 152.6±73.3×109/L and 9.6±1.2 fL, respectively. A strong inverse correlation was found between platelet count and haemoglobin concentration and MPV. During the study, there were 39 deaths, and 21 thrombotic and 43 bleeding events. On univariate Cox regression analysis, patients with a platelet count <100×109/L had a twofold increased mortality (HR 2.10, 95% CI 1.10 to 4.01, p=0.024). Platelet count was not associated with an increased risk of thrombosis. However, there was a threefold increased thrombotic risk with MPV >9.5 fL (HR 3.50, 95% CI 1.28 to 9.54, p=0.015). Patients with either severe secondary erythrocytosis (>220g/L) or anaemia (<130g/L) were at higher risk of thrombotic events (HR 3.93, 95% CI 1.60 to 9.67, p=0.003; and HR 4.75, 95% CI 1.03 to 21.84, p=0.045, respectively). CONCLUSIONS: Thrombocytopaenia significantly increased the risk of mortality in ES. Furthermore, raised MPV, severe secondary erythrocytosis and anaemia, but not platelet count, were associated with an increased risk of thrombotic events in our adult cohort.

Non-invasive assessment of liver changes in Eisenmenger patients.

BACKGROUND: Eisenmenger syndrome as a severe form of cyanotic congenital heart disease results in a complex multisystemic disorder. Due to increased systemic venous pressure and the inability to ensure systemic perfusion and metabolic requirements, the liver may develop congestion, fibrosis or cirrhosis. This study aimed to assess hepatic abnormalities in Eisenmenger patients non-invasively. METHODS AND RESULTS: 10 adults with Eisenmenger syndrome (six female; median age 44.2years; range 23-62years) were enrolled and hepatic involvement was assessed - using clinical assessment, laboratory analysis, hepatic fibrotic markers, abdominal sonography and liver stiffness measurements (transient elastography (TE) and acoustic radiation force impulse imaging (ARFI)). Using imaging and laboratory analysis, 60% (6/10) of the Eisenmenger patients had signs of liver fibrosis (5/10) or cirrhosis (1/10). While TE, however, showed no relevant liver abnormalities in any Eisenmenger patient, ARFI detected liver fibrosis in 5/10 and cirrhosis and 1/10 patients. CONCLUSIONS: Adult Eisenmenger patients are at increased risk of hepatic impairment. Non-invasive screening could be helpful in detecting liver alterations. In our small series, however, TE could not detect fibrosis or cirrhosis in any affected patient, while ARFI was very reliable. Patients should be transferred to centres, where a multidisciplinary expert knowledge is available and a close collaboration between cardiologists and hepatologists exists.

Elevated serum HMGB1 in pulmonary arterial hypertension secondary to congenital heart disease.

AIMS: This study investigated the potential value of serum high mobility group box-1 (HMGB1) level in the diagnosis, staging and treatment response of patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD). METHODS AND RESULTS: This was a single-center prospective study in 106 CHD patients. Serum HMGB1 levels were measured by enzymelinked immunosorbent assay. HMGB1 levels were significantly increased in patients with PAH compared to patients without PAH (P<0.01) and healthy controls (P<0.001). HMGB1 levels significantly correlated with pulmonary arterial pressure (P<0.001) and pulmonary vascular resistance (PVR) (P<0.001). In patients with severe PAH, HMGB1 levels were significantly higher in patients with Eisenmenger syndrome (ES) than in patients exhibiting low PVR (P<0.001). Severe PAH and ES was identified by serum HMGB1 with a cutoff value of 13.62ng/mL (P<0.001) with a specificity of 82.8% and a sensitivity of 90%, and a cutoff value of 21.62ng/mL (P=0.001) with a specificity of 85.2% and a sensitivity of 64.3%, respectively. HMGB1 levels were significantly decreased after sildenafil therapy for 6months (P<0.01). CONCLUSIONS: Our study suggests that serum HMGB1 level may be used as a biomarker to identify PAH in CHD patients, assess pulmonary vascular remodeling, and evaluate the treatment response to sildenafil.

Impaired Right, Left, or Biventricular Function and Resting Oxygen Saturation Are Associated With Mortality in Eisenmenger Syndrome: A Clinical and Cardiovascular Magnetic Resonance Study.

BACKGROUND: Patients with Eisenmenger syndrome (ES) have better survival, despite similar pulmonary vascular pathology, compared with other patients with pulmonary arterial hypertension. Cardiovascular magnetic resonance (CMR) is useful for risk stratification in idiopathic pulmonary arterial hypertension, whereas it has not been evaluated in ES. We studied CMR together with other noninvasive measurements in ES to evaluate its potential role as a noninvasive risk stratification test. METHODS AND RESULTS: Between 2003 and 2005, 48 patients with ES, all with a post-tricuspid shunt, were enrolled in a prospective, longitudinal, single-center study. All patients underwent a standardized baseline assessment with CMR, blood test, echocardiography, and 6-minute walk test and were followed up for mortality until the end of December 2013. Twelve patients (25%) died during follow-up, mostly from heart failure (50%). Impaired ventricular function (right or left ventricular ejection fraction) was associated with increased risk of mortality (lowest quartile: right ventricular ejection fraction, <40%; hazard ratio, 4.4 [95% confidence interval, 1.4-13.5]; P=0.01 and left ventricular ejection fraction, <50%; hazard ratio, 6.6 [95% confidence interval, 2.1-20.8]; P=0.001). Biventricular impairment (lowest quartile left ventricular ejection fraction, <50% and right ventricular ejection fraction, <40%) conveyed an even higher risk of mortality (hazard ratio, 8.0 [95% confidence interval, 2.5-25.1]; P=0.0004). No other CMR or noninvasive measurement besides resting oxygen saturation (hazard ratio, 0.90 [0.83-0.97]/%; P=0.007) was associated with mortality. CONCLUSIONS: Impaired right, left, or biventricular systolic function derived from baseline CMR and resting oxygen saturation are associated with mortality in adult patients with ES. CMR is a useful noninvasive tool, which may be incorporated in the risk stratification assessment of ES during lifelong follow-up.

Clinical and Prognostic Value of Depressive Symptoms and N-Terminal Pro-B-Type Natriuretic Peptide in Patients With Eisenmenger Syndrome.

OBJECTIVES: Eisenmenger syndrome (ES) is commonly associated with depressive symptoms and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP). We investigated the predictive value of depressive symptoms and NTproBNP levels for long-term outcomes in patients with ES. METHODS: Blood was drawn to measure NT-proBNP, and depressive symptoms were measured using the Korean version of the Beck Depression Inventory (BDI) in an outpatient clinic sample of 64 patients with ES (67% female; median age = 41.5 years [range, 21.0-74.8 years]). Cardiac events (hospitalization, emergency department visits, and cardiac death) were monitored during 3 years of follow-up. RESULTS: During the follow-up period, 15 (23.4%) patients experienced a cardiac event. The combination of depressive symptoms and NT-proBNP levels better predicted future cardiac events than either variable alone. Patients with NT-proBNP > 510 pg/ml and a total BDI score > 10 had a 9.6 times higher risk for cardiac events than did patients with NT-proBNP ≤ 510 pg/ml or total BDI score ≤ 10 (p < .001). CONCLUSIONS: Depressive symptoms and NT-proBNP levels are both associated with adverse clinical outcomes in ES.

Red blood cell distribution width predicts survival in patients with Eisenmenger syndrome.

BACKGROUND: Previous studies identified an independent relationship between red blood cell distribution width (RDW) and prognosis in patients with pulmonary hypertension of mixed etiologies and idiopathic pulmonary arterial hypertension. This study aimed to investigate the significance of RDW for predicting survival in patients with Eisenmenger syndrome (ES). METHODS: We retrospectively reviewed the clinical records and collected baseline data for patients newly diagnosed with ES in our hospital between January 2005 and October 2009. Follow-up data were collected periodically using a specifically designed network database until December 31, 2012. The end point was all-cause death. RESULTS: A total of 109 patients with ES were included in the study. Twenty-one patients (19.3%) died during a median follow-up period of 4.2 years (interquartile range 3.7-5.0 years). Baseline RDW was significantly correlated with mixed venous oxygen saturation (r=-0.286, p=0.003), arterial oxygen saturation (r=-0.423, p<0.001), mean pulmonary arterial pressure (r=0.271, p=0.004) and total pulmonary resistance (r=0.465, p<0.001). The 1-, 3- and 5-year survival rates for all 109 patients were 94%, 87% and 78%, respectively. Kaplan-Meier analysis showed that patients with RDW ≥13.9% had a lower survival rate than patients with RDW <13.9% (p=0.001). Multivariate Cox regression analysis showed that RDW was an independent prognostic marker in ES, with a hazard ratio of 1.162 (95% CI 1.036-1.302; p=0.010). CONCLUSIONS: Baseline RDW correlates with hemodynamics and is an independent prognostic marker in ES.

Inflammatory markers are elevated in Eisenmenger syndrome.

Inflammation may be an important contributing factor to the progression of Eisenmenger syndrome (ES). Markers of systemic inflammation in ES have not been systematically studied. Inflammatory markers including high-sensitivity C-reactive protein (hs-CRP), interleukin-2 (IL-2), IL-6, and interferon-γ (IFN-γ) were measured in 42 consecutive ES patients (mean age, 24.3 ± 10.6 years) compared with their levels in 22 healthy control subjects. The patients were followed up for a mean duration of 16.3 ± 13.7 months. The levels of inflammatory markers were correlated with clinical and hemodynamic variables at baseline and the outcomes of death, hospitalization, and worsening World Health Organization (WHO) functional class at follow-up evaluation. Compared with the control subjects, ES patients showed a significant elevation in hs-CRP (2.99 ± 3.5 vs 1.1 ± 0.9 mg/dl; p = 0.002) and IFN-γ (41.3 ± 43.6 vs 10.4 ± 6.9 pg/ml; p < 0.001) levels. The levels of IL-2 and IL-6 also were elevated but did not differ significantly from those in the control subjects. The patients with hs-CRP levels higher than 3 mg/dl were significantly older (28.9 ± 10.6 vs 21.5 ± 9.8 years) and had a significantly shorter 6-min walk distance (421.5 ± 133.2 vs 493.3 ± 74.8 m). The levels of inflammatory markers did not correlate with baseline parameters or clinical outcomes. To conclude, the levels of hs-CRP and IFN-γ are significantly elevated in ES. Elevated hs-CRP in ES was associated with older age and shorter 6-min walk distance, but the levels of inflammatory markers were not predictive of clinical events.

High-sensitivity troponin T is associated with poor outcome in adults with pulmonary arterial hypertension due to congenital heart disease.

OBJECTIVE: Pulmonary arterial hypertension due to congenital heart disease (CHD-PAH) has a poor prognosis. We sought to determine whether the biomarker high-sensitivity troponin T (hsTnT) measured on routine visit at the outpatient clinic is associated with prognosis. PATIENTS: Consecutive adult CHD-PAH (86% Eisenmenger syndrome) patients referred for advanced medical therapy between January 2005 and March 2007 in the Academic Medical Center in Amsterdam. Patients with severe renal impairment were excluded. MAIN OUTCOME MEASURE: The primary outcome was mortality. RESULTS: Of all 31 patients (mean age 45 ± 12 years) with CHD-PAH, eight patients died during a median follow-up of 5.6 (range 1.6 to 6.8) years. A hsTnT level >0.014 µg/L was the 99th percentile cutoff of the normal distribution and therefore defined as elevated. At baseline, elevated levels of hsTnT were found in eight patients (26%). In univariate Cox regression, hsTnT elevated at baseline, NT-pro-BNP and right ventricular function were determinants of death (P < .05 for all). Patients with elevated levels of hsTnT showed a significantly higher mortality rate as compared to patients with normal hsTnT levels (62% vs. 13%, P = .005). CONCLUSION: Levels of hsTnT were abnormal in a substantial proportion of CHD-PAH patients. A significant inverse relationship was found between hsTnT and survival.

Usefulness of serum brain natriuretic peptide to predict adverse events in patients with the Eisenmenger syndrome.

The aim of this study was to evaluate the prognostic value of brain natriuretic peptide (BNP) in outpatients with the Eisenmenger syndrome (ES). BNP is often elevated in patients with cyanotic congenital heart disease. The clinical utility of BNP in patients with cyanotic congenital heart disease and the ES has not been clearly delineated. Records of adults with ES who had undergone serum BNP measurement were reviewed. The primary end point was death or heart failure admission. Fifty-three patients were included, with 15 patients (28%) meeting the primary end point (death in 7, heart failure hospitalization in 8). Mean and median baseline BNP in patients meeting the primary end point were 322 ± 346 and 179 pg/ml, compared to 100 ± 157 and 41 pg/ml in those not meeting the primary end point (p = 0.0029). A Cox proportional-hazards model using baseline BNP between the 2 groups yielded a hazard ratio of 1.84 (95% confidence interval [CI] 1.19 to 2.85, p = 0.006). The relative risk for baseline BNP level >140 pg/ml was 4.62 (95% CI 1.80 to 11.3, p = 0.008). Patients who met the primary end point increased their BNP levels by 42.5 pg/ml per year (95% CI 12.09 to 72.95, p = 0.006) compared to 7.2 pg/ml per year (95% CI 2.01 to 12.47, p = 0.007) in patients who did not meet the primary end point. In conclusion, elevated BNP levels are predictive of death or heart failure admission in patients with the ES. A serum BNP level >140 pg/ml is a useful tool in identifying high-risk patients.

Changes in exercise capacity and cardiac performance in a series of patients with Eisenmenger's syndrome transitioned from selective to dual endothelin receptor antagonist.

BACKGROUND: Differences in clinical effects between selective and dual endothelin (ET) receptor antagonists (ERA) in patients with pulmonary arterial hypertension (PAH) are currently unknown. We aimed to assess prospectively how transition from selective (sitaxsentan) to dual (bosentan) ERA affected exercise capacity and cardiocirculatory performance in patients with Eisenmenger's syndrome. METHODS: A series of seven stable patients with Eisenmenger's syndrome aged 40.0 (30.0-56.0) years old treated with sitaxsentan were assessed before and three months after transition to bosentan. Six minute walk test and magnetic resonance to assess LV and RV mass, volume and ejection fraction, and pulmonary flow, and laboratory tests were performed. RESULTS: We observed an increase in LV mass [96.5 (66.0-116.0) vs. 123.0 (93.0-146.0)g; p=0.03], LV ejection fraction [55.0 (44.0-63.0) vs. 65.0 (58.0-70.0)%; p=0.02)], and pulmonary flow [64 (53.0-71.0) vs. 69.0 (55.0-84.0)ml/beat; p=0.046]. This was accompanied by an increase of oxygen saturation, elongation of 6MWD [435.0 (378.0-482.3) vs. 474 (405.0-534.7); p=0.02], decrease of NTproBNP level and increase of ET-1 level. CONCLUSIONS: Three month follow-up of stable patients with Eisenmenger's syndrome transitioned from sitaxsentan to bosentan revealed improvement of exercise capacity despite significant elevation of ET-1 level. Concurrent increase of LV ejection fraction and pulmonary flow might have contributed to these favourable effects.

B-type natriuretic peptide concentrations in contemporary Eisenmenger syndrome patients: predictive value and response to disease targeting therapy.

OBJECTIVE: To assess the relationship between elevated levels of B-type natriuretic peptide (BNP) and outcome in patients with Eisenmenger syndrome. DESIGN: Retrospective study. SETTING: Tertiary centre for adult congenital heart disease. PATIENTS: All patients with Eisenmenger syndrome (n=181, age 36.9±12.1 years, 31% with Down syndrome) in whom BNP concentrations were measured as part of routine clinical care were included. MAIN OUTCOME MEASURES: The study end point was all cause mortality. RESULTS: During a median follow-up period of 3.3 years, 20 patients (7 with Down syndrome) died. Higher BNP concentrations were predictive of all cause mortality on univariate analysis in patients with or without Down syndrome. On multivariable Cox proportional hazard analysis, BNP predicted survival independently of renal function, Down syndrome, or 6 min walk test distance (p=0.004). Temporal increases in BNP concentration were also found to predict mortality. Treatment with disease targeting therapies was associated with a significant reduction in BNP concentrations. CONCLUSIONS: BNP concentrations predict outcome in contemporary Eisenmenger patients. Increases in BNP concentrations over time are also of prognostic significance. In addition, disease targeting therapies may help to reduce BNP concentrations in this population, while treatment-naïve patients have static or rising BNP concentrations.

Does anticoagulation in Eisenmenger syndrome impact long-term survival?

OBJECTIVE: To determine the impact of anticoagulation on survival in Eisenmenger syndrome. BACKGROUND: The use of anticoagulation for primary prevention of adverse events in patients with Eisenmenger syndrome has been proposed but not studied. Strong arguments have been made both for and against anticoagulation based on the known risk of hemoptysis and pulmonary vascular thrombosis. DESIGN AND SETTING: Retrospective cohort study at a tertiary referral hospital. PATIENTS AND INTERVENTIONS: One hundred forty-four patients with established Eisenmenger physiology all underwent initial laboratory, echocardiographic, and catheterization evaluation after initial referral. We retrospectively identified patients who were started on anticoagulation (AC) and compared them to patients who did not receive anticoagulation therapy (non-AC). Baseline variables were compared between groups, as well as between survivors and nonsurvivors. Analyses of prognostic factors and survival were done using Cox and Kaplan-Meier methods. OUTCOME MEASURES: The primary outcome was death since time of baseline evaluation. RESULTS: We identified 48 anticoagulated and 44 non-anticoagulated patients with Eisenmenger physiology (oxygen saturation 82 ± 9%, PaO(2) 48 ± 8 mm Hg, hemoglobin 18.6 ± 4 g/dL). More atrial septal defect patients were in the AC group, but there were no other baseline differences in clinical, functional, or hemodynamic data. After mean follow-up of 7 ± 5.4 years (range 1-31), 11 patients died in the AC and 10 died in the non-AC group. There was no survival difference between groups (log rank test = 1.78; P is not significant). For the entire cohort, mortality was significantly associated with New York Heart Association class 3-4 (hazard ratio = 4.2), evidence of right heart failure (hazard ratio = 13.6), and a mean corpuscular volume <80 fL (hazard ratio = 3.8). Use of anticoagulation did not impact survival. Bleeding complications occurred in seven (16%) of AC patients, including two fatalities. CONCLUSIONS: Anticoagulation had no impact on long-term survival in this limited study. These data may be useful in considering future studies addressing this question.

[Clinical and hemodynamic features of Eisenmenger syndrome patients at the time of first admission: a tertiary referral-center experience]. / Eisenmenger sendromlu hastalarin ilk basvuru anindaki klinik ve hemodinamik özellikleri: Tersiyer merkez deneyimi.

OBJECTIVE: In this study, patients admitted with the diagnosis of Eisenmenger syndrome (ES) in a tertiary referral center were analyzed. METHODS: The data of 20 consecutive patients (mean age: 27.6+1.8 years, 7 male and mean follow-up time: 35.6 ± 9.1 months) with ES were retrospectively analyzed. Demographic characteristics, symptoms, physical examination, laboratory and hemodynamic parameters were analyzed at the time of first admission. RESULTS: The most frequent underlying heart diseases were ventricular septal defect (VSD) with complex congenital disease (n:8, 40%) and isolated VSD (n:7, 35%). 6-minute walking test distance was 347.9 ± 33.7 meters and 15 patients (75%) had a functional capacity of NYHA Class III, at the time of admission. ES was diagnosed with catheterization in all patients and mean systolic pulmonary arterial pressure measured by catheterization was 112 ± 6.8 mmHg. Pulmonary function tests, FVC (forced vital capacity), FEV1 (forced expiratory volume), FEV1/FVC values were respectively, 3.1 ± 0.4, 2.5 ± 0.4 L and 76.7 ± 3.3%. Metabolic tests were performed in all patients at the first visit. Mean VO2 max was 16.7 ± 1.0 ml / kg/min and VE/VCO2 rate was 53.9 ± 3.2%. Although PH and partial pressure of carbon dioxide levels were within normal range in blood gas analysis, oxygen saturation and partial pressure of oxygen levels were low. CONCLUSION: The most common underlying heart disease of ES patients is VSD. In this cases exercise capacity is restricted and this restriction is reflected in laboratory parameters.

Efficacy and safety of bosentan in adults with simple and complex Eisenmenger's syndrome.

BACKGROUND: Eisenmenger's syndrome (ES) is associated with decreased longevity and reduced functional capacity. Targeted pharmacologic therapies improve functional capacity and survival in these patients. We sought to compare the response of patients with simple vs. complex ES following initiation of bosentan. METHODS: ES patients with a history of bosentan use were identified by chart review. Simple ES was defined as ES associated with atrial septal defect, ventricular septal defect, or patent ductus arteriosus. Complex ES consisted of patients with truncus arteriosus and single ventricle congenital heart disease. Six-minute walking distance (6MWD), maximal oxygen consumption (VO(2) max), brain natriuretic peptide (BNP), and resting oxygen saturation were compared between simple and complex ES patients before and after bosentan treatment. RESULTS: Twenty-four patients were included (11 simple, 13 complex). Resting oxygen saturation, 6MWD, VO(2) max, and BNP were not significantly different between the two groups prior to bosentan initiation. Ten patients received bosentan monotherapy, and bosentan was used in combination with sildenafil in 13 (five simple, eight complex). One patient received bosentan with iloprost. Mean duration of therapy was 38 ± 14 months in the simple group and 40 ± 8.1 months in the complex group (P= NS). Posttreatment, 6MWD increased from 274 ± 135 m to 326 ± 106 m in simple ES patients (P= .32). 6MWD in patients with complex ES increased from 332 ± 51 m to 364 ± 109 (P= .028). VO(2) max improved from 13.4 ± 3.8 to 17 ± 6 (P= .54) in the simple group, while VO(2) max in the complex group improved from 12.7 ± 2.3 to 15.5 ± 2.2 (P= .17). There was minimal change in BNP or resting oxygen saturation between the groups. CONCLUSIONS: Treatment with bosentan is both safe and effective in patients with both simple and complex forms of ES.

Clinical efficacy of phosphodiesterase-5 inhibitor tadalafil in Eisenmenger syndrome--a randomized, placebo-controlled, double-blind crossover study.

OBJECTIVES: In a randomized double-blind crossover trial, we compared the efficacy of phosphodiesterase-5 (PDE-5) inhibitor tadalafil with placebo in patients of Eisenmenger Syndrome (ES). The primary end point was the change in 6-minute walk test distance (6 MWD). Secondary end points were the effect of the drug on systemic oxygen saturation (SO(2) ), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), effective pulmonary blood flow (EPBF), and World Health Organization (WHO) functional class. BACKGROUND: ES is a disorder with limited treatment options. Uncontrolled studies have shown PDE-5 inhibitors to be beneficial in patients of ES. METHODS: Twenty-eight symptomatic adult patients of ES with weight ≥30 kg in WHO class II and III were enrolled. Patients were given 40 mg of tadalafil or matching placebo for 6 weeks followed by crossover to the other drug after a washout period of 2 weeks. Assessment of WHO class, exercise capacity by 6 MWD, and various hemodynamic parameters by cardiac catheterization was done at baseline, after 6 weeks and at the end of the study. RESULTS: All patients completed the study. There was significant increase in 6 MWD following drug administration compared with baseline (404.18 ± 69.54 m vs. 357.75 ± 73.25 m, P < .001). Compared with placebo, tadalafil produced significant decrease in PVR (-7.32 ± 1.58, P < .001), resulting in significant increase in EPBF (0.12 ± 0.05, P= .03), SO(2) % (1.72 ± 0.58, P= .007), and WHO functional class (1.96 ± 0.18 vs. 2.14 ± 0.44, P= .025), with no significant change in SVR (P= NS). CONCLUSION: In this first short-term placebo-controlled trial of tadalafil in patients of ES, the drug was well tolerated and significantly improved exercise capacity, functional class, SO(2) , and pulmonary hemodynamics.

Iron deficiency is associated with adverse outcome in Eisenmenger patients.

AIMS: Iron deficiency is common in patients with Eisenmenger syndrome (ES). This study aimed at evaluating (i) whether iron deficiency is related with adverse outcome, (ii) the determinants of iron deficiency, and (iii) the relation between iron reserves and haemoglobin level in a contemporary cohort of ES patients. METHODS AND RESULTS: All ES patients, older than 18 years, selected from the Belgian Eisenmenger registry, were prospectively followed using a web-based registry. Univariate Cox-regression analysis was performed to evaluate the relation with outcome, defined as all-cause mortality, transplantation, and hospitalisation due to cardiopulmonary causes. Bivariate analysis was performed where applicable. A total of 68 patients with a complete dataset (mean age 36.9 ± 14.2 years; 30.9% male) were included. During a median follow-up time of 3.1 years, 21 patients (30.9%) reached the predefined endpoint. New York Heart Association (NYHA) class ≥ III (HR 4.76; 95% CI 1.84-12.30; P = 0.001), iron deficiency (HR 5.29; 95% CI 2.04-13.76; P = 0.001), mean corpuscular volume (MCV) (HR 0.94; 95% CI 0.90-0.99; P = 0.021), and mean corpuscular haemoglobin (MCH) (HR 0.87; 95% CI 0.76-0.98; P = 0.027) were related with adverse outcome. The use of oral anticoagulation and frequent phlebotomies were independently related with iron deficiency (P = 0.005 and P = 0.008). In iron-deplete patients, MCV (R = -0.408; P= 0.014) and MCH (R = -0.437; P = 0.026) were inversely related with haematocrit. In patients with low oxygen saturation, iron reserves were related with haemoglobin levels (R = 0.587; P = 0.001). CONCLUSIONS: Iron deficiency was associated with a higher risk of adverse outcome. Moreover, the use of oral anticoagulation OAC and frequent phlebotomies were related to iron deficiency. Patients under anticoagulation should be monitored rigorously for iron deficiency. However, in patients with low oxygen saturations, careful iron substitution to avoid too high haemoglobin levels is suggested.

Retinal oxygen saturation in patients with systemic hypoxemia.

PURPOSE: To assess spectrophotometric oximetry across a broad range of arterial saturation levels and to study the effect of chronic systemic hypoxemia on retinal oxygen extraction. METHODS: The study included 16 patients with Eisenmenger syndrome, a cyanotic cardiac defect, and 17 healthy volunteers. Oxygen saturation in selected major retinal arteries and veins was assessed using noninvasive spectrophotometric oximetry. Arterial blood gases were determined within 1 day of the ophthalmic examination in blood samples from the femoral artery. RESULTS: The retinal arterial oxygen saturation of 81% ± 9% (mean ± SD) in patients with Eisenmenger syndrome was subnormal and demonstrated more interindividual variation than the 93% ± 3% observed in healthy subjects (P < 0.001). A comparable difference was found for the respective retinal venous oxygen saturations of 44% ± 12% and 59% ± 5% (P < 0.001). Fractional arteriovenous oxygen extraction was comparable between the two groups (37% ± 6% and 34% ± 5%, respectively; P = 0.29). Retinal and femoral artery oxygen saturation were correlated (ρ = 0.82; P < 0.001), the former approximating the latter at least as well as fingertip oximetry. CONCLUSIONS: When compared to arterial blood gas analysis of blood samples drawn by arterial puncture, the gold standard in the field, fundus oximetry was found to be in good overall agreement with the arterial blood samples. Blood flow measurements will be needed to determine whether the systemic hypoxia is completely compensated, as suggested by oxygen extraction being comparable between the two groups.