Ryo Inuzuka

Improved Survival Among Patients With Eisenmenger Syndrome Receiving Advanced Therapy for Pulmonary Arterial Hypertension

Background— Advanced therapy (AT) for pulmonary arterial hypertension in the context of congenital heart disease (Eisenmenger syndrome) improves pulmonary hemodynamics, functional class, and the 6-minute walk test. We examined the potential effect of AT on survival in this population. Methods and Results— Data on all Eisenmenger patients attending our center over the past decade were collected. Survival rates were compared between patients on and off AT with the use of a modified version of the Cox model, which treats AT as a time-varying covariate. Baseline differences were adjusted for the use of propensity scores. A total of 229 patients (aged 34.5±12.6 years; 35.4% male) were included. The majority had complex anatomy, and 53.7% were in New York Heart Association class ≥III at baseline assessment. Mean resting saturations were 84.3%. Sixty-eight patients (29.7%) either were on AT or had AT initiated during follow-up. During a median follow-up of 4.0 years, 52 patients died, only 2 of them while on AT. Patients on AT were at a significantly lower risk of death, both unadjusted and after adjustment for baseline clinical differences by propensity score regression adjustment (C statistic=0.80; hazard ratio, 0.16; 95% confidence interval, 0.04 to 0.71; P=0.015) and propensity score matching (hazard ratio, 0.10; 95% confidence interval, 0.01 to 0.78; P=0.028). Conclusions— AT for pulmonary arterial hypertension in a contemporary cohort of adults with Eisenmenger syndrome was associated with a lower risk of death. Survival benefits should be considered together with improved hemodynamics and functional class when decisions are made about AT in this population.

Contemporary predictors of death and sustained ventricular tachycardia in patients with repaired tetralogy of Fallot enrolled in the INDICATOR cohort

Objective Patients with repaired tetralogy of Fallot (TOF) experience increased rates of mortality and morbidity in adulthood. This study was designed to identify risk factors for death and ventricular tachycardia (VT) in a large contemporary cohort of patients with repaired TOF. Methods Subjects with repaired TOF from four large congenital heart centres in the USA, Canada and Europe were enrolled. Clinical, ECG, exercise, cardiac magnetic resonance (CMR) and outcome data were analysed. Results Of the 873 patients (median age 24.4 years), 32 (3.7%) reached the primary outcome (28 deaths, 4 sustained VT; median age at outcome 38 years; median time from CMR to outcome 1.9 years). Cox proportional-hazards regression identified RV mass-to-volume ratio ≥0.3 g/mL (HR, 5.04; 95% CI 2.3 to 11.0; p<0.001), LV EF z score<−2.0 (HR, 3.34; 95% CI 1.59 to 7.01; p=0.001), and history of atrial tachyarrhythmia (HR, 3.65; 95% CI 1.75 to 7.62; p=0.001) as outcome predictors. RV dysfunction was predictive of the outcome similar to LV dysfunction. In subgroup analysis of 315 subjects with echocardiographic assessment of RV systolic pressure, higher pressure (HR 1.39; 95% CI 1.19 to 1.62; p<0.001) was associated with death and sustained VT independent of RV hypertrophy and LV dysfunction. Conclusions RV hypertrophy, ventricular dysfunction and atrial tachyarrhythmias are predictive of death and sustained VT in adults with repaired TOF. These findings may inform risk stratification and the design of future therapeutic trials.

Left Ventricular Longitudinal Function Predicts Life-Threatening Ventricular Arrhythmia and Death in Adults With Repaired Tetralogy of Fallot

Background— Sudden cardiac death and life-threatening ventricular arrhythmia remain a concern in adult patients with repaired tetralogy of Fallot. Longitudinal left ventricular (LV) function is sensitive in detecting early myocardial damage and may have prognostic implications in this setting. Methods and Results— We included 413 tetralogy of Fallot patients (age, 36±13 years; QRS duration, 148±27 milliseconds; LV ejection fraction, 55±10%). A composite end point of sudden cardiac death/life-threatening ventricular arrhythmia (sustained ventricular tachycardia, resuscitated sudden cardiac death, or appropriate implantable cardioverter-defibrillator discharge) was used. During a median follow-up of 2.9 years, 5 patients died suddenly, 9 had documented sustained ventricular tachycardia, and another 5 had appropriate implantable cardioverter-defibrillator shocks. On univariate Cox analysis, QRS duration (hazard ratio [HR], 1.02 per 1 ms; P=0.046), right atrial area (HR, 1.05 per 1 cm2; P=0.02), right ventricular fractional area change (HR, 0.94 per 1%; P=0.02), right ventricular outflow tract diameter (HR, 1.08 per 1 mm; P=0.01), mitral annular plane systolic excursion (HR, 0.84 per 1 mm; P=0.03), and LV global longitudinal 2-dimensional strain (HR, 0.87 per 1%; P=0.03) were related to the combined end point. On bivariable analysis, mitral annular plane systolic excursion and LV global longitudinal 2-dimensional strain were related to outcome independently of QRS duration (P=0.002 and P=0.01, respectively). In addition, a combination of echocardiographic variables, including right atrial area, right ventricular fractional area change, and LV global longitudinal 2-dimensional strain or mitral annular plane systolic excursion, was also found to be significantly related to outcome (P<0.001; c statistic, 0.70). Conclusions— LV longitudinal dysfunction was associated with greater risk of sudden cardiac death/life-threatening ventricular arrhythmias. In combination with echocardiographic right heart variables, also available from routine echocardiography, these measures provide important outcome information and should be considered a useful adjunct to established markers such as QRS duration in the estimation of prognosis in this challenging population.

Replacement therapy for iron deficiency improves exercise capacity and quality of life in patients with cyanotic congenital heart disease and/or the Eisenmenger syndrome

INTRODUCTION Iron deficiency is common in cyanotic congenital heart disease (CHD) and results in reduced exercise tolerance. Currently, iron replacement is advocated with limited evidence in cyanotic CHD. We investigated the safety and efficacy of iron replacement therapy in this population. METHODS Twenty-five iron-deficient cyanotic CHD patients were prospectively studied between August 2008 and January 2009. Oral ferrous fumarate was titrated to a maximum dose of 200mg thrice-daily. The CAMPHOR QoL questionnaire, 6 minute walk test (6MWT) and cardiopulmonary exercise testing were conducted at baseline and after 3 months of treatment. RESULTS Mean age was 39.9 ± 10.9 years, 80% females. Fourteen had Eisenmenger syndrome, 6 complex cyanotic disease and 5 Fontan circulation. There were no adverse effects necessitating termination of treatment. After 3 months of treatment, hemoglobin (19.0 ± 2.9 g/dL to 20.4 ± 2.7 g/dL, p<0.001), ferritin (13.3 ± 4.7 μg/L to 54.1 ± 24.2 μg/L, p<0.001) and transferrin saturation (17.8 ± 9.6% to 34.8 ± 23.4%, p<0.001) significantly increased. Significant improvements were also detected in the total CAMPHOR score (20.7 ± 10.9 to 16.2 ± 10.4, p=0.001) and 6MWT distance (371.7 ± 84.7 m to 402.8.0±74.9m, p=0.001). Peak VO(2) remained unchanged (40.7 ± 9.2% to 43.8 ± 12.4% of predicted, p=0.15). CONCLUSION Three months of iron replacement therapy in iron-deficient cyanotic CHD patients was safe and resulted in significant improvement in exercise tolerance and quality of life. Identification of iron deficiency and appropriate replacement should be advocated in these patients.

Usefulness of natriuretic peptide levels to predict mortality in adults with congenital heart disease

Neurohormonal activation is prevalent in adults with congenital heart disease, but its relation to outcome remains unknown. B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) were measured prospectively in 49 patients with adult congenital heart disease, who were followed up for a median of 7.9 years (interquartile range 7.7 to 8.2). Cox proportional hazards regression analysis was used to determine the relation of BNP and ANP concentrations to all-cause mortality. The mean age at baseline was 33.9 +/- 11.3 years, and 46.9% of patients were men. Most patients (77.5%) were symptomatic (20.4% had New York Heart Association class III), 10 (20.4%) were cyanotic, and 28 (57.1%) had systemic ventricular dysfunction (moderate or severe in 18.4%). The median concentration of BNP was 52.7 pg/ml (interquartile range 39.1 to 115.4) and of ANP was 47.4 pg/ml (interquartile range 19.7 to 112.8). Of the 49 patients, 11 (22.4%) died during the follow-up period. Both BNP and ANP were strong predictors of mortality (hazard ratio per 100-pg/ml increase 1.80, 95% confidence interval 1.38 to 2.34, p <0.0001; and hazard ratio per 100-pg/ml increase 1.21, 95% confidence interval 1.12 to 1.32, p <0.0001, respectively). A BNP value >78 pg/ml predicted death with a sensitivity of 100% and specificity of 76.3% (area under the curve 0.91, p = 0.0001). An ANP value of >146 pg/ml predicted death with a sensitivity of 72.7% and specificity 94.7% (area under the curve 0.89, p = 0.0001). No patients with a BNP level <78 pg/ml died during the follow-up period. In conclusion, the BNP and ANP levels strongly predicted death in symptomatic ambulatory patients with adult congenital heart disease during mid-term follow-up and could be used as a simple clinical marker for risk stratification in this population.

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.

Quality of life and functional capacity can be improved in patients with Eisenmenger syndrome with oral sildenafil therapy.

BACKGROUND Patients with Eisenmenger syndrome (ES) have a decreased exercise capacity and poor quality of life (QoL). While patients may survive to middle adulthood, the burden of disease is disabling. Sildenafil seems to improve exercise tolerance and hemodynamics, but there is no data to date on its impact on QoL. METHODS Eisenmenger patients in New York Heart Association (NYHA) class III were recruited in a prospective study of efficacy and safety of oral sildenafil. The QoL endpoint was assessed using a disease-specific questionnaire (CAMPHOR). Exercise capacity was assessed by means of six minute walk test (6MWT). All patients underwent comprehensive assessment at baseline and after 3months of treatment. RESULTS Twelve patients (mean age was 34.3±10.2, 83% female) with various cardiac anatomies were recruited. No major adverse events during the follow-up or significant drop in resting oxygen saturation were recorded. After 3months of oral sildenafil therapy, all patients improved to NYHA II with a concomitant improvement in 6MWT distance (347.3±80.7 to 392.5±82.0m, p=0.002). All components of the CAMPHOR score, relating to symptoms, activity and QoL, improved significantly resulting in substantial improvement in the total CAMPHOR score (27.6±10.5 to 15.8±10.4, p=0.002). CONCLUSIONS Three months of sildenafil therapy in adults with ES was well tolerated and associated with significant improvement in the QoL CAMPHOR questionnaire and in NYHA class and exercise capacity. Larger studies are warranted to assess long term efficacy of oral sildenafil and potential impact on survival.

Atrial tachyarrhythmias late after Fontan operation are related to increase in mortality and hospitalization

BACKGROUND Atrial tachyarrhythmias are a known complication late after Fontan operation. Limited information is available on their prognostic value. METHODS All patients with previous Fontan operation followed at our institution since 1999 were identified from the electronic database and included in this study. Demographic and clinical characteristics including history of atrial tachyarrhythmias were recorded at the earliest full clinical assessment and patients were followed thereafter for all-cause mortality and hospitalization. RESULTS A total of 98 patients, mean age 31.5 ± 8.9 years, 43.8% male, 31.6% with a total cavopulmonary connection (TCPC) were identified. A history of atrial tachyarrhythmia was present at baseline in 60.2% of patients who were older (33.0 ± 8.3 vs 29.1 ± 9.4 years, p=0.002), less likely to have a TCPC (13.5% vs 58.9%, p<0.001), and more symptomatic in terms of NYHA class (51.9% vs 26.7%, p=0.007) compared to arrhythmia-free patients. During a median follow-up of 6.7 years 18 patients died and 64 patients were hospitalized. Even after adjustment for baseline clinical characteristics, atrial tachyarrhythmia was an independent predictor of death (propensity score adjusted HR 9.35, 95% CI: 1.10-79.18, p=0.04, c-statistic 0.88) and composite of death or hospitalization (propensity score adjusted HR 5.00, 95% CI: 2.47-10.09, p<0.0001). CONCLUSIONS In adult patients with a Fontan-type operation, the presence of atrial tachyarrhythmias is associated with higher morbidity and mortality at mid-term follow-up. Whether early arrhythmia targeting intervention may improve clinical outcome needs to be studied in a prospective manner.

Survival prospects of treatment naïve patients with Eisenmenger: a systematic review of the literature and report of own experience

Objectives To investigate survival in patients with Eisenmenger syndrome based on a systematic review of the literature and reanalysis of data. We specifically tested the hypothesis that previous publications have been subject to immortal time bias, confounding survival analyses. Methods A systematic review of the literature was performed to evaluate survival in treatment naïve patients with Eisenmenger syndrome and standardised mortality ratios were calculated. Furthermore, we used a contemporary cohort of 219 treatment naïve patients with Eisenmenger syndrome from the own institution as a comparison group. Results Overall, 12 studies (published 1971–2013) were identified, including a total of 1131 patients. Only one study seemed to deal appropriately with immortal time bias in this setting. All other studies did not account for this effect, thus overestimating survival prospects of patients with Eisenmenger syndrome by up to 20 years. After accounting for this effect we found high standardised mortality ratios, a 10-year mortality rate approaching 30–40% and no evidence of superior survival prospects of current era patients compared with those seen in the 1970s, 1980s and 1990s. Only, a historical Eisenmenger-cohort from the 1950s/1960s had worse survival. Conclusions The current analysis challenges the traditional view of benign survival prospects of patients with Eisenmenger syndrome. In addition, survival prospects do not seem to have considerably improved over the last decades in untreated patients. These results support a proactive treatment strategy including a more aggressive approach trying to avoid the development of the condition.

Peak oxygen uptake, ventilatory efficiency and QRS-duration predict event free survival in patients late after surgical repair of tetralogy of Fallot.

OBJECTIVE Patients with repaired tetralogy of Fallot (ToF) have an increased long-term risk of cardiovascular morbidity and mortality. Risk stratification in this population is difficult. Initial evidence suggests that cardiopulmonary exercise testing (CPET) may be helpful to risk-stratify patients with repaired ToF. METHODS AND RESULTS We studied 875 patients after surgical repair for ToF (358 females, age 25.5 ± 11.7 year, range 7-75 years) who underwent CPET between 1999 and 2009. During a mean follow-up of 4.1 ± 2.6 years after CPET, 30 patients (3.4%) died or had sustained ventricular tachycardia (VT). 225 patients (25.7%) had other cardiac related events (emergency admission, surgery, or catheter interventions). On multivariable Cox regression-analysis, %predicted peak oxygen uptake (V˙O2 %) (p=0.001), resting QRS duration (p=0.030) and age (p<0.001) emerged as independent predictors of mortality or sustained VT. Patients with a peak V˙O2 ≤ 65% of predicted and a resting QRS duration ≥ 170 ms had a 11.4-fold risk of death or sustained VT. Ventilatory efficiency expressed as V˙E/V˙CO2 slope (p<0.001), peak V˙O2 % (p=.001), QRS duration (p=.001) and age (p=0.046) independently predicted event free survival. V˙E/V˙CO2 slope ≥ 31.0, peak V˙O2 % ≤ 65% and QRS duration ≥ 170 ms were the cut-off points with best sensitivity and specificity to detect an unfavorable outcome. CONCLUSIONS CPET is an important predictive tool that may assist in the risk stratification of patients with ToF. Subjects with a poor exercise capacity in addition to a prolonged QRS duration have a substantially increased risk for death or sustained ventricular tachycardia, as well as for cardiac-related hospitalizations.