Prophylactic effect of angiotensin receptor blockers in children with genetic aortopathies: the early bird catches the worm.

AIMS: In genetic aortopathies (GA) particular attention is paid to aortic root dilatation which has an impact on morbidity and mortality. This study focuses on the effects of therapy with angiotensin-II-receptor-blockers (ARB) or beta-blockers (BB) on aortic root growth and the question which therapy should be initiated at which dosage and at what age. METHODS: Since 1998 we diagnosed 208 patients with GA (170 FBN-1). 81 patients between 5 months and 18 years receiving either ARB or BB therapy were included. We retrospectively analyzed the progression of the dilatation of Sinus Valsalva aortae (SV) using calculated z-scores before and after therapy initiation and compared BB and ARB treatment. RESULTS: Both ARB and BB (p < 0.05) therapy showed significant improvement in aortic root growth, while the effect is significantly more pronounced in ARB (p < 0.01) independent of age and genetic cause. A detailed comparison of the two drug groups showed a more sustained effect in limiting the progression of the dilatation of the aortic root in patients treated with ARB. Progression of dilatation of the SV was significantly lower in children treated with ARBs compared to BB (delta z-score, p < 0.05). In addition, ARBs were better tolerated and had a significantly lower discontinuation rate (3%) compared to BB (50%) (p < 0.01). Independently of age at initiation all children and adolescents were able to reach the target dose under ARB. CONCLUSION: We demonstrated a significant change in both treatment options, with the effect of ARB being more pronounced while being better tolerated throughout the treatment period.

Rescue Nuss procedure for inferior vena cava compression syndrome following posterior scoliosis surgery in Marfan syndrome.

PURPOSE: Scoliosis surgery in Marfan syndrome is common, even in the presence of a funnel chest. However, to date, no case has been reported with acute intra-/postoperative decompensation caused by vena cava compression following posterior spinal derotation and fusion. METHODS: A 15-year-old male patient with Marfan syndrome, a funnel chest and severe scoliosis was treated with surgery for the spinal deformity. Intraoperatively, the patient developed a clinically relevant compression of the inferior vena cava with severe circular depression. Postoperatively, a cava compression syndrome with severe pleural effusion, ascites and enormous swelling of the lower limbs was developed. A conservative treatment of the symptoms, consisting of thoracic drainage and negative fluid balance, failed. Subsequently, the patient was transferred to pediatric intensive care unit for further treatment. Echocardiography and a CT scan demonstrated cava compression syndrome. A rescue Nuss procedure of the funnel chest deformity was performed since conservative treatment failed. The clinical course proceeded without complications and with a decrease in clinical symptoms of inferior inflow congestion. The patient was discharged after almost 3 weeks. CONCLUSION: The problem of congenital stenosis of the inferior vena cava in Marfan syndrome has not yet been investigated. In the case of simultaneously existing funnel chest and scoliosis in Marfan syndrome, an interdisciplinary discussion is required to decide whether a repair of the funnel chest should be performed first in order to prevent a clinically relevant compression syndrome. For the detection of a preoperatively relevant stenosis of the inferior vena cava, an MRI or thoracic/abdominal CT should be used preoperatively.

Pediatric patients with Marfan syndrome: frequency of dural ectasia and its correlation with common cardiovascular manifestations.

PURPOSE: Marfan syndrome (MFS) is a genetic disorder of the connective tissue. Aortic root dilation is a main criterion of the Ghent Nosology. Dural ectasia and the presence of mitral valve prolapse (MVP) contribute to its systemic score. The purpose of this study was to investigate the frequency of dural ectasia and its correlation with cardiovascular manifestations in a pediatric study population. PATIENTS AND METHODS: 119 pediatric patients with confirmed or suspected MFS were examined in the local Marfan Clinic. 31 children with MFS who underwent magnetic resonance imaging (MRI) were included. Each patient was evaluated according to the Ghent nosology. Echocardiography was used to measure the aortic root diameter and assess the presence of MVP and mitral regurgitation. Z-scores were calculated for the evaluation of the aortic root diameters. MRI was performed to determine the dural sac ratio (DSR). RESULTS: The prevalence of dural ectasia was 90.3 %, of aortic root dilation 32.2 %, of MVP 64.5 % and of mitral regurgitation 51.6 %. DSR at L5 correlated with the intraindividual z-scores (slope, 3.62 ±â€Š1.5 [0.56; 6.68]; r = 0.17; p = 0.02; F = 5.84). Z-scores ≥ 2 were accompanied by dural ectasia in 100 %, MVP in 95 % and mitral regurgitation in 100 % of cases. MVP was accompanied by mitral regurgitation in 70 % of cases. CONCLUSION: As the examined cardiac manifestations show a coincidence with dural ectasia in 95 - 100 % of cases, MRI for diagnostic dural sac imaging should be reserved for MFS suspicions with the absence of those manifestations in order to establish the diagnosis according to the Ghent criteria. Thus, the present study supports the recent downgrading of dural ectasia to a contributor to the systemic score.

Dural ectasia in Loeys-Dietz syndrome: comprehensive study of 30 patients with a TGFBR1 or TGFBR2 mutation.

The purpose of this study was to assess the frequency, severity, and clinical associations of dural ectasia (DE) in Loeys-Dietz syndrome (LDS). Database analysis of three German metropolitan regions identified 30 patients with LDS and TGFBR1 mutation in 6 and a TGFBR2 mutation in 24 individuals (17 men; mean age: 31 ± 19 years), as well as 60 age and sex-matched control patients with Marfan syndrome carrying a FBN1 mutation. DE was present in 22 patients with LDS (73%), and it related to skeletal score points (p = 0.008), non-skeletal score points (p < 0.001), and to the presence of ≥7 systemic score points (p = 0.010). Similarly, the severity of DE was related to body height (p = 0.010) and non-skeletal score points (p = 0.004). Frequency (p = 0.131) and severity of DE (p = 0.567) was similar in LDS and Marfan syndrome. DE is a manifestation of LDS that occurs with similar frequency and severity as in Marfan syndrome. Severity of DE may serve as a marker of the overall connective tissue disease severity. LDS may be considered in patients with DE.

Cardiac characterization of 16 patients with large NF1 gene deletions.

The aim of this study was to characterize cardiac features of patients with neurofibromatosis 1 (NF1) and large deletions of the NF1 gene region. The study participants were 16 patients with large NF1 deletions and 16 age- and sex-matched NF1 patients without such deletions. All the patients were comprehensively characterized clinically and by echocardiography. Six of 16 NF1 deletion patients but none of 16 non-deletion NF1 patients have major cardiac abnormalities (p = 0.041). Congenital heart defects (CHDs) include mitral insufficiency in two patients and ventricular septal defect, aortic stenosis, and aortic insufficiency in one patient each. Three deletion patients have hypertrophic cardiomyopathy. Two patients have intracardiac tumors. NF1 patients without large deletions have increased left ventricular (LV) diastolic posterior wall thickness (p < 0.001) and increased intraventricular diastolic septal thickness (p = 0.001) compared with a healthy reference population without NF1, suggestive of eccentric LV hypertrophy. CHDs and other cardiovascular anomalies are more frequent among patients with large NF1 deletion and may cause serious clinical complications. Eccentric LV hypertrophy may occur in NF1 patients without whole gene deletions, but the clinical significance of this finding is uncertain. All patients with clinical suspicion for NF1 should be referred to a cardiologist for evaluation and surveillance.

A simple clinical model to estimate the probability of Marfan syndrome.

BACKGROUND: Marfan syndrome is a heritable connective tissue disease. Definitive diagnosis is complex, and requires sequencing of a large gene, FBN1. AIM: We aimed to develop a simple model to estimate the pre-test probability of Marfan syndrome. DESIGN: Prospective cross-sectional study. METHODS: We applied diagnostic standards for definitive diagnosis or exclusion of Marfan syndrome in 329 consecutive persons. In 208 persons with random assignment to our derivation group, we performed multivariate logistic regression to assess 14 clinical variables for inclusion in a prediction model with derivation of score points from the estimated coefficients. We created cut-offs to classify low, moderate and high probability of Marfan syndrome. For validation, we applied the model to the remaining 121 persons. RESULTS: We identified seven variables for inclusion in the final model, where we assigned four score points to ectopia lentis, two points to a family history of Marfan syndrome, and one point to previous thoracic aortic surgery, to pectus excavatum, to a wrist and thumb sign, to previous pneumothorax, and to skin striae. In the derivation group 12, 42 and 92% of persons with low (≤1 point), moderate (>1-3.5 points) or high pre-test probability (>3.5 points) had Marfan syndrome, compared to 12, 57 and 91%, respectively, in the validation group. Positive likelihood ratios were 13.96 and 8.54 in the high probability group of the derivation and validation group, respectively. CONCLUSION: A simple prediction model provides evidence for Marfan syndrome. This model can be used to identify patients who require definitive diagnostic work-up.

Aortic arch repair: let it beat!

Objective aortic arch repair (AAR) on the beating heart may reduce cross-clamping times and offer improved postoperative cardiac function.Methods A single-center review of all patients (n = 24) who underwent surgical AAR during biventricular repair between 01/2006 and 01/2008 was done. All patients were operated on under cardiopulmonary bypass (CPB) with antegrade cerebral perfusion (ACP). During AAR, 13 patients (group 1) received cardioplegic arrest, and were compared to 11 patients (group 2) who underwent a beating-heart modification with selective myocardial perfusion. Seventeen patients had additional intracardiac lesions and underwent simultaneous correction during the procedure.Results Durations of CPB, AAR and ACP did not differ statistically between groups. Cardioplegic arrest time was significantly lower in group 1 (34 ± 13 vs. 76 ± 11 min, p = 0.02) and resulted in a subsequent reduction of myocardial ischemic damage as borne out by lower postoperative levels of troponin T and CK-MB (2.5 ± 0.7 vs. 7.1 ± 1.4 ng/mL, p = 0.02; 68.7 ± 11.5 vs. 149.1 ± 27.2 U/l, p = 0.03). We observed an enhanced patient recovery with shorter inotropic and ventilatory support times (p < 0.05).Conclusion Pediatric aortic arch correction on a CPB beating heart with selective myocardial perfusion is technically feasible and safe. The reduction of the myocardial ischemic time is effective and results in less myocardial damage.

Dural ectasia in individuals with Marfan-like features but exclusion of mutations in the genes FBN1, TGFBR1 and TGFBR2.

Mutations in the genes FBN1, TGFBR1, and TGFBR2 can result in heritable connective tissue disorders comprising the Marfan syndrome and the Loeys-Dietz syndrome. Dural ectasia is a characteristic manifestation of both syndromes. However, dural ectasia has not yet been investigated in connective tissue disorders that are unrelated to mutations in the FBN1, TGFBR1 or TGFBR2 genes. Here, we assessed dural ectasia in 33 individuals both with typical manifestations of heritable connective tissue disease and in whom mutations in all three genes had been excluded. We identified 19 individuals with dural ectasia (58%), who exhibited major skeletal manifestations of the Marfan syndrome more frequently than the remaining 14 persons without dural ectasia (p = 0.06). Moreover, only persons with dural ectasia fulfilled clinical criteria of the Marfan syndrome (p = 0.01). Conversely, aortic aneurysm (12 patients; p = 0.8), aortic dissection (five patients; p = 0.1), spontaneous dissection of the carotid arteries (five patients; p = 1), and mitral valve prolapse (13 patients; p = 0.4) were similarly frequent irrespective of dural ectasia. We conclude that dural ectasia is a marker for connective tissue disease which coincides with skeletal rather than with cardiovascular manifestations, and which may involve currently uncharacterized pathogenetic mechanisms and syndromes.

Marfan syndrome and the evolving spectrum of heritable thoracic aortic disease: do we need genetics for clinical decisions?

Marfan syndrome (MFS) is a disorder of the connective tissue that is inherited in an autosomal dominant fashion and that is classically caused by mutations in the gene coding for fibrillin-1, FBN1. The high mortality of untreated MFS results almost exclusively from aortic complications such as aortic dissection and rupture. However, more than half of patients with Marfan-like features do not have MFS, but have other diseases including inherited aortic aneurysms and dissections (TAAD). We elucidate the increasing spectrum of syndromes associated with Marfan-like features and discuss the clinical implications of these diseases. We performed a systematic review to tabulate all known inherited diseases and syndromes carrying a risk for thoracic aortic disease. We discuss evidence that different syndromes with different causative genes and mutations have different prognoses and profiles of cardiovascular manifestations. We conclude that future decisions for optimized management of patients with inherited TAAD require a comprehensive clinical and genetic work-up.

Utility of N-terminal brain natriuretic peptide plasma concentrations in comparison to lactate and troponin in children with congenital heart disease following open-heart surgery.

We conducted a prospective study in a pediatric cardiac intensive care unit in order to determine the diagnostic value of N-terminal brain natriuretic peptide (N-BNP) plasma concentration in the perioperative care of children with congenital heart disease (CHD). N-BNP plasma concentrations were determined by using a validated enzyme immunoassay. We measured N-BNP the day before surgery and up to 15 days postoperatively in 23 children (age range, 0.25-11 years) undergoing cardiac surgery due to various CHDs. Supply and duration of catecholamines, vasodilators, and respiratory therapy were determined and correlated to N-BNP. In addition, troponin T (TnT) and arterial Lactat (aL) concentrations were measured simultaneously. We found a significant correlation between preoperative and maximal N-BNP levels and dosage of vasodilators (r = 0.41, p < 0.02 and r = 0.83, p < 0.01, respectively). Maximal TnT and aL levels were not correlated to dosage of vasodilators. The dosage and duration of catecholamines, the duration of respiratory therapy, and the plasma concentration of TnT and aL were not correlated to pre- or perioperative N-BNP. Maximal TnT and aL levels were correlated to duration (r = 0.53, p < 0.01 and r = 0.48, p < 0.02) and dosage (r = 0.52, p < 0.02 and r = 0.60, p < 0.01) of catecholamines and duration of respiratory therapy (r = 0.57, p < 0.01 and r = 0.50, p < 0.02). As recent studies show, N-BNP appears to be a powerful neurohumoral indicator of ventricular function and prognosis for guiding therapy in the outpatient department or for discriminating cardiac from noncardiac symptoms. In contrast, the value of N-BNP for guiding perioperative therapy in pediatric cardiac intensive care units is limited.

Plasma concentrations of N-terminal brain natriuretic peptide in healthy children, adolescents, and young adults: effect of age and gender.

Children with congenital heart disease need adequate diagnostic classification regarding their cardiovascular status (CVS). N-terminal brain natriuretic peptide (N-BNP) plasma concentration indicates dysfunction of the cardiovascular system and guides decisions concerning treatment and prognosis. Reference values are established for adults, with age-dependent increasing values and higher values in women. To avoid misclassification concerning the CVS, a large group of healthy children and adolescents can be used show the relationship between gender, age, and N-BNP and these can serve as reference values. N-BNP was measured in 434 healthy subjects (240 female and 194 male) with ages ranging from 0 to 32 years without any cardiovascular disease or renal or hepatic impairment. Measurements were performed with an electrochemiluminescence immunoassay from Roche Diagnostics. Mean N-BNP decreased from 12.6 fmol/ml (0-9 years; n = 79) to 9.41 fmol/ml (10-14 years; n = 154) and in adolescents from 6.1 (15-19 years; n = 99) to 4.8 fmol/ml (> 19 years; n = 102) in adults (p < 0.05). Mean N-BNP concerning gender did not differ in any age group younger than 19 years. In contrast, the adult female group had 78% higher N-BNP compared to the male group (p < 0.05). There was a significant peak in N-BNP at the age of 12-14 years. This study shows that reference values for N-BNP differed profoundly in children compared to adults and were up to 260% higher in children without any gender difference. Therefore, these reference values will help to avoid CVS misclassification in children for the biomarker N-BNP.

C2 blood concentrations of orally administered cyclosporine in pediatric liver graft recipients with a body weight below 10 kg.

Pharmacokinetic studies in adult and pediatric liver transplant recipients have shown that the C(2) monitoring is superior to the traditional determination of CsA trough levels (C(0)) as an estimate of CsA exposure. However, target reference values for C(2) in very small infants have not been established yet. The objective of our study was to assess the distribution of C(2) levels in the first week following Ltx and to analyze enteral absorption of CsA for this group of patients. We documented CsA C(0) and C(2) levels in 25 infants with a body weight below 10 kg (median 6.8 kg; range 3.0-9.8 kg) in the first 7 days after Ltx. The infants had a median age at transplantation of 7 months (range 0.3-20.0 months). The underlying diagnoses were biliary atresia (n = 17), acute liver failure (n = 4), metabolic disease (n = 4). All children received CsA microemulsion (Neoral, initial 10 mg/kg/day), prednisolone, and two single doses of basiliximab as immunosuppressive drugs. The mean C(0) and C(2) levels were as follows: day 1: C(0) 77.0 +/- 39.6, C(2) 340.5 +/- 140.0 ng/mL; day 2: C(0) 135.5 +/- 53.2, C(2) 467.0 +/- 168.2 ng/mL; day 3: C(0) 146.5 +/- 70.8, C(2) 519.0 +/- 219.1 ng/mL; day 4: C(0) 168.5 +/- 55.1, C(2) 570.0 +/- 163.7 ng/mL; day 5: C(0) 156.5 +/- 38.0, C(2) 612.0 +/- 132.4 ng/mL; day 6: C(0) 177.0 +/- 41.1, C(2) 606.0 +/- 149.2 ng/mL; day 7: C(0) 174.0 +/- 27.2, C(2) 622.0 +/- 98.8 ng/mL (r = 0.82, p < 0.05). This analysis demonstrates that there is a good enteral absorption of CsA in very small children post-Ltx in the early post-operative period. Based on the C(2) levels achieved, we conclude that there is a good correlation between C(0) and C(2) levels even in very small infants.

Subjective and objective prospective, long-term analysis of quality of life during inhaled interleukin-2 immunotherapy.

PURPOSE: We conducted both a subjective and objective, prospective quality-of-life analysis during high-dose (36 x 10(6) immunizing units/d) inhalational interleukin (IL)-2 treatment (mean treatment time, 13.4 months) of 15 patients with metastatic renal cell carcinoma (mRCC). Additionally, quality of life for 10 patients with mRCC receiving low-dose (9 x 10(6) IU/m(2)/d for 5 days) intravenous IL-2 treatment also was evaluated. PATIENTS AND METHODS: Patients responded to the European Organization for Research and Treatment of Cancer quality-of-life questionnaire QLQ-C30 before and during inhalational IL-2 treatment at 1, 3, 6, 9, and 12 months and before and once during intravenous IL-2 treatment. A clinician assessed patient well-being using the Quality of Well-Being scale to calculate once weekly quality-adjusted life-years (QALYs) during inhalational IL-2 treatment. RESULTS: Patients completed 103 questionnaires and clinicians performed 892 QALY calculations. For patients treated with inhalational IL-2, the mean quality-of-life score deteriorated modestly but significantly 1 month after treatment initiation (15.1%, P =.01) but did not differ significantly from pretreatment scores after 3, 6, 9, and 12 months of treatment. Inhalational IL-2 therapy stabilized patient quality of life for a mean of 13.4 months. The resulting QALY calculation for patients on inhalation IL-2 was 70.1% of 13.4 months, representing 9.4 months of QALY. In comparison, patients who received intravenous IL-2 showed a more marked, statistically significant deterioration in mean quality-of-life score during treatment (27%, P =.006); moreover, three of these 10 patients experienced treatment-related toxicity that prevented questionnaire completion. CONCLUSION: Quality-of-life analysis during immunotherapy provides valuable information regarding cancer treatment outcomes.

Inhaled interleukin-2 therapy in pulmonary metastatic renal cell carcinoma: six years of experience.

PURPOSE: Patients with advanced metastatic renal cell carcinoma often cannot or do not want to tolerate high-dose systemic interleukin-2 (IL-2) therapy and the toxicity associated with it. To reduce toxicity and still maintain or even increase effectiveness, we developed a method to deliver IL-2 locally for the treatment of pulmonary and mediastinal metastases in metastatic renal cell carcinoma patients. PATIENTS AND METHODS: We report here 6 years of experience treating 116 metastatic renal cell carcinoma patients who had pulmonary or mediastinal metastases with inhaled IL-2. We have utilized three different IL-2 preparations (natural human IL-2 purified from the supernatants of mitogen-activated peripheral blood lymphocytes, glycosylated recombinant IL-2 produced by Chinese hamster ovary cells, and non-glycosylated recombinant IL-2 produced by bacteria). All protocols used high-dose inhalation of IL-2, either exclusively (11%), with coadministration of low-dose systemic IL-2 (33%), or with coadministration of low-dose systemic IL-2 and interferon-alpha (56%). RESULTS: Maximal toxicity per total treatment time was mild (median treatment time, 7.2 months); there was a low incidence (16%) of World Health Organization grade 3 toxicity. Toxicity associated with exclusive inhalation of IL-2 was local and consisted mainly of cough. Thus, patients who could not tolerate high-dose systemic IL-2 were able to tolerate inhalation IL-2 therapy. Progressive pulmonary metastases responded in 15% of patients for a median of 15.5 months (range, 4.1-33 months) and were stabilized in 55% of patients for a median of 6.6 months (range, 3-51.7 months). The overall response rate was 16%; disease was stabilized in 49% of patients and disease progressed in 35% of patients. The overall median response duration was 9.6 months. Median survival was 11.8 months (range, 1.7-68.8 months); expected survival according to risk analysis was 5.3 months. CONCLUSIONS: Inhalation of IL-2 is a nontoxic and effective treatment for patients with progressive pulmonary and mediastinal metastases. Inhaled IL-2 effectively prevented progress of pulmonary metastases in 70% of patients. Furthermore, patients could be treated as outpatients and remain employed. Local administration of IL-2 increases therapeutic effectiveness with little or no toxicity.