Cardiac phenotype in propionic acidemia - Results of an observational monocentric study.

BACKGROUND: Propionic acidemia (PA) is an organic aciduria caused by inherited deficiency of propionyl-CoA carboxylase. Left ventricular dysfunction and QT prolongation may lead to life-threatening complications. Systematic analyses of cardiac phenotypes, in particular effects of specific cardiac therapies, are scarce. METHODS: In this longitudinal observational monocentric study (data from 1989 to 2017) all PA patients treated at our center were included. Echocardiographic parameters (left ventricular end-diastolic diameter: LVEDD, left ventricular shortening fraction, mitral valve Doppler inflow pattern) and 12­lead electrocardiogram recordings (corrected QT interval: QTc) were analyzed. Symptomatic patients were dichotomized to the group "early-onset" (symptoms within 28 days of life) and "late-onset" (symptoms after 28 days). Associations between cardiac function, LVEDD, QTc and clinical parameters (age at onset, beta-blocker or Angiotensin-converting enzyme inhibitor = ACE-I therapy) were analyzed. RESULTS: 18 patients with PA were enrolled, 17 of them were symptomatic and one asymptomatic, with a median age at diagnosis of 6 days. 14/17 (82%) had early onset disease manifestation. Systolic left ventricular dysfunction (i.e. hypokinetic phenotype of cardiomyopathy) was diagnosed in 7/18 (39%) patients at a median age of 14.4 years, all had early onset. Two patients had a dilated left ventricle and systolic left ventricular dysfunction (i.e. dilated hypokinetic phenotype - dilated cardiomyopathy). Diastolic left ventricular dysfunction was found in 11/18 (61%) individuals, typically preceding systolic left ventricular dysfunction. ACE-I therapy did not improve systolic left ventricular function. Mean QTc was 445 ms (+/- 18.11 ms). Longer QTc was associated with larger LVEDD. CONCLUSIONS: Systolic left ventricular dysfunction was found in 39% of patients, reflecting high disease severity. Two thirds of all individuals showed signs of diastolic left ventricular dysfunction usually preceding systolic left ventricular dysfunction; it therefore may be considered as an indicator for early cardiac disease manifestation, possibly allowing earlier treatment modification. Unresponsiveness to routine cardiac therapy highlights the need to evaluate further strategies, such as liver transplantation.

[Pulmonary hypertension in grown-ups with congenital heart disease: Recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Erwachsenen mit angeborenen Herzfehlern: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed recommendations for different forms of PH, and specifically address PH associated with congenital heart disease (CHD). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to PH in grown-ups with congenital heart disease (GUCH). This article summarizes the results and recommendations of this working group.

[Pulmonary arterial hypertension in patients with congenital heart disease: current issues and health care situation]. / Pulmonalarterielle Hypertonie bei angeborenen Herzfehlern: Problemstellung und Versorgungslage.

Defects of the heart and associated large vessels (CHD) are among the most frequent congenital anomalies. Owing to improved interdisciplinary management, about 90% of CHD patients reach adulthood. Up to 10% maintain or newly develop pulmonary arterial hypertension (PAH) over time, which impairs exercise tolerance and prognosis. Data on the health care situation of patients with PAH-CHD are limited. The ongoing Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA, ClinTrials.gov Identifier NCT01347216) prospectively documents adult patients with all forms of pulmonary hypertension, if treated with PAH drugs (mean follow-up 40 months). As of 16 November 2012, 8% of the 3642 patients in the database had PAH-CHD. Of the latter, 104 were documented in great detail in specific CHD report forms. These patients were on average 39 years old, men in 39%, had a mean 6-minute walk distance of 370 ± 102 meters, and were in NYHA functional class I/II in 39%, III in 59%, und IV in 3%. Mean quality of life on the 100-point visual analogue scale (EQ-5 D) was 51. PAH-CHD patients received monotherapy in 80%, combination therapy in 9%, and no PAH drugs in 11%. Only 20% were on oral anticoagulation (OAC). Mean 4-year survival in incident patients (PAH-CHD diagnosis after start of the registry in 2007) was 79%, compared with 72% in patients with idiopathic PAH (IPAH). According to these registry data, patients with PAH-CHD have impaired exercise capacity, and substantially reduced quality of life. They receive combination therapy or OAC, respectively, less frequently than IPAH patients, however, their survival rate is higher.

[Pulmonary hypertension due to chronic lung disease. Recommendations of the Cologne Consensus Conference 2010]. / Pulmonale Hypertonie bei chronischen Lungenerkrankungen. Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of pulmonary hypertension which may affect quality of life and survival of these patients in a similar manner. In June 2010, a group of German experts met in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology. One of the working groups was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

Balloon valvuloplasty in the treatment of congenital aortic valve stenosis--a retrospective multicenter survey of more than 1000 patients.

BACKGROUND: The value of balloon valvuloplasty of the aortic valve in childhood is still under debate. OBJECTIVE: To evaluate the results of the procedure in a retrospective multicenter survey of a large cohort over a long time interval. METHODS: Retrospective analysis of 1004 patients with balloon valvuloplasty of the aortic valve performed between 9/1985 and 10/2006 at 20 centers in Germany, Austria and Switzerland. Amongst others, the following parameters were evaluated before and after the procedure as well as at the end of follow-up or before surgery: clinical status, left ventricular function, transaortic pressure gradient, degree of aortic regurgitation, freedom from re-intervention or surgery. PATIENTS: Patients from 1 day to 18 years of age with aortic valve stenosis were divided into four groups: 334 newborns (1-28 days); 249 infants (29-365 days); 211 children (1-10 years), and 210 adolescents (10-18 years). RESULTS: Median follow-up was 32 months (0 days to 17.5 years). After dilatation the pressure gradient decreased from 65 (± 24)mm Hg to 26 (± 16)mm Hg and remained stable during follow-up. The newborns were the most affected patients. Approximately 60% of them had clinical symptoms and impaired left ventricular function before intervention. Complication rate was 15% in newborns, 11% in infants and 6% in older children. Independently of age, 50% of all patients were free from surgery 10 years after intervention. CONCLUSIONS: In this retrospective multicenter study, balloon valvuloplasty of the aortic valve has effectively postponed the need for surgery in infants, children and adolescents up to 18 years of age.

[Pulmonary hypertension due to chronic lung disease. Recommendations of the Cologne Consensus Conference 2010]. / Pulmonale Hypertonie bei chronischen Lungenerkrankungen: Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of pulmonary hypertension which may affect quality of life and survival of these patients in a similar manner. In June 2010, a group of German experts met in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology. One of the working groups was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

[Non-invasive diagnosis of pulmonary hypertension: ESC/ERS Guidelines with commentary of the Cologne Consensus Conference 2010]. / Nicht-invasive Diagnostik der pulmonalen Hypertonie: ESC/ERS-Leitlinien mit Kommentierung der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations for the diagnosis of pulmonary hypertension. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update y appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to non-invasive diagnosis of PH. This commentary summarizes the results and recommendations of the working group on treatment of PAH.

[Treatment of pulmonary arterial hypertension (PAH): recommendations of the Cologne Consensus Conference 2010]. / Therapie der pulmonal arteriellen Hypertonie (PAH): Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations for the treatment of pulmonary arterial hypertension (PAH). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the treatment of PAH. This commentary summarizes the results and recommendations of the working group on treatment of PAH.

Surgical treatment of long-segment tracheal anomalies in infants and children.

BACKGROUND: Tracheal stenosis in combination with vascular and/or cardiac anomalies is a life-threatening condition in infants and children presenting with severe symptoms of airway obstruction. The optimal surgical treatment of these cases remains controversial. OBJECTIVES: We present here a group of infants and children with combined tracheal malformations and vascular and/or cardiac anomalies. More than 30 % of the stenotic trachea was resected in a subgroup of the patients. A reconstruction with end-to-end anastomosis was achieved on the basis of extensive mobilization of the whole tracheobronchial tree and use of CPB. METHODS: The clinical outcome in 37 children with a median age of 8 (1 - 72) months was analyzed retrospectively. The patients presented with severe airway obstruction in combination with congenital heart defects and/or vascular anomalies. Cardiac catheterization, bronchoscopy and thoracic computer tomography were performed prior to operation. The operations were performed under CPB and consisted of tracheal resection with end-to-end anastomosis or external stabilization. Associated intracardiac and vascular anomalies were repaired simultaneously. RESULTS: All but 1 patient survived and had a straightforward recovery. The patients were extubated under bronchoscopic control with a median intubation time after airway repair of 12.2 days. The average follow-up was 8.4 years (1 - 14 years) and the surviving patients did not show signs of restenosis clinically. A segment longer than 30 % of the tracheal length was resected and reconstructed with end-to-end anastomosis in 57 % of the patients (12 of 21 patients). CONCLUSIONS: Our experience demonstrates that resection of tracheal stenosis and end-to-end anastomosis can be achieved successfully even in cases with stenosis of more than 30 % of the total tracheal length. The use of CBP allowed extensive mobilization of the tracheobronchial tree and resection with end-to-end tension-free anastomotic reconstruction.

[Compliance of the normal-sized aorta in adolescents with Marfan syndrome: comparison of MR measurements of aortic distensibility and pulse wave velocity]. / Compliance der morphologisch unauffälligen Aorta bei Jugendlichen mit Marfan Syndrom: Vergleich von MR-Messungen der aortalen Dehnbarkeit und der Pulswellengeschwindigkeit.

PURPOSE: To compare the aortic compliance of the normal-sized aorta of adolescents with Marfan syndrome and healthy controls using MR measurements of the aortic distensibility and pulse wave velocity. MATERIALS AND METHODS: Fourteen patients (median age: 15 years) and 11 healthy subjects (23 [12 - 32] years) were examined at 1.5 T. The MR protocol included 2D steady-state free precession (SSFP)-CINE MRI of the aortic distensibility and PC-MRI of the pulse wave velocity. All measurements were positioned perpendicular to the descending aorta at the level of the diaphragm for assessing the changes in the aortic cross-sectional areas and additionally above and below this plane for assessing the pulse wave velocity. In addition contrast-enhanced 3D-MR angiography was performed in adolescents with Marfan syndrome to exclude morphologic changes and to prove normal-sized aorta. RESULTS: Compared with control subjects, adolescents with Marfan syndrome had significantly decreased distensibility and significantly increased pulse wave velocity (chi (2)-test, p = 0.0002) using an age-related non-linear regression analysis. The related aortic compliance was significantly decreased (chi (2)-test, p = 0.0002). There was a good correlation between the two methods (r = 0.86). A low intraobserver variability was found for both methods (< or = 2 %). CONCLUSIONS: MRI allows detecting abnormal elastic aortic wall properties already in the normal-sized aorta of adolescents with Marfan syndrome. Monitoring of these properties could be relevant for evaluating disease onset and progression. MRI has the potential value of compliance measurements for the follow-up and to guide therapy indications.

Right ventricular expression of extracellular matrix proteins, matrix-metalloproteinases, and their inhibitors over a period of 3 years after heart transplantation.

Fibrillar collagens I and III, nonfibrillar collagen IV, and the glycoproteins fibronectin and laminin, are elements of the myocardial extracellular matrix (ECM). Alterations in the normal concentrations and ratios of these elements may reflect remodeling in response to physiologic stress. In the case of patients' post-heart transplantation (HTx), specific patterns of alteration may herald myocardial dysfunction. Right ventricular biopsies were taken from the same 28 HTx patients before implantation and 1 week, 2 weeks, and 1, 2, and 3 years after HTx. The above-noted five ECM proteins, six matrix metalloproteinases (MMPs) and two of their tissue inhibitors (TIMPs) were detected by immunohistochemistry and scored as cells per square millimeter or semiquantitatively. The total connective tissue fibers were detected by connective tissue stain and morphometry. Variations in these ECM components were followed in the same patient cohort over 3 years. In summary, during the first 2 weeks after HTx, a predominant increase in connective tissue occurred. Increases in MMP-8 and MMP-9 were found. By 3 years after transplantation, there was a decrease of connective tissue fibers and a significant reduction of all ECM components and an increase in MMPs and TIMPs. These findings may reflect a pattern of remodeling specific to the transplanted heart.

Treatment of an aneurysmal dilatation of the ductus arteriosus with indomethacin in a premature infant.

A large ductus arteriosus aneurysm can lead to potentially serious and life-threatening complications. We report a case of aneurysmal dilatation of the ductus arteriosus in a premature infant that was successfully treated with indomethacin. Thus, surgical intervention with general anesthesia could be avoided.

Long-term results after repair of truncus arteriosus communis in neonates and infants.

BACKGROUND: We reviewed our experience of truncus arteriosus communis (TAC) repair. METHODS: Between 05/90 and 10/01, 16 patients underwent complete repair of TAC (primary repair: group I, 12 patients, secondary repair: group II, 4 patients). Age was 2.4 months [5 days-8.8 months] (median [range]) in group I, and 8.3 [5.6-13.5] years in group II. Continuity from the right ventricle to the pulmonary artery was achieved using a valved conduit. All patients had regular follow-up examinations. RESULTS: There was one early death in each group (12.5%). Follow-up was 9 [1.2-12.7] years. Valved conduit failure occurred in 8 patients (67 %) in group I (group II, 1 patient, 33 %) requiring replacement at 2.5 [0.3-4.3] years (group II, 5.8 years). Severe neo-aortic valve regurgitation after truncal valve repair was observed in one patient, requiring valve replacement at 8.5 years in association with repeat homograft replacement (group I). Actual echocardiographic examination revealed normal ventricular function. Moderate conduit dysfunction was noted in 2 patients (group I). CONCLUSIONS: Complete repair of truncus arteriosus communis can be performed with excellent long-term results.

Pathological changes of the myocardium in patients after atrial repair for transposition of the great arteries: a possible explanation for left ventricular dysfunction after secondary arterial switch.

BACKGROUND: Patients with transposition of the great arteries who underwent an atrial repair in infancy are likely to develop right ventricular dysfunction later in life. For these patients a two-stage arterial switch operation has been advocated by some groups but mortality even from the initial pulmonary banding procedure for retraining the left ventricle has been reported to be considerable. We asked whether pathological alterations of the left ventricular myocardium could explain for the failure of the left ventricle observed in patients after two-stage arterial switch operations. METHODS: Twelve patients aged 16.9 [8-25.4] years (median [range]) with transposition of the great arteries after atrial repair in infancy were enrolled. Median follow-up interval was 15.8 [7.8-22.1] years. Measurements of right and left ventricular systolic function were performed by echocardiography. In addition all patients underwent cardiac catheterization. Endomyocardial biopsies were taken from the right and left ventricle and examined histopathologically. RESULTS: Two out of twelve patients showed mildly reduced systolic right ventricular function. Systolic function of the left ventricle was normal in all patients on echocardiography but six out of twelve patients showed clusters of fibrous and fatty degeneration on biopsy specimens obtained from the left ventricle. CONCLUSION: We conclude that degenerative left ventricular myocardial changes could serve as an explanation for left ventricular failing when retraining the left ventricle during two-stage arterial switch operations.

The index of pulmonary vascular disease in children with congenital heart disease: relationship to clinical and haemodynamic findings.

OBJECTIVE: We asked whether a scoring system [index of pulmonary vascular disease (IPVD)] that quantifies the individual pulmonary vascular pathology would relate to postoperative survival in patients with congenital heart disease and pulmonary hypertension (PH). METHODS: Lung biopsy specimens from 28 patients at a median age of 6 months (1 month to 21 years) were analysed qualitatively and morphometrically. The IPVD and other morphometric parameters were related to haemodynamic findings and survival. RESULTS: Mean pulmonary artery pressure (PAP) was 44 mmHg (15-72 mmHg), and the resistance to pulmonary perfusion was 5 U x m(2) (0.9-14 U x m(2)). There were three early (in-hospital) and three late deaths during the follow-up period of 2.5 years (6 months to 7 years). Incipient plexiform lesions were observed in one infant with trisomy 21 and complete atrioventricular septal defect (cAVSD). An IPVD score above the upper critical limit (>2.2) was not observed during the first year of life. On discriminant analysis, morphometric parameters could not predict mortality ( P=0.08). CONCLUSIONS: The IPVD is not helpful to predict surgical mortality during the first year of life. Patients with trisomy 21 and cAVSD may show advanced pulmonary vascular disease in infancy.

Metabolites of the L-arginine-NO pathway in patients with left-to-right shunt.

OBJECTIVES: The endogenous production of metabolites of the L-arginine-NO pathway has been found to be altered in patients with left-to-right shunt and pulmonary hypertension. The objective of this study was to analyze the influence of age and of the magnitude of the left-to-right shunt on plasma levels of L-arginine, cyclic guanosine monophosphate (cGMP), nitrite and nitrate in children and young adults presenting with left-to-right shunt. METHODS: Twenty-nine patients with ventricular septal defect (n=18), atrial septal defect (n=6) and atrioventricular canal (n=5) were assigned to group I when the ratio of pulmonary to systemic blood flow (Qp/Qs) was less than 1.5 (n=10) and to group II when Qp/Qs > or = 1.5 (n=19). At cardiac catheterization blood samples were taken from the pulmonary vein or left ventricle. In 33 controls peripheral venous blood was obtained. cGMP levels were determined by radioimmunoassay, L-arginine, nitrite and nitrate by high performance liquid chromatography (HPLC). RESULTS: L-arginine plasma levels were lower in group II than in controls (51.7 [23.3-82.2] versus 60.5 [32.4-85.9] pmol/l; p < 0.05 by KRUSKAL-WALLIS). Age did not influence the L-arginine plasma levels (p = 0.30). cGMP levels depended on age (p<0.01) and mean pulmonary artery pressure (p <0.01) but not on high pulmonary blood flow (p=0.85; ANOVA). Plasma nitrite and nitrate were not different in both groups and when compared with controls (nitrite: 26.0 [23.5-31.0] micromol/l; nitrate: 26.8 [24.0-32.0] micromol/l). CONCLUSIONS: Age and pulmonary artery pressure exert important effects on plasma cGMP. Measurement of nitrite and nitrate in plasma alone may not reflect the endogenous NO production. Future studies should evaluate the role of plasma levels of L-arginine in patients with high pulmonary blood flow undergoing repair of their defect.

Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension.

Asymmetrical dimethyl-L-arginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. We hypothesized that plasma levels of ADMA could be increased in patients with congenital heart disease and pulmonary hypertension. Cardiac catheterization was performed in 20 children and young adults with congenital heart disease with a median age of 10 years (range, 4 months to 33 years). The patients were assigned to group I (high flow, low pressure; n = 14) when Qp/Qs was 1.5 or greater and the mean PAP was less than 25 mm Hg or to group II (high pressure, high resistance; n = 6) when the mean PAP was greater than 25 mm Hg and Rp/Rs was greater than 0.3. Blood samples were taken from pulmonary vein or left ventricle. ADMA was measured by high-performance liquid chromatography. In addition, levels of ADMA were measured in peripheral venous blood obtained from eight control patients. Levels of ADMA in control patients (median, 0.21 microM/l; range, 0.08-0.27 microM/l) did not differ from levels obtained in group I (median, 0.30 microM/l; range, 0.06-0.49) microM/l). Patients in group II showed increased plasma levels of ADMA (median, 0.55; range, 0.25-0.79) (p < 0.01). Inhibition of nitric oxide synthase by increased levels of ADMA might contribute to pulmonary hypertension in patients with congenital heart disease.