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 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.

[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.

[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.

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.

Influence of clinical and ventilatory parameters on morphology of bronchopulmonary dysplasia.

Our aim was to assess multiple factors which contribute to bronchopulmonary dysplasia (BPD) in prematurely born neonates. Specific morphologic features might relate to cumulative oxygen dose, barotrauma, prematurity, infection, and persistent ductus arteriosus (PDA). Seventy-two patients dying from BPD as defined by the histopathologic criteria of Stocker were analyzed retrospectively. Median (range) gestational age was 28 (25-35) weeks, and median survival was 16 (5-386) days. The infants were ventilated for 15 (15-149) days with a mean inspired oxygen fraction (FiO2) of 0.78. The cumulative oxygen dose and mean airway pressures were determined. The presence of neonatal infection, PDA, and interstitial lung emphysema (ILE) was assessed. Baseline lung disease was estimated as proposed by Palta. At autopsy, the degree of hyaline membranes, epithelial cell necrosis, emphysema, atelectasis, interstitial cell proliferation, and lung fibrosis was scored semiquantitatively (0 to 3+). The influence of neonatal infection, PDA, gestational age, survival, oxygen dose, or barotrauma on morphological findings was examined by multivariate analysis. We found "acute" BPD in 22, "reparative" in 34 and long-standing-"healed" in 16 cases. ILE within the first week was associated with interstitial cell proliferation and lung fibrosis in infants surviving more than 28 days. Initial barotrauma contributes to lung fibrosis in infants with BPD.

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.

Morphometric techniques in the evaluation of pulmonary vascular changes due to congenital heart disease.

Open lung biopsy is performed in patients with congenital heart disease to determine the suitability for surgical correction. Controversy exists as to whether arterial density can be graded with certainty. We studied the influence on the grading (Heath-Edwards) of two morphometric techniques. Lung tissue from 14 controls and biopsy specimens from 80 patients with atrial septal defect (n=10) ventricular septal defect (n=27), complete atrioventricular canal (n=27), miscellaneous lesions (n=8) and tetralogy of Fallot (n=8) were analyzed with a planimetric method. Additionally, wall thickness was determined in 52 patients by distance measurements. The ratio of alveoli/arteries per area of lung tissue was measured. Medial thickness was "increased" on distance measurements in 15% of the cases where planimetric data showed normal wall thickness. The ratio of alveoli/arteries varied up to 43% from the mean. Hemodynamic data obtained at a median (range) time of 2 months (1 day to 18 months) before the operation did not correlate with morphologic findings. In 27 patients hemodynamic data were recorded at a median time of 1 year (3 days to 44 months) after the operation. Intimal fibrosis occupying more than 10% of the vessel lumen was associated with persistent high pulmonary vascular resistance. We conclude that morphometric techniques are useful to determine the degree of fibrosis in advanced vascular lesions. Arterial density cannot be determined in biopsy specimens with adequate certainty.

[Microangiographic findings in experimental intestinal anastomoses]. / Mikroangiographische Befunde experimenteller Darmanastomosen.

Microangiography of anastomosis at the rat colon and the pig jejunum did reveal the postoperative state of vessel regeneration. Findings for evaluation were avascular areas, dislocation and dilatation of vessels, vessel break, vessel-anastomosis to the opposite site and to adhesions as well as the complete regeneration of the vessel architecture. A suture technique leading to correct apposition of the wound edges without destroying the circulation will be followed by an almost complete regeneration of the vessel architecture.

[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.

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.