[Pulmonary hypertension in adults with congenital heart disease in light of the 2022-ESC-PAH guidelines - Part II: Supportive therapy, special situations (pregnancy, contraception, non-cardiac surgery), targeted pharmacotherapy, organ transplantation, special management (shunt lesions, left ventricular disorders, univentricular hearts), interventions, intensive care, follow-up, future perspectives]. / Pulmonale Hypertonie bei Erwachsenen mit angeborenen Herzfehlern im Lichte der 2022-ESC-PAH-Leitlinien.

The number of adults with congenital heart defects (CHD) is steadily rising and amounts to approximately 360,000 in Germany. CHD is often associated with pulmonary hypertension (PH), which may develop early in untreated CHD. Despite timely treatment of CHD, PH not infrequently persists or recurs in older age and is associated with significant morbidity and mortality.The revised European Society of Cardiology/European Respiratory Society 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart disease" is addressed only relatively superficial in these guidelines. Therefore, in the present article, this topic is commented in detail from the perspective of congenital cardiology.

Determinants of Diet Quality in Adolescents: Results from the Prospective Population-Based EVA-Tyrol and EVA4YOU Cohorts.

(1) Background: Unhealthy dietary behaviors are estimated to be one of the leading causes of death globally and are often shaped at a young age. Here, we investigated adolescent diet quality and its predictors, including nutrition knowledge, in two large Central European cohorts. (2) Methods: In 3056 participants of the EVA-Tyrol and EVA4YOU prospective population-based cohort studies aged 14 to 19 years, diet quality was assessed using the AHEI-2010 and DASH scores, and nutrition knowledge was assessed using the questionnaire from Turconi et al. Associations were examined utilizing multivariable linear regression. (3) Results: The mean overall AHEI-2010 score was 42%, and the DASH score was 45%. Female participants (60.6%) had a significantly higher diet quality according to the AHEI-2010 and DASH score. AHEI-2010 and DASH scores were significantly associated (p < 0.001) with sex, school type, smoking, and total daily energy intake. The DASH score was additionally significantly associated (p < 0.001) with age, socioeconomic status, and physical activity. Participants with better nutrition knowledge were more likely to be older, to attend a general high school, to live in a high-income household, to be non-smokers, and to have a higher diet quality according to the AHEI-2010 and DASH score. (4) Conclusions: Predictors of better diet quality included female sex, physical activity, educational level, and nutrition knowledge. These results may aid focused interventions to improve diet quality in adolescents.

Cardiovascular health profiles in adolescents being born term or preterm-results from the EVA-Tyrol study.

BACKGROUND AND AIMS: Preterm birth has been linked with an increased risk of cardiovascular (CV) disease from childhood into adolescence and early adulthood. In this study, we aimed to investigate differences in CV health profiles between former term- and preterm-born infants in a cohort of Tyrolean adolescents. METHODS: The Early Vascular Aging (EVA)-Tyrol study is a population-based non-randomized controlled trial, which prospectively enrolled 14- to 19-year-old adolescents in North Tyrol, Austria and South Tyrol, Italy between 2015 and 2018. Metrics of CV health (body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), smoking, physical activity, dietary patterns, total cholesterol and fasting blood glucose) were assessed and compared between former term- and preterm-born girls and boys. RESULTS: In total, 1,491 study participants (59.5% female, mean age 16.5 years) were included in the present analysis. SBP and DBP were significantly higher in former preterm-born adolescents (mean gestational age 34.6 ± 2.4 weeks) compared to term-born controls (p < 0.01). In the multivariate regression analysis these findings remained significant after adjustment for potential confounders in all models. No differences were found in all other CV health metrics. The number of participants meeting criteria for all seven health metrics to be in an ideal range was generally very low with 1.5% in former term born vs. 0.9% in former preterm born adolescents (p = 0.583). CONCLUSIONS: Preterm birth is associated with elevated SBP and DBP in adolescence, which was even confirmed for former late preterm-born adolescents in our cohort. Our findings underscore the importance of promoting healthy lifestyles in former term- as well as preterm-born adolescents. In addition, we advise early screening for hypertension and long-term follow-up in the group of preterm-born individuals.

Cormatrix® for vessel reconstruction in paediatric cardiac surgery-a word of caution.

OBJECTIVES: The aim of this retrospective study was to determine if Cormatrix® (CM) represents a safe alternative to conventional patch materials used in congenital heart surgery. METHODS: A total of 57 paediatric patients who underwent cardiac surgery using an Extracellular Matrix Bioscaffold (CM) were categorized into 4 groups according to the patch implant location. Patch-related complications and reintervention rates were analysed. A subgroup of 18 patients was subsequently compared to a matched group of 36 patients who underwent similar surgical procedures with autologous pericardium as patch material. RESULTS: No patient died during hospitalization. There were 2 late deaths, not related to the implanted CM patch. Fourteen (66.7%) out of 21 patients with arterial patch plasty developed progressive vessel/right ventricular outflow tract stenosis or aneurysm. All 3 patients with a valved CM conduit developed haemodynamically relevant valve stenosis or regurgitation. A total of 18 (31.5%) patients needed reintervention and 12 (21.1%) related to CM. Four (7%) patients needed surgical treatment with operative removal of the stenosis. Redo valve replacement was performed on 2 (3.5%) patients. Six (10.5%) patients required an interventional cardiology procedure at a median interval of 5 months from surgery. The subgroup analysis revealed a significantly lower patch-related reintervention rate in patients treated with autologous pericardium when compared to CM (P = 0.006). CONCLUSIONS: CM is safe for atrial and ventricular defect closure. The use of CM for arterial vessel reconstruction is associated with higher reintervention rates when compared to autologous pericardium.

Amino Acid and Phospholipid Metabolism as an Indicator of Inflammation and Subtle Cardiomyopathy in Patients with Marfan Syndrome.

Patients with Marfan syndrome (MFS) have an increased risk of aortic aneurysm formation, dissection and development of a subtle cardiomyopathy. We analyzed amino acid and lipid metabolic pathways in MFS patients, seeking biomarker patterns as potential monitoring tools of cardiovascular risk with deterioration of myocardial function. We assessed myocardial function in 24 adult MFS patients and compared traditional laboratory values and mass spectrometry-based amino acid, phospholipid and acylcarnitine metabolomes in patients with those in healthy controls. Analytes for which values differed between patients and controls were subjected to regression analysis. A high proportion of patients had signs of impaired diastolic function and elevated serum levels of NT-proBNP. Patients had lower serum levels of taurine, histidine and PCaeC42:3 than controls. The evidence of diastolic dysfunction, aortic root dimensions and history of aortic root surgery correlated with NT-proBNP and taurine levels. Alterations in serum levels of metabolism derived analytes link MFS pathophysiology with inflammation, oxidative stress and incipient cardiomyopathy.

Long-term outcomes after the paediatric Ross and Ross-Konno procedures.

OBJECTIVES: The Ross procedure is an attractive option for the management of aortic valve disease in paediatric patients. We reviewed our experience with the paediatric Ross procedure to determine survival and freedom from reoperation in the third decade after surgery. METHODS: We reviewed the data of 124 paediatric patients [71% male, median age at time of surgery 11.1 years (interquartile range 6-14.8 years); 63.7% bicuspid aortic valve], who underwent the Ross procedure at 2 tertiary centres from April 1991 to April 2020. The Ross-Konno procedures were performed on 14 (11.3%) patients. Deaths were cross-checked with the national health insurance database, and survival status was available for 96.8% of the patients. The median follow-up time was 12.1 years (interquartile range 3-18 years). RESULTS: There were 3 early and 6 late deaths. All early deaths occurred in patients aged <1 year at the time of surgery. The 25-year survival was 90.3%. Actuarial freedom from reoperation (linearized rates in parentheses) was as follows: Autograft reoperation was 90.8% (0.48%/patient-year) and right ventricular outflow tract (RVOT) reoperation was 67% (2.07%/patient year) at 25 years. The univariable Cox-proportional hazard analysis revealed younger age at time of surgery (P < 0.001), smaller implanted valve size (P < 0.001) and the use of a xenograft rather than a homograft (P < 0.001) as predictors of RVOT reoperation. At multivariable Cox-proportional hazard analysis, only age was an independent risk factor for RVOT reoperation (P = 0.041). CONCLUSIONS: The Ross and the Ross-Konno procedures are associated with good outcomes in paediatric patients. Reoperation of the RVOT is frequent and associated with younger age.

Cardiovascular health behaviors and associations of sex, age, and education in adolescents - Results from the EVA Tyrol study.

BACKGROUND AND AIMS: Ideal cardiovascular health (CVH) behaviors in adolescents are defined by body mass index (BMI), diet, physical activity and smoking, and are directly associated with better health in later life. To further improve health prevention programs we investigated the prevalence of these behaviors in a cohort of healthy adolescents and focused on the associations with sex, age, and education. METHODS AND RESULTS: The Early Vascular Aging Tyrol study is a cross-sectional study assessing 14- to 19-year-old pupils and apprentices in Western Austria and South Tyrol. Between May 2015 and July 2018 2047 adolescents (43.6% males, mean age 16.4 years) with complete data for all 4 health behaviors were included. The prevalence of ideal body mass index (BMI) was 78.3%, of ideal physical activity 42.5%, of non-smoking 70.4% and of ideal diet 8.1%. Females showed a higher smoking prevalence and a lower physical activity, but better dietary habits than males. Older adolescents of both sexes had lower prevalence of ideal smoking and diet. Apprentices and pupils of vocational schools had a higher BMI and a less favorable diet compared to secondary academic school students. Smoking prevalence was highest in apprentices. Non-ideal BMI was independently associated with smoking. CONCLUSION: In our cohort, only a minority showed ideal CVH behaviors which were best in adolescents younger than 16 years. We observed significant differences between males and females and a clear impact of school education with apprentices being at risk for non-ideal CVH behaviors. CLINICAL TRIAL REGISTRATION NUMBER: NCT03929692, clinicaltrials.gov.

Impact of lifestyle and cardiovascular risk factors on early atherosclerosis in a large cohort of healthy adolescents: The Early Vascular Ageing (EVA)-Tyrol Study.

BACKGROUND AND AIMS: Atherosclerosis starts early in life. We aimed to assess the dimension and progression of the intima-media thickness, a surrogate marker for early vascular aging, and its association with a broad palette of cardiovascular risk and lifestyle factors in a large cohort of healthy adolescents. METHODS: The EVA-Tyrol cohort study enrolled 1573 adolescents with a mean age of 16.0 years (SD 0.9). 1000 participants had a prospective follow-up after 22.1 months on average (SD 3.4). Cardiovascular risk and lifestyle factors were evaluated by standardized interviews, physical examination, and fasting blood analyses. Carotid intima-media thickness (cIMT) was measured at baseline and follow-up by high-resolution ultrasound. Aortic intima-media thickness (aIMT) was assessed during follow-up only. RESULTS: Several vascular risk factors like elevated blood pressure (4.7% > 95th percentile), overweight (9.2% > 95th percentile) and smoking (29.7%) were already prevalent at this age. Maximum cIMT progressed by 2.78 µm (95% CI, 0.39-5.17) per year. In multivariable linear regression analysis, sex, body weight, systolic blood pressure, LDL-cholesterol and physical activity were independent predictors of cIMT both at baseline and follow-up. In addition, alanine-aminotransferase, a laboratory surrogate of non-alcoholic fatty liver disease, was independently associated with cIMT at follow-up and pack-years of smoking with aIMT. CONCLUSIONS: Unfavourable lifestyle and vascular risk factors were prevalent in adolescents and several of them were associated with vessel wall thickness, even though effect sizes were modest and cIMT variability was limited. These data suggest adolescence as a prime age range for early vascular prevention.

Prophylactic low-dose paracetamol administration associated with lowered rate of patent ductus arteriosus in preterm infants - Impact on outcome and pain perception.

BACKGROUND: To determine the rate of patent ductus arteriosus after prophylactic low-dose paracetamol administration, the impact on outcome parameters, possible treatment side-effects and the influence on pain perception. METHODS: We report retrospective single-centre outcome data of premature infants ≤ 32 weeks of gestation (n = 476). The intervention group received intravenous paracetamol, the control group obtained no preventive therapy. Ductal closure rate and outcome parameters were compared between the two groups. Adverse effects were determined by laboratory parameters. For the assessment of pain the Bernese Pain Scale for Neonates was used. RESULTS: The rate of patent ductus arteriosus was significantly lower in the paracetamol-treated group compared to the control group (13.6% vs. 38.2%, p < 0.001). With regard to secondary outcome parameters, severe and moderate bronchopulmonary dysplasia (2.7% vs. 7.4%, p = 0.023), severe retinopathy of prematurity (0% vs. 4.4%, p = 0.002) and late onset sepsis (2.7% vs. 8.3%, p = 0.009) were significantly less frequent in the paracetamol group. Except for a 1.5-fold increased risk for hyperbilirubinemia (86.0% vs. 77.6%, p = 0.035) in the paracetamol group following treatment, no significant differences in laboratory parameters were found. Relating to pain, the administration of Glucose 33% was significantly more often necessary in the control group compared to the paracetamol-treated group (mean 13.48 vs. 8.71, p < 0.001), just as the need for additional treatment with systemic analgesics, which was more frequent in the control group (mean 0.72 vs. 0.57, p = 0.361). CONCLUSION: In our study we were able to show a significantly lower rate of patent ductus arteriosus after prophylactic paracetamol administration without serious adverse effect, but a beneficial influence of this regime on the patient's pain perception.

Impact of the Fontan Operation on Organ Systems.

In patients having undergone the Fontan operation, besides the well discussed changes in the cardiac, pulmonary and gastrointestinal system, alterations of further organ systems including the hematologic, immunologic, endocrinological and metabolic are reported. As a medical adjunct to Fontan surgery, the systematic study of the central role of the liver as a metabolizing and synthesizing organ should allow for a better understanding of the pathomechanism underlying the typical problems in Fontan patients, and in this context, the profiling of endocrinological and metabolic patterns might offer a tool for the optimization of Fontan follow-up, targeted monitoring and specific adjunct treatment.

Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets.

OBJECTIVE: To study angiotensin-converting enzyme 2 in a piglet model with acute respiratory distress syndrome and to evaluate the therapeutic potential of this substance in a preclinical setting, as this model allows the assessment of the same parameters required for monitoring the disease in human intensive care medicine. The acute respiratory distress syndrome is the most severe form of acute lung injury with a high mortality rate. As yet, there is no specific therapy for improving the clinical outcome. Recently, angiotensin-converting enzyme 2, which inactivates angiotensin II, has been shown to ameliorate acute lung injury in mice. DESIGN: Prospective, randomized, double-blinded animal study. SETTING: Animal research laboratory. SUBJECTS: Fifteen anesthetized and mechanically ventilated piglets. INTERVENTIONS: Acute respiratory distress syndrome was induced by lipopolysaccharide infusion. Thereafter, six animals were assigned randomly into angiotensin-converting enzyme 2 group, whereas another six animals served as control. Three animals received angiotensin-converting enzyme 2 without lipopolysaccharide pretreatment. MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary hemodynamics, blood gas exchange parameters, tumor necrosis factor-alpha, and angiotensin II levels were examined before acute respiratory distress syndrome induction and at various time points after administering angiotensin-converting enzyme 2 or saline. In addition, ventilation-perfusion distribution of the lung tissue was assessed by the multiple inert gas elimination technique. Animals treated with angiotensin-converting enzyme 2 maintained significantly higher PaO2 than the control group, and pulmonary hypertension was less pronounced. Furthermore, angiotensin II and tumor necrosis factor-alpha levels, both of which were substantially increased, returned to basal values. Multiple inert gas elimination technique revealed a more homogeneous pulmonary blood flow after treatment with angiotensin-converting enzyme 2. In intergroup comparisons, there were no differences in pulmonary blood flow to lung units with subnormal ventilation/perfusion ratios. CONCLUSIONS: Angiotensin-converting enzyme 2 attenuates arterial hypoxemia, pulmonary hypertension, and redistribution of pulmonary blood flow in a piglet model of acute respiratory distress syndrome, and may be a promising substance for clinical use.

Tolerability of inhaled N-chlorotaurine in the pig model.

BACKGROUND: N-chlorotaurine, a long-lived oxidant produced by human leukocytes, can be applied in human medicine as an endogenous antiseptic. Its antimicrobial activity can be enhanced by ammonium chloride. This study was designed to evaluate the tolerability of inhaled N-chlorotaurine (NCT) in the pig model. METHODS: Anesthetized pigs inhaled test solutions of 1% (55 mM) NCT (n = 7), 5% NCT (n = 6), or 1% NCT plus 1% ammonium chloride (NH4Cl) (n = 6), and 0.9% saline solution as a control (n = 7), respectively. Applications with 5 ml each were performed hourly within four hours. Lung function, haemodynamics, and pharmacokinetics were monitored. Bronchial lavage samples for captive bubble surfactometry and lung samples for histology and electron microscopy were removed. RESULTS: Arterial pressure of oxygen (PaO2) decreased significantly over the observation period of 4 hours in all animals. Compared to saline, 1% NCT + 1% NH4Cl led to significantly lower PaO2 values at the endpoint after 4 hours (62 +/- 9.6 mmHg vs. 76 +/- 9.2 mmHg, p = 0.014) with a corresponding increase in alveolo-arterial difference of oxygen partial pressure (AaDO2) (p = 0.004). Interestingly, AaDO2 was lowest with 1% NCT, even lower than with saline (p = 0.016). The increase of pulmonary artery pressure (PAP) over the observation period was smallest with 1% NCT without difference to controls (p = 0.91), and higher with 5% NCT (p = 0.02), and NCT + NH4Cl (p = 0.05).Histological and ultrastructural investigations revealed no differences between the test and control groups. The surfactant function remained intact. There was no systemic resorption of NCT detectable, and its local inactivation took place within 30 min. The concentration of NCT tolerated by A549 lung epithelial cells in vitro was similar to that known from other body cells (0.25-0.5 mM). CONCLUSION: The endogenous antiseptic NCT was well tolerated at a concentration of 1% upon inhalation in the pig model. Addition of ammonium chloride in high concentration provokes a statistically significant impact on blood oxygenation.

Intravenous tezosentan improves gas exchange and hemodynamics in acute lung injury secondary to meconium aspiration.

OBJECTIVE: Meconium aspiration induces acute lung injury (ALI) and subsequent pulmonary arterial hypertension (PAH) which may lead to right ventricular failure. Increase of endothelin-1, thromboxane-A, and phosphodiesterases are discussed molecular mechanisms. We investigated the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration. DESIGN: Animal study. SETTING: University-affiliated research laboratory. SUBJECTS: White farm pigs. INTERVENTIONS: Acute lung injury was induced in 24 pigs by instillation of meconium. Animals were randomly assigned to four groups to receive either intravenous tezosentan, inhalational iloprost, or combined tezosentan and iloprost, or to serve as controls. MEASUREMENTS AND RESULTS: After meconium aspiration-induced lung injury each treatment increased oxyhemoglobin saturations (TEZO: 88 +/- 6% (p = 0.02), ILO: 85 +/- 13% (p = 0.05), TEZO-ILO: 89 +/- 6% (p = 0.02), control: 70 +/- 18%). TEZO but not ILO significantly decreased pulmonary arterial pressure and pulmonary vascular resistance (both p < 0.01). ILO alone decreased intrapulmonary shunt blood flow (p < 0.01). Compared with control, TEZO-ILO yielded the highest arterial partial pressure of oxygen (70 +/- 6 torr vs.49 +/- 9 torr, p = 0.04), although it decreased arterial blood pressure (change from 71 +/- 13 mmHg to 62 +/- 12 mmHg vs.85 +/- 14 mmHg to 80 +/- 11 mmHg (p = 0.01). CONCLUSIONS: Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration. Inhaled ILO improves gas exchange only, thereby reducing intrapulmonary shunt blood flow. Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity.

Tezosentan decreases pulmonary artery pressure and improves survival rate in an animal model of meconium aspiration.

Acute pulmonary arterial hypertension in acute lung injury aggravates the clinical course and complicates treatment. Increased release and turnover of endogenous endothelin-1 is known to be a major determinant in the pathophysiology of pulmonary arterial hypertension of various etiologies. We tested whether intravenous tezosentan, a dual endothelin receptor antagonist, reduced pulmonary artery pressure in a pig model of acute lung injury induced by meconium aspiration. Acute pulmonary arterial hypertension was induced in 12 anesthetized and instrumented pigs by instillation of human pooled meconium in a 20% solution. Hemodynamic and gas exchange parameters were recorded every 30 min. Six animals received tezosentan 5 mg/kg after 0 and 90 min; six animals served as controls. Tezosentan led to a decrease of mean pulmonary artery pressure (PAP) from 33.4 +/- 4.0 mm Hg to 24.7 +/- 2.1 mm Hg and pulmonary vascular resistance (PVR) from 7.8 +/- 1.4 mm Hg.L(-1).min.m2 to 5.2 +/- 0.7 mm Hg.L(-1).min.m2. All animals treated with tezosentan survived, whereas in the control group four out of six animals died. Tezosentan improved survival and decreased pulmonary artery pressure in a porcine model of acute pulmonary arterial hypertension after meconium aspiration. Tezosentan has the potential for effective pharmacological treatment of pulmonary arterial hypertension following acute lung injury.

Pulmonary blood pressure, not flow, is associated with net endothelin-1 production in the lungs of patients with congenital heart disease and normal pulmonary vascular resistance.

OBJECTIVE: Endothelin-1 concentrations are increased in patients with increased mean pulmonary arterial pressure, pulmonary blood flow, and pulmonary vascular resistance. However, endothelin-1 concentrations have not been well characterized in patients with congenital heart disease and normal pulmonary vascular resistance. In particular, it is unclear whether pressure or flow is the key regulator of endothelin- 1 in this setting. We tested the hypothesis that pulmonary blood pressure and not flow is associated with net endothelin-1 production in patients with congenital heart disease and normal pulmonary vascular resistance. METHODS: With a commercially available immunoassay, we measured endothelin-1 concentrations in pulmonary arterial and pulmonary venous plasma of 56 consecutive patients with congenital heart disease and pulmonary vascular resistance less than 2 U. m(2) undergoing cardiac catheterization. We used multiple linear regression to analyze the effect of demographic and hemodynamic variables on pulmonary arterial and venous endothelin-1 concentrations and on the change of endothelin-1 concentration over the pulmonary vascular bed. RESULTS: Multiple linear regression revealed that of all the hemodynamic variables tested, mean pulmonary arterial pressure had the greatest effect on increasing the change of endothelin-1 concentration over the pulmonary vascular bed (P <.0001). Pulmonary blood flow did not have any effect on endothelin-1 concentrations or on the change of endothelin-1 concentration over the pulmonary vascular bed. CONCLUSIONS: This study shows that pulmonary blood pressure and not flow is associated with net endothelin-1 production in patients with congenital heart disease and normal pulmonary vascular resistance.