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Macitentan is a safe and effective substance for treatment of adults with pulmonary arterial hypertension. Data on its use in paediatric patients are limited. In this single-centre prospective study, we report on our experience with macitentan in children focusing on applicability and practical aspects. Between December 2014 and July 2018, macitentan was introduced to paediatric patients according to a dosing protocol adjusted to body weight. Blood pressure, heart rate, saturation and clinical symptoms were recorded daily during introduction. Liver function parameters and haemoglobin levels were measured at baseline, four weeks and three months after initiation and after one year of treatment. Twenty-four patients (14 male, 10 female) were enrolled for treatment with macitentan. The mean age was 10.7 ± 7.6 years (range: 0.1 year–23 years). Fifteen out of 24 patients were World Health Organization functional class (FC) II, 7 patients in FC III and 2 patients in FC IV. Twenty out of 24 patients (83%) received additional advanced therapy with sildenafil and/or prostacyclines. We had two early discontinuations because of clinical relevant oedema. In the remaining 22 patients, macitentan was well tolerated. Liver function parameters and blood count levels remained stable during the observational time. The introduction of macitentan was feasible and mostly well tolerated in paediatric patients. Special attention should be paid to oedema during introduction of the drug. To the best of our knowledge, this is the first study to report on its applicability in infants and children. However, larger prospective trials are warranted to verify these preliminary findings.

Background and Purpose— Cerebral microbleed (CMB) location (deep versus strictly lobar) may elucidate underlying pathology with deep CMBs being more associated with hypertensive vascular disease and lobar CMBs being more associated with cerebral amyloid angiopathy. The objective of this study was to determine whether neuroimaging signs of vascular disease and Alzheimer pathology are associated with different types of CMBs. Methods— Among 1677 nondemented ARIC (Atherosclerosis Risk in Communities) participants (mean age=76±5 years; 40% men; 26% black) with 3-Tesla MRI scans at the fifth examination (2011–2013), we fit multinomial logistic regression models to quantify relationships of brain volumes (Alzheimer disease signature regions, total gray matter, frontal gray matter, and white matter hyperintensity volumes), infarct frequencies (lacunar, nonlacunar, and total), and apolipoprotein E (number of ε4 alleles) with CMB location (none, deep/mixed, or strictly lobar CMBs). Models were weighted for the sample selection scheme and adjusted for age, sex, education, hypertension, ever smoking status, diabetes mellitus, race site membership, and estimated intracranial volume (brain volume models only). Results— Deep/mixed and strictly lobar CMBs had prevalences of 8% and 16%, respectively. Larger white matter hyperintensity burden, greater total infarct frequency, smaller frontal volumes (in women only), and smaller total gray matter volume were associated with greater risk of both deep and lobar CMBs relative to no CMBs. Greater white matter hyperintensity volume was also associated with greater risk of deep relative to lobar CMBs. Higher lacunar and nonlacunar infarct frequencies were associated with higher risk of deep CMBs, whereas smaller Alzheimer disease signature region volume and apolipoprotein E ε4 homozygosity were associated with greater risk of lobar CMBs. Conclusions— CMBs are a common vascular pathology in the elderly. Markers of hypertensive small-vessel disease may contribute to deep CMBs while cerebral amyloid angiopathy may drive development of lobar CMBs.

We provide a practical approach on the initial assessment and diagnostic work-up of children and adolescents with pulmonary hypertension (PH). Transthoracic echocardiography (TTE) often serves as initial study tool before invasive cardiac catheterization. Misinterpretation of TTE variables may lead to missed or delayed diagnosis with devastating consequences, or unnecessary invasive diagnostics that have inherited risks. In addition to clinical and biochemical markers, serial examination of patients with PH using a standardized TTE approach, determining conventional and novel echocardiographic variables, may allow early diagnosis and treatment in paediatric PH. Cardiac magnetic resonance imaging and computed tomography represent important non-invasive imaging modalities, that together with TTE may enable comprehensive assessment of ventricular function and pulmonary hemodynamics. Invasive assessment of haemodynamics (ventricular, pulmonary) and testing of acute vasoreactivity in the catheterization laboratory is still the gold standard for the diagnosis of PH and pulmonary hypertensive vascular disease (PHVD) in children and for the initiation of specific PH therapy. We suggest the regular assessment of prognostic TTE variables as part of a standardized approach for initial diagnosis of children with PH. Overreliance on any single TTE variable should be avoided as it detracts from the overall diagnostic potential of a standardized TTE examination for PH.

Cardiac catheterization is important in the diagnosis and risk stratification of pulmonary hypertensive vascular disease (PHVD) in children. Acute vasoreactivity testing provides key information about management, prognosis, therapeutic strategies, and efficacy. Data obtained at cardiac catheterization continue to play an important role in determining the surgical options for children with congenital heart disease and clinical evidence of increased pulmonary vascular resistance. The Pediatric and Congenital Heart Disease Task Forces of the Pulmonary Vascular Research Institute met to develop a consensus statement regarding indications for, conduct of, acute vasoreactivity testing with, and pitfalls and risks of cardiac catheterization in children with PHVD. This document contains the essentials of those discussions to provide a rationale for the hemodynamic assessment by cardiac catheterization of children with PHVD.

Pulmonary hypertension in children is a disease with very high morbidity and mortality if left untreated. There has been increasing recognition of the need to appropriately classify and categorize childhood pulmonary hypertension with modifications in the 5th World Symposium classification and the Pulmonary Vascular Research Institute categorization of pulmonary hypertensive vascular disease into 10 groups at the Panama conference. There have also been efforts to appropriately describe the functional class pertinent to various age groups, and most recently, the American Heart Association and American Thoracic Society Guidelines on Pediatric Pulmonary Hypertension were published to appropriately diagnose and manage children with pulmonary hypertension. In this chapter, the authors discuss the evolution of various classifications, epidemiology, natural history, pathobiology, clinical presentation, diagnostic testing, and management principles for pediatric pulmonary hypertension.

Introduction: Cerebral microbleed (CMB) location may predict underlying pathology. Deep CMBs are more associated with hypertensive vascular disease, while lobar CMBs are more associated with cerebral amyloid angiopathy (CAA). The objective of this study was to determine the neuroimaging pathology associated with CMBs. Methods: We analyzed 1,831 nondemented ARIC participants (mean age=76.3 ±5.3 years, 40% male, 27% black) with 3T MRI scans at the fifth exam (2011-13). We fit multinomial logistic regression models to assess the effect of brain volumes (AD signature region atrophy, total gray matter, frontal, and log 2 -transformed white matter hyperintensities (WMH) volume), infarct frequencies (lacunar, non-lacunar, and total), and APOE (number of ε4 alleles) on CMB location (no, any deep, or lobar only CMBs). Models were weighted for the sample selection scheme and adjusted for age, male, education, hypertension, ever smoking status, diabetes, race-site membership, and estimated intracranial volume (brain volume models only). Results: The frequency of CMBs was 24.1%. A larger WMH volume, greater total infarct frequency, and smaller total grey volume increased the relative risks (RR) of both deep and lobar CMBs compared to no CMBs; increasing the WMH volume also increased the RR of deep to lobar CMBs. Additional lacunar infarcts increased the RR of deep compared to no CMBs, whereas AD signature region atrophy and APOE ε4 homozygosity increased the RR of lobar CMBs. Conclusion: CMBs are a common vascular pathology in the elderly. Deep CMB presence is associated with MRI features of hypertensive small vessel disease, while lobar CMB presence is associated with MRI features of CAA and Alzheimer’s disease.

Pulmonary hypertensive vascular disease (PHVD) is characterized by progressive narrowing of pulmonary arterioles, abnormally high pulmonary vascular resistance (PVR), right ventricular (RV) dysfunction, left ventricular (LV) compression, and death in ≈25% to 60% of patients with pulmonary arterial hypertension (PAH) 5 years after diagnosis.1,2 Meanwhile, consensus statements have been developed in North America and Europe specifically to guide the clinical care of children with pulmonary hypertension (PH).3,4 The challenges in the diagnosis5 and treatment6 of pediatric PH include early detection in the absence of specific symptoms or biomarkers, the complexity of the underlying etiologies, broad comorbidities, genetic syndromes, and the paucity of pediatric trial data to support and guide clinical management.7,8 See Article by Burkett et al The estimated prevalence of PAH is 2 to 16 cases per million children.9–11 Children diagnosed with PAH associated with congenital heart disease and those with idiopathic/heritable PAH have a similar 5-year mortality in North America (29% versus 25%; REVEAL registry).1 Untreated idiopathic PAH results in death within 2 to 3 years in adults and within 1 year after diagnosis in children,12 indicating that early diagnosis and early, sufficient (probably combinatory) PAH-targeted therapy is paramount. In children, PH is evident with a mean PA pressure ≥25 mm Hg when over 3 months of age at sea level.5,13 The term pediatric PAH (ie, group 1 PH) defines a subgroup of precapillary PH with an end-expiratory pulmonary artery wedge pressure (PAWP) 3 WU m2. In 2011, the Pulmonary Vascular Research Institute introduced the disease entity pediatric PHVD (mean PA pressure ≥25 …

A cohort of white males who had attended elementary schools in Hagerstown, Md., between 1923 and 1928, and whose height-weight records for those years were available, was examined during 1961-63. A study of their childhood relative weight at ages 9-13, and of their adult relative weight 35-40 years later, was made in relation to selected physiological variables and diagnosed morbidity.Essential findings were as follows: Childhood relative weight at ages 9-13 had no significant relationship to adult levels of fasting blood sugar, serum cholesterol, beta-lipoprotein, or blood pressure, or to cardiovascular renal disease.Childhood relative weight at ages 9-13 was significantly related to hypertensive vascular disease. The below average weight group experienced a higher prevalence than observed in either average or moderately overweight childhood groups.Approximately 30 percent of the below average weight children became average weight adults and 21 percent became overweight adults. Of the average weight children, approximately 40 percent became overweight adults. Overweight children tended to remain overweight as adults.Adult relative weight of the same cohort, viewed 35-40 years later, was significantly associated with fasting blood sugar, beta-lipoprotein, and systolic and diastolic blood pressure. Elevated levels of each of these variables occurred with greater frequency in the overweight child.Adult relative weight was significantly associated with hypertensive vascular disease and cardiovascular renal disease; the higher prevalence occurred in the overweight adults.The highest risk for hypertensive vascular and cardiovascular renal disease was associated with the persons who acquired their overweight status as adults. The higher prevalence of these diseases among the overweight adults was largely attributable to the adults who moved from a below average childhood weight category to an overweight adult group. The moderately or markedly overweight adults who was similarly classified as a child did not appear to be at greater risk than the average weight adult who had been an average weight child.

Congenital anomalies of the pulmonary veins are rare. Meandering right pulmonary vein, considered a part of the Scimitar syndrome spectrum, is often an incidental finding during chest imaging. We present the case of a 4-year-old girl diagnosed with meandering pulmonary vein, who developed pulmonary hypertensive disease with an aggressive course, in spite of absence of hypoxia or elevated pulmonary wedge pressure.