Efficacy and safety of macitentan in Fontan-palliated patients: 52-week randomized, placebo-controlled RUBATO Phase 3 trial and open-label extension.

OBJECTIVES: The efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL). METHODS: Patients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer from baseline to week 16. Safety was assessed throughout both studies. RESULTS: In RUBATO-DB, 137 patients were randomized to macitentan 10 mg (n = 68) or placebo (n = 69); 92.7% completed 52-week double-blind treatment. At week 16, mean ± SD change in peak oxygen consumption was -0.16 ± 2.86 versus -0.67 ± 2.66 mL/kg/minute with macitentan versus placebo (median unbiased treatment difference estimate, 0.62 mL/kg/minute [99% repeated CI, -0.62 to 1.85]; P = .19). No treatment effect was observed in either of the secondary end points. During RUBATO-DB, most common adverse events with macitentan were headache, nasopharyngitis, and pyrexia. Across RUBATO-DB and RUBATO-OL, most common adverse events were COVID-19, headache, and fatigue. RUBATO-OL was prematurely discontinued because RUBATO-DB did not meet its primary or secondary end point. CONCLUSIONS: The primary end point of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in patients with Fontan palliation. Macitentan was generally well tolerated over long-term treatment.

Prognostic Significance of Hemodynamics in Patients With Transposition of the Great Arteries and Systemic Right Ventricle.

BACKGROUND: Patients with transposition of the great arteries (TGA) and systemic right ventricle often confront significant adverse cardiac events. The prognostic significance of invasive hemodynamic parameters in this context remains uncertain. Our hypothesis is that the aortic pulsatility index and hemodynamic profiling utilizing invasive measures provide prognostic insights for patients with TGA and a systemic right ventricle. METHODS: This retrospective multicenter cohort study encompasses adults with TGA and a systemic right ventricle who underwent cardiac catheterization. Data collection, spanning from 1994 to 2020, encompasses clinical and hemodynamic parameters, including measured and calculated values such as pulmonary capillary wedge pressure, aortic pulsatility index, and cardiac index. Pulmonary capillary wedge pressure and cardiac index values were used to establish 4 distinct hemodynamic profiles. A pulmonary capillary wedge pressure of ≥15 mm Hg indicated congestion, termed wet, while a cardiac index <2.2 L/min per m2 signified inadequate perfusion, labeled cold. The primary outcome comprised a composite of all-cause death, heart transplantation, or the requirement for mechanical circulatory support. RESULTS: Of 1721 patients with TGA, 242 individuals with available invasive hemodynamic data were included. The median follow-up duration after cardiac catheterization was 11.4 (interquartile range, 7.5-15.9) years, with a mean age of 38.5±10.8 years at the time of cardiac catheterization. Among hemodynamic parameters, an aortic pulsatility index <1.5 emerged as a robust predictor of the primary outcome, with adjusted hazard ratios of 5.90 (95% CI, 3.01-11.62; P<0.001). Among the identified 4 hemodynamic profiles, the cold/wet profile was associated with the highest risk for the primary outcome, with an adjusted hazard ratio of 3.83 (95% CI, 1.63-9.02; P<0.001). CONCLUSIONS: A low aortic pulsatility index (<1.5) and the cold/wet hemodynamic profile are linked with an elevated risk of adverse long-term cardiac outcomes in patients with TGA and systemic right ventricle.

Medical Therapy and Monitoring in Adult Congenital Heart Disease Heart Failure.

Heart failure (HF) in adult congenital heart disease (ACHD) is an increasingly common problem facing ACHD and advanced heart disease and transplant providers. Patients are highly nuanced, and therapies are poorly studied. Standard HF medications are often used in patients who are not targets of large clinical trials. HF management in this data-free zone requires focused, comprehensive team-based care and close follow-up and communication with patients.

End-stage heart failure in congenitally corrected transposition of the great arteries: a multicentre study.

BACKGROUND AND AIMS: For patients with congenitally corrected transposition of the great arteries (ccTGA), factors associated with progression to end-stage congestive heart failure (CHF) remain largely unclear. METHODS: This multicentre, retrospective cohort study included adults with ccTGA seen at a congenital heart disease centre. Clinical data from initial and most recent visits were obtained. The composite primary outcome was mechanical circulatory support, heart transplantation, or death. RESULTS: From 558 patients (48% female, age at first visit 36 ± 14.2 years, median follow-up 8.7 years), the event rate of the primary outcome was 15.4 per 1000 person-years (11 mechanical circulatory support implantations, 12 transplantations, and 52 deaths). Patients experiencing the primary outcome were older and more likely to have a history of atrial arrhythmia. The primary outcome was highest in those with both moderate/severe right ventricular (RV) dysfunction and tricuspid regurgitation (n = 110, 31 events) and uncommon in those with mild/less RV dysfunction and tricuspid regurgitation (n = 181, 13 events, P < .001). Outcomes were not different based on anatomic complexity and history of tricuspid valve surgery or of subpulmonic obstruction. New CHF admission or ventricular arrhythmia was associated with the primary outcome. Individuals who underwent childhood surgery had more adverse outcomes than age- and sex-matched controls. Multivariable Cox regression analysis identified older age, prior CHF admission, and severe RV dysfunction as independent predictors for the primary outcome. CONCLUSIONS: Patients with ccTGA have variable deterioration to end-stage heart failure or death over time, commonly between their fifth and sixth decades. Predictors include arrhythmic and CHF events and severe RV dysfunction but not anatomy or need for tricuspid valve surgery.

COVID-19-Related Thrombotic and Bleeding Events in Adults With Congenital Heart Disease.

Background: Altered coagulation is a striking feature of COVID-19. Adult patients with congenital heart disease (ACHD) are prone to thromboembolic (TE) and bleeding complications. Objectives: The purpose of this study was to investigate the prevalence and risk factors for COVID-19 TE/bleeding complications in ACHD patients. Methods: COVID-19-positive ACHD patients were included between May 2020 and November 2021. TE events included ischemic cerebrovascular accident, systemic and pulmonary embolism, deep venous thrombosis, myocardial infarction, and intracardiac thrombosis. Major bleeding included cases with hemoglobin drop >2 g/dl, involvement of critical sites, or fatal bleeding. Severe infection was defined as need for intensive care unit, endotracheal intubation, renal replacement therapy, extracorporeal membrane oxygenation, or death. Patients with TE/bleeding were compared to those without events. Factors associated with TE/bleeding were determined using logistic regression. Results: Of 1,988 patients (age 32 [IQR: 25-42] years, 47% male, 59 ACHD centers), 30 (1.5%) had significant TE/bleeding: 12 TE events, 12 major bleeds, and 6 with both TE and bleeding. Patients with TE/bleeding had higher in-hospital mortality compared to the remainder cohort (33% vs 1.7%; P < 0.0001) and were in more advanced physiological stage (P = 0.032) and NYHA functional class (P = 0.01), had lower baseline oxygen saturation (P = 0.0001), and more frequently had a history of atrial arrhythmia (P < 0.0001), previous hospitalization for heart failure (P < 0.0007), and were more likely hospitalized for COVID-19 (P < 0.0001). By multivariable logistic regression, prior anticoagulation (OR: 4.92; 95% CI: 2-11.76; P = 0.0003), cardiac injury (OR: 5.34; 95% CI: 1.98-14.76; P = 0.0009), and severe COVID-19 (OR: 17.39; 95% CI: 6.67-45.32; P < 0.0001) were independently associated with increased risk of TE/bleeding complications. Conclusions: ACHD patients with TE/bleeding during COVID-19 infection have a higher in-hospital mortality from the illness. Risk of coagulation disorders is related to severe COVID-19, cardiac injury during infection, and use of anticoagulants.

Long-Term Outcomes After Atrial Switch Operation for Transposition of the Great Arteries.

BACKGROUND: For patients with d-loop transposition of the great arteries (d-TGA) with a systemic right ventricle after an atrial switch operation, there is a need to identify risks for end-stage heart failure outcomes. OBJECTIVES: The authors aimed to determine factors associated with survival in a large cohort of such individuals. METHODS: This multicenter, retrospective cohort study included adults with d-TGA and prior atrial switch surgery seen at a congenital heart center. Clinical data from initial and most recent visits were obtained. The composite primary outcome was death, transplantation, or mechanical circulatory support (MCS). RESULTS: From 1,168 patients (38% female, age at first visit 29 ± 7.2 years) during a median 9.2 years of follow-up, 91 (8.8% per 10 person-years) met the outcome (66 deaths, 19 transplantations, 6 MCS). Patients experiencing sudden/arrhythmic death were younger than those dying of other causes (32.6 ± 6.4 years vs 42.4 ± 6.8 years; P < 0.001). There was a long duration between sentinel clinical events and end-stage heart failure. Age, atrial arrhythmia, pacemaker, biventricular enlargement, systolic dysfunction, and tricuspid regurgitation were all associated with the primary outcome. Independent 5-year predictors of primary outcome were prior ventricular arrhythmia, heart failure admission, complex anatomy, QRS duration >120 ms, and severe right ventricle dysfunction based on echocardiography. CONCLUSIONS: For most adults with d-TGA after atrial switch, progress to end-stage heart failure or death is slow. A simplified prediction score for 5-year adverse outcome is derived to help identify those at greatest risk.

COVID-19 in Adults With Congenital Heart Disease.

BACKGROUND: Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications. OBJECTIVES: This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes. METHODS: Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide. Data collection included anatomic diagnosis and subsequent interventions, comorbidities, medications, echocardiographic findings, presenting symptoms, course of illness, and outcomes. Predictors of death or severe infection were determined. RESULTS: From 58 adult CHD centers, the study included 1,044 infected patients (age: 35.1 ± 13.0 years; range 18 to 86 years; 51% women), 87% of whom had laboratory-confirmed coronavirus infection. The cohort included 118 (11%) patients with single ventricle and/or Fontan physiology, 87 (8%) patients with cyanosis, and 73 (7%) patients with pulmonary hypertension. There were 24 COVID-related deaths (case/fatality: 2.3%; 95% confidence interval: 1.4% to 3.2%). Factors associated with death included male sex, diabetes, cyanosis, pulmonary hypertension, renal insufficiency, and previous hospital admission for heart failure. Worse physiological stage was associated with mortality (p = 0.001), whereas anatomic complexity or defect group were not. CONCLUSIONS: COVID-19 mortality in adults with CHD is commensurate with the general population. The most vulnerable patients are those with worse physiological stage, such as cyanosis and pulmonary hypertension, whereas anatomic complexity does not appear to predict infection severity.

Transition of Adolescents and Young Adults with Congenital Heart Disease: Challenges, Progress, and Future Improvements.

Congenital heart disease (CHD) is the most common and perhaps most widely variable birth defect. Decades of improved CHD care has resulted in a steady growth in the number and complexity of adults with CHD, and many of these patients require lifelong, specialized follow-up care. This begins with successful transition from pediatric-based to adult-based care. Despite the remarkable advances in this field, many adults with CHD still experience lapses in care that have significant health consequences. This review outlines some of the challenges, progress, and areas for improvement in CHD transition medicine. [Pediatr Ann. 2017;46(6):e224-e228.].

Progress in the diagnosis and management of pulmonary hypertension in children.

PURPOSE OF REVIEW: Pulmonary hypertension is a complex disease that extends beyond merely elevated pulmonary blood pressures and right ventricular dysfunction. Its multiple causes and ever-expanding diagnostic tools and therapeutic approaches make it a heterogeneous disease with widely variable clinical sequelae. There are still many unanswered questions that challenge our understanding of this disease. RECENT FINDINGS: The study of pulmonary hypertension in the pediatric patient is as robust as ever, with the creation and inclusion of pediatric-specific disease characteristics in the most recent WHO classification system, improved understanding of the pathophysiology of pulmonary hypertension in pediatric diseases such as bronchopulmonary dysplasia, and increasingly expanding diagnostic tools and management possibilities. Although the use of pulmonary hypertension therapies in children previously often relied on expert opinion and inferences from studies involving adults, pediatric-targeted research is becoming more widely supported and pursued, and has even come under recent debate, which at the very least stimulates further collaboration and discussion. SUMMARY: This review will highlight the changes in the pulmonary hypertension classification system, briefly explore pulmonary hypertension in bronchopulmonary dysplasia, and provide updates on the diagnostic and management tools used by experts in the field.

Perioperative management of shock in two fontan patients with plastic bronchitis.

Plastic bronchitis is potentially a life-threatening complication of long-standing surgically palliated single ventricle congenital heart disease. Patients can present with hypoxia requiring urgent bronchoscopy for removal of bronchial casts. Perioperative care for these patients is challenging and anesthesia is associated with significant cardiac risk. As more surgically corrected single ventricle patients survive to adulthood, these patients are expected to present more frequently. This report details the perioperative management of 2 Fontan patients with hypoxia and significant plastic bronchitis disease burden.

Bicuspid aortic valve: inter-racial difference in frequency and aortic dimensions.

OBJECTIVES: The objective of this study was to examine the similarities and differences in Caucasian (C) and African-American (AA) patients with bicuspid aortic valve (BAV) with respect to morphology, severity of aortic stenosis/insufficiency, and aortic dilation. BACKGROUND: BAV is a common congenital valve abnormality, accounting for a large number of valve replacements. METHODS: A total of 229 patients with the diagnostic code BAV were identified retrospectively from our computerized adult echocardiographic database, which consists of 91,896 studies performed at the University of Chicago Medical Center from 1998 to 2009, representing 40,878 patients. Of those, 183 patients with BAV were included in this retrospective BAV single-center cohort study and reanalyzed with a comprehensive assessment of aortic dimensions, aortic valve morphology and function, clinical cardiovascular risk factors, and patient characteristics. RESULTS: Of the 183 patients with BAV, 138 were C and 45 were AA. Our echocardiographic database encompasses approximately 65% AA, 31% C, and 4% other races, for an estimated frequency of BAV in AA patients of 0.17% and a frequency in C patients of 1.1% (p = 0.001). There were no significant inter-racial differences regarding sex, height, weight, hyperlipidemia, diabetes, tobacco use, cardiac medications, and left ventricular ejection fraction. The AA cohort was older (age 50 ± 17 years vs. 43 ± 17 years, p < 0.05) and had a higher prevalence of hypertension (51% vs. 24%, p < 0.05). After adjusting for comorbidities, aortic dimensions were larger in C (C vs. AA: annulus, 2.4 ± 0.4 vs. 2.1 ± 0.4 cm; sinuses of Valsalva, 3.4 ± 0.7 vs. 3.1 ± 0.6 cm; sinotubular junction, 3.0 ± 0.6 vs. 2.6 ± 0.5 cm; and ascending aorta, 3.5 ± 0.7 vs. 3.2 ± 0.5 cm; all p values <0.05). CONCLUSIONS: This is the first study to report racial differences among patients with BAV with reduced aortic dimensions in AA patients despite the presence of more risk factors, suggestive of marked heterogeneity in the BAV population and indicating race as a potential disease modifier in BAV.

Cardiac sarcoidosis presenting as mitral regurgitation.

Cardiac sarcoidosis is most often clinically silent. When symptomatic, it commonly involves the conduction system. This inflammatory and infiltrative process may be manifest as conduction delays and/or important ventricular ectopy. More diffuse myocardial infiltration may result in congestive heart failure (CHF). This case report illustrates how a more focal infiltrative process in sarcoidosis may cause severe CHF with involvement of the papillary muscle, resulting in worsening of mitral regurgitation. After a cardiac workup that revealed evidence of sarcoidosis, a gadolinium-enhanced magnetic resonance imaging series showed focal infiltration of the left ventricular wall over the region of the posterior papillary muscle, giving a pathophysiologic explanation for the patient's severe mitral regurgitation. This case report depicts sarcoidosis-associated CHF arising in an unusual fashion, resulting not from widespread myocardial infiltration, but rather from focal papillary muscle involvement and, consequently, mitral valve dysfunction. This example suggests that cardiac sarcoidosis should be considered in the differential diagnosis of mitral regurgitation leading to progressive CHF. We briefly review the diagnostic approach to cardiac sarcoidosis, with representative images from this case.

Inhibition of protein kinase C epsilon causes ciliated bovine bronchial cell detachment.

This study defines the in vitro phenomenon of ciliated bovine bronchial epithelial cell (BBEC) detachment from the basal epithelium and regulation of cilia motility mediated through protein kinase C epsilon (PKCepsilon). The authors determined the time course of activation and downregulation of PKCepsilon by the known PKC activator phorbol 12-myristate 13-acetate (PMA) and demonstrate that chemical inhibition of PKC by calphostin C or the novel PKC isoform inhibitor Ro 31-8220 induced striking detachment of ciliated BBECs from the basal cell monolayer within 1 hour, independent of apoptosis or necrotic cell death. The results of this study support a possible novel PKCepsilon-mediated signaling pathway through which ciliated cell attachment is maintained.

Ubiquitin-proteasome degradation of serum- and glucocorticoid-regulated kinase-1 (SGK-1) is mediated by the chaperone-dependent E3 ligase CHIP.

SGK-1 (serum- and glucocorticoid-regulated kinase-1) is a stress-induced serine/threonine kinase that is phosphorylated and activated downstream of PI3K (phosphoinositide 3-kinase). SGK-1 plays a critical role in insulin signalling, cation transport and cell survival. SGK-1 mRNA expression is transiently induced following cellular stress, and SGK-1 protein levels are tightly regulated by rapid proteasomal degradation. In the present study we report that SGK-1 forms a complex with the stress-associated E3 ligase CHIP [C-terminus of Hsc (heat-shock cognate protein) 70-interacting protein]; CHIP is required for both the ubiquitin modification and rapid proteasomal degradation of SGK-1. We also show that CHIP co-localizes with SGK-1 at or near the endoplasmic reticulum. CHIP-mediated regulation of SGK-1 steady-state levels alters SGK-1 kinase activity. These data suggest a model that integrates CHIP function with regulation of the PI3K/SGK-1 pathway in the stress response.