Aortopulmonary Collateral Arteries in Noncyanotic Congenital Heart Disease.

Development of major aortopulmonary collateral arteries are strongly associated with cyanotic congenital heart disease. However, they have rarely been reported in noncyanotic congenital heart disease. We report a rare case of a newborn originally diagnosed with an atrial septal defect, a ventricular septal defect, and pulmonary arterial hypertension who underwent complete repair. Failure to progress postoperatively lead to the delayed diagnosis of aortopulmonary collateral arteries. Percutaneous embolization and surgical ligation of aortopulmonary collateral arteries resulted in rapid recovery.

Follow-Up Study of Electrocardiographic Indices in 252 Children with Ventricular Septal Defect after Minimally Invasive Transthoracic Closure.

OBJECTIVE: The aim of this study was to explore the efficacy and safety of minimally invasive transthoracic closure (MITC) in treating ventricular septal defect (VSD). METHODS: A total of 252 children with VSD were investigated between August 2013 and March 2015. Their electrocardiographic indices were monitored at different time points (before surgery [T0], immediately after surgery [T1], and 3 days/7 days/1 month/3 months/6 months after surgery [T2-6]) and followed up every year. Related adverse events also were recorded. RESULTS: All children with VSD successfully underwent MITC. The average follow-up time was 5 years, during which no changes in the heart rate or corrected QT interval were found. The PR and QRS intervals were prolonged in the early postoperative period (T3); the SV1+RV5 amplitude decreased significantly at T6, and the left axis deviation significantly recovered at T6 (P < 0.05). A total of 32 patients developed arrhythmia within 3 days after surgery; however, no severe arrhythmia, including ventricular tachycardia, ventricular fibrillation, second-and third-degree atrioventricular block, complete left or right bundle branch block, and delayed arrhythmia, occurred during the follow-up period. Binary multivariate logistic regression revealed that the longer the surgery time and the larger the VSD diameter, the higher the risk of arrhythmia. CONCLUSIONS: The incidence of long-term arrhythmia after MITC is low, and the outcomes are good.

The midterm effect of exercise capacity and quality of life in adult patients who underwent hybrid transthoracic device closure of ventricular septal defects.

OBJECTIVE: To investigate the midterm effect of exercise capacity and quality of life (QoL) of adult patients who underwent transthoracic device closure of ventricular septal defects (VSDs) and explore the gap in the quality of life and cardiopulmonary function between those patients and healthy people. METHODS: From January 2010 to January 2015, 58 adult patients who underwent transthoracic device closure of VSD and 60 healthy people matched for age and sex were selected and analyzed. Echocardiography and exercise capacity tests were performed, and the MOS 36-item short-form health survey (SF-36) was used to investigate the changes in QoL. RESULTS: Fifty-five patients completed the study. At the 1-year and 5-year follow-ups, the patients' left ventricular end-systolic and end-diastolic diameters were smaller than those preoperatively, but the difference was not statistically significant. In the QoL survey, the patients' scores after treatment showed a trend of improvement, and the improvement effect was not transient. After VSD closure, the difference in QoL between the patients and the control group was significantly reduced. However, in the exercise capacity test, the patients' results were still worse than those of the controls. CONCLUSION: Transthoracic device closure of VSDs is significant in improving adult patients' QoL at the midterm follow-up, reflected in their physical and psychological fields. However, they are still unable to achieve normal levels of peak exercise ability. Therefore, further exploration and interventions are worth considering.

Computational simulation-derived hemodynamic and biomechanical properties of the pulmonary arterial tree early in the course of ventricular septal defects.

Untreated ventricular septal defects (VSDs) can lead to pulmonary arterial hypertension (PAH) characterized by elevated pulmonary artery (PA) pressure and vascular remodeling, known as PAH associated with congenital heart disease (PAH-CHD). Though previous studies have investigated hemodynamic effects on vascular mechanobiology in late-stage PAH, hemodynamics leading to PAH-CHD initiation have not been fully quantified. We hypothesize that abnormal hemodynamics from left-to-right shunting in early stage VSDs affects PA biomechanical properties leading to PAH initiation. To model PA hemodynamics in healthy, small, moderate, and large VSD conditions prior to the onset of vascular remodeling, computational fluid dynamics simulations were performed using a 3D finite element model of a healthy 1-year-old's proximal PAs and a body-surface-area-scaled 0D distal PA tree. VSD conditions were modeled with increased pulmonary blood flow to represent degrees of left-to-right shunting. In the proximal PAs, pressure, flow, strain, and wall shear stress (WSS) increased with increasing VSD size; oscillatory shear index decreased with increasing VSD size in the larger PA vessels. WSS was higher in smaller diameter vessels and increased with VSD size, with the large VSD condition exhibiting WSS >100 dyn/cm[Formula: see text], well above values typically used to study dysfunctional mechanotransduction pathways in PAH. This study is the first to estimate hemodynamic and biomechanical metrics in the entire pediatric PA tree with VSD severity at the stage leading to PAH initiation and has implications for future studies assessing effects of abnormal mechanical stimuli on endothelial cells and vascular wall mechanics that occur during PAH-CHD initiation and progression.

Transthoracic echocardiography monitoring during atrial septal defect and ventricular septal defect device closures using a three-dimensional printed transducer holder.

Transthoracic echocardiography (TTE) is noninvasive but can only be performed intermittently during fluoroscopy. In a prior study, we created a transducer holder device to allow for hemodynamic monitoring in the intensive care unit. The current study is the first instance of the use of a three-dimensional (3D)-printed TTE transducer holder, which is easily customized and personalized to a previous transducer holder at relatively low cost and short production time, to enable continuous TTE monitoring during device closure of an atrial septal defect (ASD) and ventricular septal defect (VSD). There were 14 ASD patients and 9 VSD patients scheduled to undergo device closure. The study's real-time TTE monitoring was performed by using a 3D-printed transducer holder over the course of the entire implantation procedure. There were 23 patients who successfully underwent septal closures using the 3D-printed holder that enabled real-time images over the entire procedure. The median duration for real-time TTE guidance was 15 minutes for the ASD and 36 minutes for the VSD and the median fluoroscopy time was 11 minutes for the ASD and 30 minutes for the VSD. One migrating VSD occluder and one case of aortic regurgitation after occluder deployment were noted by real-time TTE monitoring during the procedure. Our novel 3D-printed transducer holder can provide transesophageal echocardiography-like real-time imaging during device closure of an ASD and a VSD and may become a new alternative method in ASD and VSD closures. It can also prevent radiation exposure for the intervention team who would otherwise need to perform TTE during live fluoroscopy.

Determinants of Physical Fitness in Children with Repaired Congenital Heart Disease.

The aim of this study was to determine factors associated with physical fitness (PF) in children who underwent surgery for congenital heart disease (CHD). Sixty-six children (7-14 years) who underwent surgery for ventricular septal defect (n = 19), transposition of great arteries (n = 22), coarctation of aorta (n = 10), and tetralogy of Fallot (n = 15) were included. All children performed PF tests: cardiorespiratory fitness, upper- and lower-limb muscle strength, speed, balance, and flexibility. Cardiac evaluation was done via echocardiography and cardiopulmonary exercise test. Factors related to child's characteristics, child's lifestyle, physical activity motivators/barriers, and parental factors were assessed. Linear regression analyses were conducted. The results showed no significant differences in physical activity (PA) level by CHD type. Boys had better cardiorespiratory fitness (difference = 1.86 ml/kg/min [0.51;3.22]) and were more physically active (difference = 19.40 min/day [8.14;30.66]), while girls had better flexibility (difference = - 3.60 cm [- 7.07;- 0.14]). Physical activity motivators showed an association with four out of six PF components: cardiorespiratory fitness, coefficient = 0.063 [0.01;0.11]; upper-limb muscle strength, coefficient = 0.076 [0.01;0.14]; lower-limb muscle strength, coefficient = 0.598 [0.07;1.13]; and speed, coefficient = 0.03 [0.01;0.05]. Age, sex, and motivators together reached a maximum adjusted R2 = 0.707 for upper-limb strength. Adding other possible determinants did not significantly increase the explained variance. Apart from age and sex as non-modifiable determinants, the main target which might improve fitness would be the introduction of an intervention which increases the motivation to be active.

Does tricuspid valve detachment improve outcomes compared with the non-tricuspid valve detachment approach in ventricular septal defect closure?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether the tricuspid valve detachment (TVD) approach to ventricular septal defect repair provides superior outcomes compared with the non-TVD approach. Altogether more than 54 papers were found using the reported search, of which 10 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. A total of 2059 participants were enrolled in the 10 studies, including 2 prospective studies and 8 retrospective studies. Six studies demonstrated a longer cardiopulmonary bypass time or aortic clamp time in the TVD group, whereas 4 studies showed no difference. Only 1 study reported a lower incidence of trivial tricuspid regurgitation in the TVD group, whereas the other 9 studies showed no significant difference. One study showed that a higher incidence of residual shunting occurred in those patients who had indications for TVD but did not perform detachment during surgery. No difference in postoperative residual shunting was demonstrated in the other 9 studies. We conclude that surgeons should be reassured that if TVD is required to repair the ventricular septal defect, although it may lead to longer cardiopulmonary bypass time and cross-clamp times, outcomes are equivalent in terms of the degree of tricuspid regurgitation and incidence of the residual ventricular septal defect.

Valve patch technique for repair of ventricular septal defect: long-term results.

OBJECTIVE: This study aimed to show the long-term results in patients who underwent unidirectional valve patch repair of ventricular septal defect with pulmonary artery hypertension. METHODS: Thirty-five acyanotic patients aged 2 to 26 years (mean 9.3 years) with a large ventricular septal defect and elevated pulmonary vascular resistance (mean 9.5 Wood units) underwent surgery in Madani Heart Hospital. The medical records and clinical outcomes were reviewed from March 1998 to March 2017. RESULTS: Five patients died in the first postoperative week. In the long-term follow-up (mean 11 years), two patients were lost to follow-up. Pulmonary artery hypertension gradually decreased in 17 patients within 6-12 months with significant improvement in right ventricular end-diastolic diameter, New York Heart Association functional class, and tricuspid regurgitation. Eleven patients with persistent pulmonary artery hypertension were divided into tolerable and non-tolerable groups. Six patients in the tolerable group had satisfactory conditions compared to before the operation, and gained weight with improved functional class despite echocardiographic findings of persistent elevated pulmonary artery pressure. One had a full-term delivery by caesarean section in the fifth postoperative year. Five patients in the non-tolerable group gradually developed right heart failure and complications such as extremity edema, ascites, pleural effusions, and died after 10-30 months. CONCLUSION: Although relatively high mortality occurred during long-term follow-up, surviving patients were in a better condition and functional class despite persistent pulmonary artery hypertension. Therefore, fear of persistent pulmonary artery hypertension should not prohibit surgery in this group of patients.

COVID-19 pneumonia in an infant with a hemodynamically significant ventricular septal defect.

Reports thus far suggest a mild course for acute COVID-19 infection in children; however, its effects in vulnerable paediatric populations, including children with haemodynamically significant congenital heart disease, have rarely been reported. We therefore report on a 4-month-old Hispanic male with a moderate sized conoventricular ventricular septal defect and pulmonary overcirculation who presented with COVID-19-associated pneumonia.

Effect of transcatheter closure by AmplatzerTM Duct Occluder II in patients with small ventricular septal defect.

Transcatheter closure of ventricular septal defect (VSD) is an alternative treatment of surgery. However, because of the potential risk of the complete atrioventricular block (AVB) and the lack of available dedicated devices for VSD, this procedure rarely used most centers. Recently in Thailand, with distinct device design that may cause less clamp force and radial force, the AmplatzerTMDuct Occluder (ADO) II has become available for the closure of small VSDs. This is a retrospective review of 49 patients who underwent transcatheter VSD closure using ADO II at Songklanagarind hospital and Queen Sirikit National Institute of Child Health between January 2014 and December 2016 with an intention to report procedural success rate and 12-months-outcomes. Twenty-six cases were female. The median age and weight at treatment were 7.8 year (ranged from 1.9 to 25 year) and 25.1 kg (ranged from 11 and 57 kg). The majority (65.3%) of the VSD was a perimembranous defect. The mean diameter of LV entry was 5.2 ± 2.5 mm and the mean RV exit was 3.2 ± 0.8 mm. Four patients had more than 1 exit at RV orifice. The mean length of the VSD was 5.3 ± 1.8 mm. The mean aortic valve-VSD distance was 3.9 ± 2.0 mm. The mean tricuspid valve-VSD distance was 3.8 ± 2.5 mm. The procedural success achieved in all patients (100%), most of the implantations were performed in a retrograde approach (53.1%). The ADO II was successfully implanted in 2 cases (5%) who failed other devices in the first attempts. There were no major complications. There were no changes in the severity of tricuspid and aortic valve regurgitation immediate after implantation and at 12 months' follow-up. Three patients (6%) had tiny to small residual shunt at 12 months' follow-up. None of the patients had a complete heart block. However, new-onset of left bundle branch block and right bundle branch block occurred in 2 (5%) cases and 5 (10%) cases, respectively. With symmetrical double-disc design and softness of the device, the ADO II can be safely and effectively used for closure of the VSDs with the defect size less than 6 mm.

Percutaneous closure of moderate to large perimembranous ventricular septal defect in small children using left ventricular mid-cavity approach.

AIM & OBJECTIVE: To report mid-term follow-up result of transcatheter closure of perimembranous Ventricular septal defect (VSD) in children weighing less than 10 kg using Amplatzer Duct Occlude-I (ADO-I) by left ventricular (LV) mid-cavity approach. MATERIAL & METHOD: This is retrospective review of 35 children weighing less than 10 kg with moderate to large perimembranous VSD who were selected for transcatheter closure of VSD using ADO-I in between October 2016 to September 2018. Mean age was 2.08 ± 0.67 years (mean ± SD) and mean weight was 7.2 ± 1.2 kg (mean ± SD). Procedure was done by crossing the VSD from right ventricular side instead of using the standard approach by forming arterio-venous loop. Average fluoroscopic time was 9.2 ± 2.9 min (mean ± SD) and mean procedure time was 34.1 ± 13.1 min (mean ± SD). Mean follow-up period was 8.7 months (3-12 months) RESULT: Device closure was successfully done in 32 patients. There was device induced aortic regurgitation (AR) in one case who was sent for surgery. One child was found to have complete heart block on first post-procedure day requiring permanent pace-maker implantation. During follow up none of them had any residual VSD, rhythm disturbance, AR and left or right ventricular outflow obstruction. CONCLUSION: Device closure can be successfully done in moderate to large perimembranous VSD using left ventricular mid cavity approach in small children. LV mid-cavity approach has advantages in terms of lesser hemodynamic instability, lesser fluoroscopy and lesser chance of device induced AR than standard technique particularly in smaller children.

Surgical Options for Transposition of the Great Arteries With Ventricular Septal Defect and Left Ventricular Outflow Tract Obstruction: Evolution and Functional Impact.

Surgery for D-transposition of the great arteries, ventricular septal defect and left ventricular outflow tract obstruction has continuously evolved to achieve optimal hemodynamic performance across the right and left ventricular outflow tracts, include predominantly native tissues, and preserve pulmonary valve function. Classically, three types of repair are applied: Rastelli, REV, and translocation procedures. The concept of translocation remains more radical and exposed to many modifications. Its extensive reconstructive nature extends its application to similar lesions with discordant ventriculo-arterial connection. We tried to compare the values and limitations of these surgical options, emphasizing how a more anatomical repair could impact the functional outcome.

Comparison of Health-Related Quality of Life in Adults Undergoing Transthoracic and Transcatheter Device Closure for Ventricular Septal Defects.

This study aims to compare and analyze the health-related quality of life (HRQoL) of adult patients with ventricular septal defects (VSDs) who underwent transthoracic or transcatheter device closure.The HRQoL data of 30 patients who underwent transthoracic device closure for VSDs and 30 who underwent transcatheter device closure for VSDs were retrospectively evaluated before and one year after the procedure. The Medical Outcomes Study 36-Item Short-Form (SF-36), the Hospital Anxiety and Depression Scale (HADS), and a self-designed questionnaire were used as evaluation tools.After treatment, both groups showed significant improvements in SF-36 and HADS scores. After comparing the two groups regarding the SF-36, there was a significant difference in the two dimensions of vitality and mental health. There were no statistically significant differences in the HADS-A and HADS-D scores between these two groups. The results of the self-designed questionnaire also showed that the subjective feedback of the two groups was roughly the same. In the process of exploring the influential factors, we found that the scores of patients on most dimensions of the SF-36 in the two groups showed a significantly negative trend with increasing age. In terms of HADS scores, patients in both groups showed a tendency toward increasing scores with age.The HRQoL of adult patients undergoing transthoracic and transcatheter device closure for VSDs was similar, and the HRQoL was affected by the patient's own condition, so it is necessary to pay more attention to patients after device closure.

Right-sided infective endocarditis in association with a left-to-right shunt complicated by haemoptysis and acute renal failure: a case report.

BACKGROUND: Infective endocarditis has a relevant clinical impact due to its high morbidity and mortality rates. Right-sided endocarditis has lower complication rates than left-sided endocarditis. Common complications are multiple septic pulmonary embolisms, haemoptysis, and acute renal failure. Risk factors associated with right-sided infective endocarditis are commonly related to intravenous drug abuse, central venous catheters, or infections due to implantable cardiac devices. However, patients with congenital ventricular septal defects might be at high risk of endocarditis and haemodynamic complications. CASE PRESENTATION: In the following, we present the case of a 23-year-old man without a previous intravenous drug history with tricuspid valve Staphylococcus aureus endocarditis complicated by acute renal failure and haemoptysis caused by multiple pulmonary emboli. In most cases, right-sided endocarditis is associated with several common risk factors, such as intravenous drug abuse, a central venous catheter, or infections due to implantable cardiac devices. In this case, we found a small perimembranous ventricular septal defect corresponding to a type 2 Gerbode defect. This finding raised the suspicion of a congenital ventricular septal defect complicated by a postendocarditis aneurysmal transformation. CONCLUSIONS: Management of the complications of right-sided infective endocarditis requires a multidisciplinary approach. Echocardiographic approaches should include screening for ventricular septal defects in patients without common risk factors for tricuspid valve endocarditis. Patients with undiagnosed congenital ventricular septal defects are at high risk of infective endocarditis. Therefore, endocarditis prophylaxis after dental procedures and/or soft-tissue infections is highly recommended. An acquired ventricular septal defect is a very rare complication of infective endocarditis. Surgical management of small ventricular septal defects without haemodynamic significance is still controversial.

Functional Capacity Past Age 40 in Patients With Congenital Ventricular Septal Defects.

Background Ventricular septal defects (VSD), when treated correctly in childhood, are considered to have great prognoses, and the majority of patients are discharged from follow-up when entering their teens. Young adults were previously found to have poorer functional capacity than healthy peers, but the question remains whether functional capacity degenerates further with age. Methods and Results A group of 30 patients with surgically closed VSDs (51±8 years) with 30 matched, healthy control participants (52±9 years) and a group of 30 patients with small unrepaired VSDs (55±12 years) and 30 matched control participants (55±10 years) underwent cardiopulmonary exercise testing using an incremental workload protocol and noninvasive gas measurement. Peak oxygen uptake was lower in participants with closed VSDs than matched controls (24±7 versus 34±9 mL/min per kg, P<0.01) and with unrepaired VSDs than matched controls (26±5 versus 32±8 mL/min per kg, P<0.01). Patients demonstrated lower oxygen uptake from exercise levels at 20% of maximal workload compared with respective control groups (P<0.01). Peak ventilation was lower in patients with surgically closed VSDs than control participants (1.0±0.3 versus 1.4±0.4 L/min per kg, P<0.01) but similar in patients with unrepaired VSDs and control participants (P=0.14). Exercise capacity was 29% lower in older patients with surgically closed VSDs than healthy peers, whereas younger patients with surgically closed VSDs previously demonstrated 18% lower capacity compared with peers. Older patients with unrepaired VSDs reached 21% lower exercise capacity, whereas younger patients with unrepaired VSDs previously demonstrated 17% lower oxygen uptake than healthy peers. Conclusions Patients with VSDs demonstrate poorer exercise capacity than healthy peers. The difference between patients and control participants increased with advancing age-and increased most in patients with operated VSDs-compared with previous findings in younger patients. Results warrant continuous follow-up for these simple defects.

Right ventricular septal pacing via transmural approach for resynchronization in a child with postoperative heart block.

An infant with transposition of the great arteries was paced for postoperative heart block (single-site, right ventricular [RV] epicardial). She developed severe left ventricular (LV) dysfunction and septal dyskinesis. Resynchronization was performed at the age of 4 with an LV epicardial lead and an RV septal endocardial lead. The endocardial lead was affixed to the interventricular septum, then tunneled through the RV free wall and attached to an abdominal pulse generator. QRS duration decreased (176 to 122 ms) and LV ejection fraction improved (26 to 61%) and remained stable for 8 years. We present a case of successful resynchronization in congenital heart disease using a transmural RV septal lead.

Comparison of Outcomes in Adults With Ventricular Septal Defect Closed Earlier in Life Versus Those in Whom the Defect Was Never Closed.

Ventricular septal defects (VSDs) have recently demonstrated poorer functional outcome with disrupted ventricular contractility during exercise in young patients. It is not known whether this will change with age. Therefore, echocardiography was performed in older patients with congenital VSDs, either surgically closed or unrepaired and all without Eisenmenger physiology, to compare functional outcomes with healthy peers. Transthoracic echocardiography was performed at rest and during supine bicycle exercise, with tissue velocity Doppler for assessment of primary end points: isovolumetric acceleration and systolic velocities. In total, 30 surgically closed VSDs (51 ± 8 years) with 30 healthy controls (52 ± 9 years) and 30 unrepaired VSDs (55 ± 12 years) with 30 matched controls (55 ± 10 years) were included. Surgical patients displayed lower right ventricular (RV) systolic and early diastolic-filling velocities compared with controls, p <0.01, lower tricuspid annular plane systolic excursion (17.8 ± 5 vs 22.7 ± 3mm, p <0.01) and lower fractional area change (37.8 ± 6 vs 46.4% ± 7%, p <0.01). Unrepaired VSDs also had lower RV fractional area change than matched controls (39.9 ± 7 vs 48.4% ± 7%, p <0.01). Both patient groups had more tricuspid regurgitation and larger RV outflow tract dimensions than controls, p <0.01. During exercise, isovolumetric acceleration and systolic velocities were lower in both patient groups compared with controls, with the difference increasing with workload level. In conclusion, adults in their mid-50s with surgically closed or unrepaired VSDs have abnormal RV function at rest, with even more pronounced differences during exercise. These results suggest that a VSD, whether repaired early or considered hemodynamically insignificant, is not a benign lesion and continuous follow-up of adults is warranted.

Exercise Capacity and Ventricular Remodeling After Transcatheter Ventricular Septal Defect Closure in Asymptomatic or Minimally Symptomatic Adolescents and Adults.

BACKGROUND: Transcatheter ventricular septal defect (VSD) closure is a safe and efficacious alternative to surgery. However, its benefits in asymptomatic or minimally symptomatic patients remain unknown. METHODS: Sixty patients with VSD aged 12 to 60 years underwent cardiopulmonary exercise test and echocardiography 1 day before transcatheter VSD closure and 6 months after intervention (closure group). Thirty patients who did not receive the intervention underwent the same evaluations over 6 months (observation group). RESULTS: No significant change in exercise function was observed after VSD closure, except for increased peak oxygen (O2) pulse (absolute increase: 0.4±1.4 mL/beat). Left ventricular end-diastolic dimension and mitral peak early filling velocity-to-early diastolic annular velocity ratio decreased (absolute decrease: 0.3±0.6 cm and 0.7±1.9, respectively). Despite unchanged overall peak O2 consumption, 33% of closure group patients exhibited clinically significant improvements in peak O2 consumption (>10% increase relative to baseline). This was not related to the pulmonary flow-to-systemic flow ratio or baseline exercise capacity. By contrast, all exercise function parameters deteriorated significantly in the observation group. Subgroup analysis revealed that patients with a baseline left ventricular end-diastolic dimension Z score of >2 exhibited a significantly greater improvement in peak O2 consumption, peak O2 pulse, and oxygen uptake efficiency slope than did the observation group. CONCLUSIONS: Compared with conservative management, transcatheter VSD closure prevents deterioration in exercise capacity and promotes left ventricular reverse remodeling in asymptomatic or minimally symptomatic patients. These benefits are most prominent in patients whose left ventricular end-diastolic dimension Z score before intervention is >2, irrespective of baseline peak O2 consumption and pulmonary flow/systemic flow ratio. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03127748.