BACKGROUND:Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS:A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS:Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes (WNT4, LEF1, STRN, and KANK2) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90-2.25; P=5.43×10-62) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS:This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.

Graphical AbstractFor image description, please refer to the figure legend and surrounding text.

AIMS:Anomalous Aortic Origin of Coronary Arteries (AAOCA) is associated with myocardial ischaemia and sudden cardiac death, particularly in young athletes. Although inducible myocardial ischaemia investigation is generally recommended, there is no clear indication of the most appropriate stress test, as the ECG exercise stress test presents low diagnostic accuracy. Dobutamine-stress cardiac magnetic resonance (dsCMR) has been proposed as a promising diagnostic tool, but its application has been limited to paediatric populations. This study aimed to evaluate the presence of inducible myocardial ischaemia assessed by dsCMR in AAOCA patients, regardless of age, and to identify factors associated with inducible myocardial ischaemia. METHODS AND RESULTS:In this single-centre observational study, 100 AAOCA patients who underwent dsCMR were enrolled from 2015 to 2024. dsCMR resulted positive in 14 cases, all showing perfusion abnormalities, with only one presenting segmental wall motion abnormalities. dsCMR was found to be safe without major adverse events. Factors significantly associated with inducible ischaemia included intramural course, the presence of ischaemic late gadolinium enhancement (LGE), and a history of acute coronary syndrome (ACS). Nine patients (9%) showed small areas of ischaemic LGE within the AAOCA territory, and they were older with a higher incidence of arterial hypertension, smoking habits and previous ACS episodes. CONCLUSION:dsCMR is a reliable test for the evaluation of myocardial ischaemia in AAOCA, especially for those with intramural course, ischaemic LGE, and previous ACS episodes. Although rare, older patients may have a myocardial ischaemic scar without alteration of ventricular function.

Congenital heart disease (CHD), the most common congenital malformation worldwide, affects approximately 8-10 per 1000 live births. Despite major advances in diagnosis and treatment, significant disparities remain between high- and low-resource settings, with a substantial impact on survival and long-term outcomes. The Aesculapius Project was conceived to address these inequalities by employing advanced imaging and three-dimensional (3D) printing as educational tools to enhance paediatric cardiac surgery training. Initiated by the humanitarian foundations Bambini Cardiopatici nel Mondo and European Heart for Children, the program offers free training to early-career surgeons from resource-limited countries. Patient-specific 3D cardiac models are generated from computed tomography (CT) and magnetic resonance imaging (MRI) data and used in structured courses that combine lectures, supervised hands-on surgical simulations, and remote mentorship. To date, 81 physicians from 16 countries have participated in the program, performing 10-20 simulated procedures on complex CHD models under expert supervision. Technical performance scores improved by an average of 30%, and participants emphasized the educational value of repeated supervised practice and video-assisted review. The Aesculapius Project demonstrates that 3D anatomical models offer an ethical and effective platform for surgical education, representing a concrete step toward expanding access to high-quality paediatric cardiac surgery training in resource-limited settings.

Abstract Background Impact of AAOCA in coronary blood flow and myocardial perfusion is an unknown field although it is well-accepted that the anomaly is one of the leading causes of sudden death during effort. The risk factors for AAOCA are the anatomical characteristics of the abnormal vessel, such as the presence of intramural (IM) segment, the ostium shape, and the take-off angle. Purpose We aim to evaluate the impact of AAOCA anatomical risk profile in the blood flow using the thermodilution technique, an accurate and reproducible method used to investigate coronary physiology. Methods This is a single-centre prospective study that included AAOCA subjects who underwent invasive thermodilution functional coronary assessment. We divided patients into two groups according to the anatomical risk profile: a) ischemic risk (IR): concomitant presence of IM segment, take-off angle<45°, and slit-like/oval shape ostium, or a IM length>10 mm; b) no-ischemic risk (no-IR): absence of IM segment, take-off angle>45°, round ostium. We obtained coronary functional measures using the thermodilution method. We measured the absolute flow, and coronary resistance at rest and maximal hyperemia. Data were reported as median and IQR and we used Wilcoxon signed-rank test for paired data in the rest vs. hyperaemia comparison. Results We included 28 AAOCA pts (22 male, 6 female, median age: 48.6 (IQR: 18.9) ) that were 20 anomalies of the right coronary and 8 of the left. Symptomatic subjects (n=16) presented with angina (n=12), syncope (n=1), presyncope (n=1), fatigue (n=1), and dyspnea associated with arrhythmia (n=1). The IR group (26 pts; R-AAOCA=24, L-AAOCA=2) has an IM segment with a median length of 10 mm (IQR: 5.5), a median take-off angle of 28° and the ostium was slit-like (n=16), oval (n=10), and round (n=1). The no-IR group consisted of 9 (R-AAOCA=3, L-AAOCA=6), median take-off angle of 69° and the ostium was oval (n=1), and round (n=8). The absolute flow and coronary resistance at rest of the IR group did not have significant differences compared to no-IR. Hyperemia determines an increment of coronary flow in both groups although the IR had a 2.9 fold increase and the no-IR as 3.5 fold increase compared to rest. In particular, the absolute flow of the IR group was significantly lower compared to the no-IR group (185 vs. 330 mL/min, p=0.012) and there was a greater coronary resistance (419 vs. 268 mmHg/(mL/min), p=0.027), as shown in Fig. 1. Conclusions Anatomical risk factors of AAOCA, such as IM take-off angle and ostium morphology, have a negative impact on the coronary blood supply that is reduced when compared to AAOCA without such anatomical features. Such impact can be revealed also at rest using the thermodilution method that induces maximal coronary vasodilatation that is the natural coronary response to physical effort. Further studies are needed to validate benefit of functional assessment in AAOCA risk stratification.

OBJECTIVES: Anomalous aortic origin of a coronary artery (AAOCA) is a group of rare congenital heart defects with various clinical presentations. The lifetime-risk of an individual living with AAOCA is unknown, and data from multicentre registries are urgently needed to adapt current recommendations and guide optimal patient management. The European AAOCA Registry (EURO-AAOCA) aims to assess differences with regard to AAOCA management between centres. METHODS: EURO-AAOCA is a prospective, multicentre registry including 13 European centres. Herein, we evaluated differences in clinical presentations and management, treatment decisions and surgical outcomes across centres from January 2019 to June 2023. RESULTS: A total of 262 AAOCA patients were included, with a median age of 33 years (12-53) with a bimodal distribution. One hundred thirty-nine (53.1%) were symptomatic, whereas chest pain (n = 74, 53.2%) was the most common complaint, followed by syncope (n = 21, 15.1%). Seven (5%) patients presented with a myocardial infarction, 2 (1.4%) with aborted sudden cardiac death. Right-AAOCA was most frequent (150, 57.5%), followed by left-AAOCA in 51 (19.5%), and circumflex AAOCA in 20 (7.7%). There were significant differences regarding diagnostics between age groups and across centres. Seventy-four (28.2%) patients underwent surgery with no operative deaths; minor postoperative complications occurred in 10 (3.8%) cases. CONCLUSIONS: Currently, no uniform agreement exists among European centres with regard to diagnostic protocols and clinical management for AAOCA variants. Although surgery is a safe procedure in AAOCA, future longitudinal outcome data will hopefully shed light on how to best decide towards optimal selection of patients undergoing revascularization versus conservative treatment.

We describe a case of a voluminous rhabdomyoma (R) detected by fetal echocardiography at 32 weeks’ gestation (w.g.) obstructing the left ventricular inflow and aortic outflow tract, with a moderate aortic gradient at birth, not needing immediate surgery. At follow-up, the mass progressively regressed, leaving the aortic valve partly damaged, with a gradient that increased to a maximum of 100 mmHg at 9 years. The girl was then operated on successfully by a plasty of the aortic valve. The literature regarding R is discussed.

The cervical aortic arch is a rare congenital vascular abnormality related to the anomalous development of the aortic arch. We present the case of a 6-year-old patient with a large aneurysmal cervical aortic arch who underwent surgical correction and arch reconstruction. Surgical repair was indicated based on the risk of progressive dilation and rupture, aiming to restore correct geometry and hemodynamics. We evaluated preoperative and postoperative hemodynamics using computational fluid dynamics simulations, and we also identified, within the repaired region, an area that remains affected by greater turbulent flow, requiring follow-up surveillance.

Background and Aim: Surgical repair of anomalous aortic origin of coronary artery (AAOCA) needs to be patient’s tailored to reduce early and late complications. We aim to assess the results of 21-years AAOCA surgical repair in a dedicated program. Methods: All consecutive AAOCA patients underwent surgical repair (01/2013- 09/2024). We collected anatomical operative and post-operative data, focusing on early complications and late outcomes. Results: From a cohort of 237 AAOCA subjects referred, 69 (29%) underwent surgical repair at a median age of 39,7 years (range: 5-71 years). The surgical techniques were unroofing of the intramural segment (n=53), osteoplasty (n=5), anatomical repair (n=4) CABG (n=3), transconal repair (n=1), external debridging of subpulmonary course (n=3). No early or late mortality was depicted. Early complications included unplanned CABG (n=1) a right coronary laceration requiring patch repair (n=1) and acute pericarditis requiring pericardiectomy (n=1). All patients were discharged in good clinical conditions, with no evidence of aortic valve regurgitation. After a mean follow-up of 4.5±3.98 years, the occurrence of late overall complications was rare, with only 1 case of RCA stenosis after unroofing treated with stenting; meanwhile we observed post-surgical pericarditis (n=3) treated medically 1 case of distal RCA spontaneous dissection. Conclusions: When tailored to the specific patient anatomy, surgical treatment of AAOCA may significantly reduce early and late complications. Surgery is safe when performed in large-volume centers, although the very long-term fate of a repaired coronary segment in young adults in terms of stenosis recurrence is still unknown.

Formato GM, Agnifili ML, Arzuffi L, Rosato A, Ceserani V, Zuniga Olaya KG, Secchi F, Deamici M, Conti M, Auricchio F, Bedogni F, Frigiola A, Lo Rito M. Morphological Changes of Anomalous Coronary Arteries From the Aorta During the Cardiac Cycle Assessed by IVUS in Resting Conditions. Circ Cardiovasc Interv. 2023 Jul;16(7):e012636. doi: 10.1161/CIRCINTERVENTIONS.122.012636. Epub 2023 Jul 7. PMID: 37417226; PMCID: PMC10348625. Abstract Background: Anomalous aortic origin of coronary artery (AAOCA) with intramural segment is associated with risk of sudden cardiac death, probably related to a compressive mechanism exerted by the aorta. However, the intramural compression occurrence and magnitude during the cardiac cycle remain unknown. We hypothesized that (1) in end diastole, the intramural segment is narrower, more elliptic, and has greater resistance than extramural segment; (2) the intramural segment experiences a further compression in systole; and (3) morphometry and its systolic changes vary within different lumen cross-sections of the intramural segment. Methods: Phasic changes of lumen cross-sectional coronary area, roundness (minimum/maximum lumen diameter), and hemodynamic resistance (Poiseuille law for noncircular sections) were derived from intravascular ultrasound pullbacks at rest for the ostial, distal intramural, and extramural segments. Data were obtained for 35 AAOCA (n=23 with intramural tract) after retrospective image-based gating and manual lumen segmentation. Differences between systolic and end-diastolic phases in each section, between sections of the same coronary, and between AAOCA with and without intramural tract were assessed by nonparametric statistical tests. Results: In end diastole, both the ostial and distal intramural sections were more elliptical (P<0.001) than the reference extramural section and the correspondent sections in AAOCA without intramural segment. In systole, AAOCA with intramural segment showed a flattening at the ostium (-6.76% [10.82%]; P=0.024) and a flattening (-5.36% [16.56%]; P=0.011), a narrowing (-4.62% [11.38%]; P=0.020), and a resistance increase (15.61% [30.07%]; P=0.012) at the distal intramural section. No-intramural sections did not show morphological changes during the entire cardiac cycle. Conclusions: AAOCA with intramural segment has pathological segment-specific dynamic compression mainly in the systole under resting conditions. Studying AAOCA behavior with intravascular ultrasound during the cardiac cycle may help to evaluate and quantify the severity of the narrowing.

IntroductionAortic root enlargement (ARE) is often required to avoid patient–prosthesis mismatch (PPM) in young patients undergoing aortic surgery, including those undergoing combined mitral and aortic valve replacement (double valve replacement, DVR). Adding ARE to DVR may increase the operative risk by extending the surgical time. Herein, we review our experience with ARE in patients who underwent DVR.Materials and methodsThe medical records of 69 patients who underwent DVR at our institution between February 2008 and November 2021 were retrospectively reviewed. The patients were divided into two groups according to the ARE procedure (ARE-DVR: 25 patients; DVR: 44 patients). Descriptive and comparative analyses of demographic, clinical, and surgical data were performed.ResultsAmong the 69 patients who underwent DVR, 35 were women (sex ratio, 0.97). The mean age at surgery was 26.7 ± 13.9 years (range: 7–62 years). Among the 47 patients aged ≤30 years, 40.4% (19/47) were aged between 10 and 20 years, and 6.3% (3/47) were aged <10 years. Patients in the ARE-DVR group were younger (23.3 ± 12.9 years vs. 28.5 ± 14.2 years, p < 0.05). The New York Heart Association Class ≥III dyspnea was the most common symptom (89.9%), with no differences between the two groups. Of all the patients, 84.1% had sinus rhythm. Rheumatic disease was the most common etiology in the entire cohort (91.3%). The mean aortic annulus diameter was 20.54 mm, with smaller sizes found in the ARE-DVR group (18.00 ± 1.47 mm vs. 22.50 ± 2.35 mm, p < 0.05). The aortic cross-clamping duration was greater in the ARE-DVR group (177.6 ± 37.9 min vs. 148.3 ± 66.3 min, p = 0.047). The operative mortality rate was 5.6% for the entire cohort (ARE-DVR: 8% vs. DVR: 4.5%, p = 0.46). Among the patients who underwent echocardiographic control at follow-up, the mean aortic gradient was 19.6 ± 7.2 mmHg (range: 6.14–33 mmHg), with no differences among the groups.ConclusionThe association between ARE and DVR did not significantly affect operative mortality. ARE can be safely used whenever indications arise to reduce the occurrence of PPM, especially in young patients with growth potential.

BACKGROUND: Anomalous aortic origin of coronary artery (AAOCA) with intramural segment is associated with risk of sudden cardiac death, probably related to a compressive mechanism exerted by the aorta. However, the intramural compression occurrence and magnitude during the cardiac cycle remain unknown. We hypothesized that (1) in end diastole, the intramural segment is narrower, more elliptic, and has greater resistance than extramural segment; (2) the intramural segment experiences a further compression in systole; and (3) morphometry and its systolic changes vary within different lumen cross-sections of the intramural segment. METHODS: Phasic changes of lumen cross-sectional coronary area, roundness (minimum/maximum lumen diameter), and hemodynamic resistance (Poiseuille law for noncircular sections) were derived from intravascular ultrasound pullbacks at rest for the ostial, distal intramural, and extramural segments. Data were obtained for 35 AAOCA (n=23 with intramural tract) after retrospective image-based gating and manual lumen segmentation. Differences between systolic and end-diastolic phases in each section, between sections of the same coronary, and between AAOCA with and without intramural tract were assessed by nonparametric statistical tests. RESULTS: In end diastole, both the ostial and distal intramural sections were more elliptical ( P <0.001) than the reference extramural section and the correspondent sections in AAOCA without intramural segment. In systole, AAOCA with intramural segment showed a flattening at the ostium (−6.76% [10.82%]; P =0.024) and a flattening (−5.36% [16.56%]; P =0.011), a narrowing (−4.62% [11.38%]; P =0.020), and a resistance increase (15.61% [30.07%]; P =0.012) at the distal intramural section. No-intramural sections did not show morphological changes during the entire cardiac cycle. CONCLUSIONS: AAOCA with intramural segment has pathological segment-specific dynamic compression mainly in the systole under resting conditions. Studying AAOCA behavior with intravascular ultrasound during the cardiac cycle may help to evaluate and quantify the severity of the narrowing.

OBJECTIVES The quality of the outcome after cardiac surgery with cardiopulmonary bypass depends on the patient demographics, co-morbidities, complexity of the surgical procedure, and expertise of surgeons and the whole staff. The purpose of the present study is to analyze the timing of surgery (morning vs afternoon) with respect to morbidity and mortality in adult cardiac surgery. Methods: The primary end-point was the incidence of major morbidity defined according to a modified Society of Thoracic Surgeon criterion. We consecutively included all the adult (> 18 years) patients receiving a cardiac surgery operation at our Institution. RESULTS From 2017 through 2019 a total of 4,003 cardiac surgery patients were operated. With a propensity-matching technique a final patient population of 1600 patients was selected, with 800 patients in the first-case surgery group and 800 in the second-case surgery group. Patients in the second-case group had a major morbidity rate of 13% vs 8.8% in the first-case group (P = 0.006), and a higher rate of 30-days mortality (4.1% vs 2.3%, P = 0.033). After correction for EuroSCORE and operating surgeon, the second-case group confirmed a higher rate of major morbidity (odds ratio 1.610, 95% confidence interval 1.16-2.23, P = 0.004). CONCLUSION Our study suggests that patients operated as second cases are exposed to an increased morbidity and mortality probably due to fatigue, loss of attention and hurriedness in the operating room, and decreased human resources in the intensive care unit.

Anomalous aortic origin of the coronary artery (AAOCA) is a rare disease associated with sudden cardiac death, usually related to physical effort in young people. Clinical routine tests fail to assess the ischemic risk, calling for novel diagnostic approaches. To this aim, some recent studies propose to assess the coronary blood flow (CBF) in AAOCA by computational simulations but they are limited by the use of data from literature retrieved from normal subjects. To overcome this limitation and obtain a reliable assessment of CBF, we developed a fully patient-specific lumped parameter model based on clinical imaging and in-vivo data retrieved during invasive coronary functional assessment of subjects with AAOCA. In such a way, we can estimate the CBF replicating the two hemodynamic conditions in-vivo analyzed. The model can mimic the effective coronary behavior with high accuracy and could be a valuable tool to quantify CBF in AAOCA. It represents the first step required to move toward a future clinical application with the aim of improving patient care. The study was registered at Clinicaltrial.gov with (ID: NCT05159791, date 2021-12-16).

Marfan syndrome (MFS) is a rare inherited autosomic disorder, which encompasses a variety of systemic manifestations caused by mutations in the Fibrillin-1 encoding gene (FBN1). Cardinal clinical phenotypes of MFS are highly variable in terms of severity, and commonly involve cardiovascular, ocular, and musculoskeletal systems with a wide range of manifestations, such as ascending aorta aneurysms and dissection, mitral valve prolapse, ectopia lentis and long bone overgrowth, respectively. Of note, an accurate and prompt diagnosis is pivotal in order to provide the best treatment to the patients as early as possible. To date, the diagnosis of the syndrome has relied upon a systemic score calculation as well as DNA mutation identification. The aim of this review is to summarize the latest MFS evidence regarding the definition, differences and similarities with other connective tissue pathologies with severe systemic phenotypes (e.g., Autosomal dominant Weill–Marchesani syndrome, Loeys–Dietz syndrome, Ehlers–Danlos syndrome) and clinical assessment. In this regard, the management of MFS requires a multidisciplinary team in order to accurately control the evolution of the most severe and potentially life-threatening complications. Based on recent findings in the literature and our clinical experience, we propose a multidisciplinary approach involving specialists in different clinical fields (i.e., cardiologists, surgeons, ophthalmologists, orthopedics, pneumologists, neurologists, endocrinologists, geneticists, and psychologists) to comprehensively characterize, treat, and manage MFS patients with a personalized medicine approach.

Baudo M, Varrica A, Reali M, Saracino A, Carminati M, Frigiola A, Giamberti A, Lo Rito M. Cervical aortic arch in the pediatric population: a meta-analysis of individual patient's data. Front Cardiovasc Med. 2023 Sep 28;10:1266956. doi: 10.3389/fcvm.2023.1266956. PMID: 37855019; PMCID: PMC10580808. Abstract Background: This is the first meta-analysis to analyze all reports of published pediatric cases of cervical aortic arch (CAA) by highlighting the clinical characteristics and treatment outcomes using the reported individual data of the patients. The aim of the study is to investigate the clinical features and surgical outcomes of such a rare disease in the pediatric population. Methods: A comprehensive search was conducted in various academic databases, including PubMed, ScienceDirect, SciELO, DOAJ, and Cochrane Library, until June 2022 for case reports describing the presence of cervical aortic arch in the pediatric age. Case reports and series were included if the following criteria were met: (1) description of the cervical aortic arch; (2) patient of pediatric age; and (3) published in the English language. All other types of publications that lacked patient-specific information were excluded from the analysis. This systematic review was conducted in accordance with the PRISMA guidelines. The primary outcome measure of the analysis was early and late mortality. Results: The literature search identified 2,272 potentially eligible articles, 72 of which met our inclusion criteria with 96 patients including the author's institutional case. At a median of 365 (90-730) days, the overall cohort registered a 7.3% (7/96) mortality rate. In the subset of patients who underwent surgery, the mortality rate was also 7.3% (4/55), and the mortality rate following surgery to treat only CAA was 2.4% (1/42). Dyspnea was identified as an independent determinant of mortality by employing the univariable Firth bias-reduced logistic regression method. Conclusion: Cervical aortic arch is a rare congenital heart disease that poses treatment challenges due to the high anatomical variability, diverse clinical presentations, and the presence of other concomitant diseases. The surgical treatment appears to be a safe and effective approach for resolving the symptoms, although it needs to be tailored individually for each patient.