Thirty-Year Survival after Cardiac Surgery for Patients with Turner Syndrome.

OBJECTIVE: To evaluate long-term survival in patients with Turner syndrome after congenital heart surgery with a focus on left heart obstructive lesions (LHOLs). STUDY DESIGN: We queried the Pediatric Cardiac Care Consortium, a US-based registry of congenital heart surgery, for patients with Turner syndrome undergoing congenital heart surgery at <21 years of age between 1982 and 2011. Outcomes were obtained from the Pediatric Cardiac Care Consortium and from national death and transplant registries through 2019. Survival of patients with Turner syndrome and nonsyndromic patients with similar LHOL was compared by Kaplan-Meier survival curves and Cox regression adjusted for age, congenital heart disease, and era. RESULTS: We identified 179 patients with Turner syndrome operated for LHOL: 161 with 2-ventricle lesions (coarctation n = 149, aortic stenosis n = 12) and 18 with hypoplastic left heart (HLH) variants. There were 157 with 2-ventricle LHOL and 6 with HLH survived to discharge. Among survivors to hospital discharge, the 30-year transplant-free survival was 90.4% for Turner syndrome with 2-ventricle lesions and 90.9% for nonsyndromic comparators (adjusted hazard ratio [aHR] 1.15, 95% CI 0.64-2.04). The postdischarge survival for HLH was 33% for Turner syndrome and 51% for nonsyndromic patients, with these numbers being too small for meaningful comparisons. There was a higher risk for cardiovascular disease events in patients with Turner syndrome vs male (aHR 3.72, 95% CI 1.64-8.39) and female comparators (aHR 4.55, 95% CI 1.87-11.06) excluding heart failure deaths. CONCLUSIONS: The 30-year transplant-free survival is similar for patients with Turner syndrome and nonsyndromic comparators with operated 2-ventricle LHOL without excess congenital heart disease risk. However, patients with Turner Syndrome still face increased cardiovascular disease morbidity, stressing the importance of lifelong comorbidity surveillance in this population.

TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in Turner syndrome.

Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in ~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10(-7)), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91-178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57-99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.

The state of Turner syndrome science: Are we on the threshold of discovery?

Turner syndrome (TS), a genetic condition affecting roughly 1 in 2,000 females, is caused by a complete or partial loss of the second sex chromosome. This special issue of the American Journal of Medical Genetics Part C is a collection of research and clinical care reviews in TS from an international group of physician and scientist leaders who attended the 2018 "Turner Network Resource Symposium: Turner Science in the 21st Century", held in Arlington Virginia, July 15th-17th, 2018. Both this special issue and the 2018 Symposium are fueled by two rationales. First, inadequate attention has been given to health and psychosocial problems in girls and women with TS; and second, that an understanding of TS might shed light on the role of sex chromosome dosage in common conditions such as heart disease and autoimmune disease. These seminars interweave multiple themes: the fundamental partnership between participants with rare diseases and researchers, new knowledge regarding clinical care in TS, and an understanding of the "molecular phenotype" of TS-associated conditions.

The genetic basis of Turner syndrome aortopathy.

Our goal is to identify the genetic underpinnings of bicuspid aortic valve and aortopathy in Turner syndrome. We performed whole exome sequencing on 188 Turner syndrome study subjects from the GenTAC registry. A gene-based burden test, SKAT-O, was used to evaluate the data using bicuspid aortic valve (BAV) and aortic dimension z-scores as covariates. This revealed that TIMP3 was associated with BAV and increased aortic dimensions at exome-wide significance. It had been previously shown that genes on chromosome Xp contribute to aortopathy when hemizygous. Our analysis of Xp genes revealed that hemizygosity for TIMP1, a functionally redundant paralogue of TIMP3, increased the odds of having BAV aortopathy compared to individuals with more than one TIMP1 copy. The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles synergistically increased the risk for BAV aortopathy to nearly 13-fold. TIMP1 and TIMP3 are tissue inhibitors of matrix metalloproteinases (TIMPs) which are involved in development of the aortic valve and protection from thoracic aneurysms. We propose that the combination of TIMP1 haploinsufficiency and deleterious variants in TIMP3 significantly increases the risk of BAV aortopathy in Turner syndrome, and suggest that TIMP1 hemizygosity may play a role in euploid male aortic disease.

Research priorities of people living with Turner syndrome.

Despite major discoveries, traditional biomedical research has not always addressed topics perceived as priorities by patients and their families. Patient-centered care is predicated on research taking such priorities into account. The present study surveyed women with Turner syndrome (TS; 18+ years; n = 543), parents of women with TS (n = 232), and parents of younger daughters with TS (<18 years; n = 563), regarding their priorities for research. The study also included a quantitative audit of research categorized as either predominantly biomedical or psychological in the medical and other scientific literature. The overwhelming majority of all surveyed stakeholders (84% and higher) rated both biomedical and psychological research in TS as "very important," yet only approximately 9% of published research focused on psychological aspects of TS. The odds of women with TS identifying psychological research as "most important" was significantly lower (OR: 0.607; 95% CI: 0.375, 0.982] than the odds of parents making the same prioritization. Despite the majority of participants rating research as very important, only approximately half-rated participation in research as similarly important. The majority of respondents in all three groups (59%-73%) indicated they would "very likely" participate in research pertaining to eating or nutrition, quality of life, or genetic studies in TS. Substantially fewer expressed similar eagerness to participate in studies involving the study of a new medicine or medical device. Increased engagement of patient and family stakeholders in research requires that investigators select topics of study important to that community.

The Turner syndrome research registry: Creating equipoise between investigators and participants.

To address knowledge gaps about Turner syndrome (TS) associated disease mechanisms, the Turner Syndrome Society of the United States created the Turner Syndrome Research Registry (TSRR), a patient-powered registry for girls and women with TS. More than 600 participants, parents or guardians completed a 33-item foundational survey that included questions about demographics, medical conditions, psychological conditions, sexuality, hormonal therapy, patient and provider knowledge about TS, and patient satisfaction. The TSRR platform is engineered to allow individuals living with rare conditions and investigators to work side-by-side. The purpose of this article is to introduce the concept, architecture, and currently available content of the TSRR, in anticipation of inviting proposals to utilize registry resources.

Determination of right ventricular function with adjusted systolic to diastolic duration ratio after transannular patch repair of tetralogy of Fallot.

BACKGROUND: Early detection of right ventricular dysfunction after transannular patch for tetralogy of Fallot (TOF-TAP) is essential for management. OBJECTIVES: To evaluate echocardiographic metrics of ventricular function correlate with functional MRI measurements, in patients with TOF-TAP. METHODS: A retrospective review of patients with TOF-TAP between 2007 and 2017 who had an echocardiogram and MRI within six months were analyzed. Systolic to diastolic ratio (SD ratio) was measured from the tricuspid regurgitation and adjusted for heart rate. Tricuspid Annular Plane Systolic Excursion (TAPSE), Fractional Area Change (FAC), and shortening fraction (SF) were additionally measured. Echocardiographic measurements were correlated with MRI assessment of right ventricular ejection fraction (RVEF), left ventricular ejection fraction (LVEF), right ventricular end-diastolic volume index (RVEDi), and right to left ventricle volume ratio (RV/LV). RESULTS: Of the 53 patients (mean age 12.8 years) that met inclusion criteria, 45 (85%) had available TR jets for SD ratio analysis. The HR adjusted SD ratio negatively correlated with RVEF (r = -.359, P = .016), LVEF (r = -.317, P = .038) and positively with RV/LV EDV ratio (r = .347, P = .024). TAPSE, FAC, and SF measurements did not show significant correlation. CONCLUSION: In patients with TOF-TAP, there is a moderate negative correlation between heart rate adjusted SD ratio and MRI metrics of ventricular function, suggesting that decreased filling time is a marker for reduced right ventricular function. The SD ratio may be a useful echocardiographic tool for serial evaluation of in this population.

Allometric considerations when assessing aortic aneurysms in Turner syndrome: Implications for activity recommendations and medical decision-making.

In Turner syndrome, the potential to form thoracic aortic aneurysms requires routine patient monitoring. However, the short stature that typically occurs complicates the assessment of severity and risk because the relationship of body size to aortic dimensions is different in Turner syndrome compared to the general population. Three allometric formula have been proposed to adjust aortic dimensions, all employing body surface area: aortic size index, Turner syndrome-specific Z-scores, and Z-scores based on a general pediatric and young adult population. In order to understand the differences between these formula we evaluated the relationship between age and aortic size index and compared Turner syndrome-specific Z-scores and pediatric/young adult based Z-scores in a group of girls and women with Turner syndrome. Our results suggest that the aortic size index is highly age-dependent for those under 15 years; and that Turner-specific Z-scores are significantly lower than Z-scores referenced to the general population. Higher Z-scores derived from the general reference population could result in stigmatization, inappropriate restriction from sports, and increasing the risk of unneeded medical or operative treatments. We propose that when estimating aortic dissection risk clinicians use Turner syndrome-specific Z-score for those under fifteen years of age.

Autosomal and X chromosome structural variants are associated with congenital heart defects in Turner syndrome: The NHLBI GenTAC registry.

Turner Syndrome (TS) is a developmental disorder caused by partial or complete loss of one sex chromosome. Bicuspid aortic valve and other left-sided congenital heart lesions (LSL), including thoracic aortic aneurysms and acute aortic dissections, are 30-50 times more frequent in TS than in the general population. In 454 TS subjects, we found that LSL are significantly associated with reduced dosage of Xp genes and increased dosage of Xq genes. We also showed that genome-wide copy number variation is increased in TS and identify a common copy number variant (CNV) in chromosome 12p13.31 that is associated with LSL with an odds ratio of 3.7. This CNV contains three protein-coding genes (SLC2A3, SLC2A14, and NANOGP1) and was previously implicated in congenital heart defects in the 22q11 deletion syndrome. In addition, we identified a subset of rare and recurrent CNVs that are also enriched in non-syndromic BAV cases. These observations support our hypothesis that X chromosome and autosomal variants affecting cardiac developmental genes may interact to cause the increased prevalence of LSL in TS. © 2016 Wiley Periodicals, Inc.

Aortic dimensions in Turner syndrome.

In Turner syndrome, linear growth is less than the general population. Consequently, to assess stature in Turner syndrome, condition-specific comparators have been employed. Similar reference curves for cardiac structures in Turner syndrome are currently unavailable. Accurate assessment of the aorta is particularly critical in Turner syndrome because aortic dissection and rupture occur more frequently than in the general population. Furthermore, comparisons to references calculated from the taller general population with the shorter Turner syndrome population can lead to over-estimation of aortic size causing stigmatization, medicalization, and potentially over-treatment. We used echocardiography to measure aortic diameters at eight levels of the thoracic aorta in 481 healthy girls and women with Turner syndrome who ranged in age from two to seventy years. Univariate and multivariate linear regression analyses were performed to assess the influence of karyotype, age, body mass index, bicuspid aortic valve, blood pressure, history of renal disease, thyroid disease, or growth hormone therapy. Because only bicuspid aortic valve was found to independently affect aortic size, subjects with bicuspid aortic valve were excluded from the analysis. Regression equations for aortic diameters were calculated and Z-scores corresponding to 1, 2, and 3 standard deviations from the mean were plotted against body surface area. The information presented here will allow clinicians and other caregivers to calculate aortic Z-scores using a Turner-based reference population. © 2015 Wiley Periodicals, Inc.

Proceedings from the Turner Resource Network symposium: the crossroads of health care research and health care delivery.

Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural "Turner Resource Network (TRN) Symposium" brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population.

Abnormal myocardial blood flow in children with mild/moderate aortic stenosis.

OBJECTIVE: To quantify myocardial blood flow in infants and children with mild or moderate aortic stenosis using adenosine-infusion cardiac magnetic resonance. BACKGROUND: It is unclear whether asymptomatic children with mild/moderate aortic stenosis have myocardial abnormalities. In addition, cardiac magnetic resonance-determined normative myocardial blood flow data in children have not been reported. METHODS: We studied 31 infants and children with either haemodynamically normal hearts (n=20, controls) or mild/moderate aortic stenosis (n=11). The left ventricular myocardium was divided into six segments, and the change in average segmental signal intensity during contrast transit was used to quantify absolute flow (ml/g/minute) at rest and during adenosine infusion by deconvolution of the tissue curves with the arterial input of contrast. RESULTS: In all the cases, adenosine was well tolerated without complications. The mean pressure gradient between the left ventricle and the ascending aorta was higher in the aortic stenosis group compared with controls (24 versus 3 mmHg, p<0.001). Left ventricular wall mass was slightly higher in the aortic stenosis group compared with controls (65 versus 50 g/m², p<0.05). After adenosine treatment, both the absolute increase in myocardial blood flow (p<0.0001) and the hyperaemic flow significantly decreased (p<0.001) in children with mild/moderate aortic stenosis compared with controls. CONCLUSION: Abnormal myocardial blood flow in children with mild/moderate aortic stenosis may be an important therapeutic target.

Single-nucleotide polymorphism array genotyping is equivalent to metaphase cytogenetics for diagnosis of Turner syndrome.

PURPOSE: Turner syndrome is a developmental disorder caused by partial or complete monosomy for the X chromosome in 1 in 2,500 females. We hypothesized that single-nucleotide polymorphism (SNP) array genotyping could provide superior resolution in comparison to metaphase karyotype analysis to facilitate genotype-phenotype correlations. METHODS: We genotyped 187 Turner syndrome patients with 733,000 SNP marker arrays. All cases met diagnostic criteria for Turner syndrome based on karyotypes (60%) or characteristic physical features. The SNP array results confirmed the diagnosis of Turner syndrome in 100% of cases. RESULTS: We identified a single X chromosome (45,X) in 113 cases. In 58 additional cases (31%), other mosaic cell lines were present, including isochromosomes (16%), rings (5%), and Xp deletions (8%). The remaining cases were mosaic for monosomy X and normal male or female cell lines. Array-based models of X chromosome structure were compatible with karyotypes in 104 of 116 comparable cases (90%). We found that the SNP array data did not detect X-autosome translocations (three cases) but did identify two derivative Y chromosomes and 13 large copy-number variants that were not detected by karyotyping. CONCLUSION: Our study is the first systematic comparison between the two methods and supports the utility of SNP array genotyping to address clinical and research questions in Turner syndrome.

Moderate aortic enlargement and bicuspid aortic valve are associated with aortic dissection in Turner syndrome: report of the international turner syndrome aortic dissection registry.

BACKGROUND: Girls and women with Turner syndrome are at risk for aortic dissection and rupture. However, the size of the aorta and the clinical characteristics among those with Turner syndrome and dissection have received little attention. METHODS AND RESULTS: We obtained medical records from 20 individuals who voluntarily participated in the International Turner Syndrome Aortic Dissection Registry. Type A dissections occurred in 17 of 20 (85%) cases, and type B occurred in 3 cases of which 1 occurred after coarctation stent placement. Of those with spontaneous aortic dissections, 18 of 19 (95%) had an associated cardiac malformation that included a bicuspid aortic valve. In 1 individual there was no predisposing finding other than the presence of Turner syndrome. Associated pregnancy was documented in 1 of 19 (5%). More than half (13/19, 68%) came to medical attention >24 hours after the onset of symptoms. For those with type A dissections, the mean ascending aortic size index was 2.7±0.6 cm/m(2) (n=9). CONCLUSIONS: Aortic dissection in Turner syndrome occurs in young individuals at smaller aortic diameters than in the general population or other forms of genetically triggered aortopathy. The absence of aortic valve or other cardiac malformations appears to markedly reduce the risk of aortic dissection However, aortic dissection can occur in Turner syndrome without cardiac malformations or hypertension. Individuals with Turner syndrome who are >18 years of age with an ascending aortic size index >2.5 cm/m(2) should be considered for an aortic operation to prevent aortic dissection.

GenTAC registry report: gender differences among individuals with genetically triggered thoracic aortic aneurysm and dissection.

Previous data suggest women are at increased risk of death from aortic dissection. Therefore, we analyzed data from the GenTAC registry, the NIH-sponsored program that collects information about individuals with genetically triggered thoracic aortic aneurysms and cardiovascular conditions. We performed cross-sectional analyses in adults with Marfan syndrome (MFS), familial thoracic aortic aneurysm or dissection (FTAAD), bicuspid aortic valve (BAV) with thoracic aortic aneurysm or dissection, and subjects under 50 years of age with thoracic aortic aneurysm or dissection (TAAD <50 years). Women comprised 32% of 1,449 subjects and were 21% of subjects with BAV, 34% with FTAAD, 22% with TAAD <50 years, and 47% with MFS. Thoracic aortic dissections occurred with equal gender frequency yet women with BAV had more extensive dissections. Aortic size was smaller in women but was similar after controlling for BSA. Age at operation for aortic valve dysfunction, aneurysm or dissection did not differ by gender. Multivariate analysis (adjusting for age, BSA, hypertension, study site, diabetes, and subgroup diagnoses) showed that women had fewer total aortic surgeries (OR = 0.65, P < 0.01) and were less likely to receive angiotensin converting enzyme inhibitors (ACEi; OR = 0.68, P < 0.05). As in BAV, other genetically triggered aortic diseases such as FTAAD and TAAD <50 are more common in males. In women, decreased prevalence of aortic operations and less treatment with ACEi may be due to their smaller absolute aortic diameters. Longitudinal studies are needed to determine if women are at higher risk for adverse events.

Intramuscular small vessel arteriovenous malformation of the left ventricle in an asymptomatic adolescent: a case report and literature review.

Primary vascular tumours of the heart are rare and heterogeneous in their presentation and classification.We present a primary intramuscular vascular malformation of the left ventricle in an asymptomatic 12-year-old girl. Characteristics on cardiac magnetic resonance imaging, specifically increased signal intensity on T2-weighted images, and marked contrast enhancement with gadolinium were suggestive of increased vascularity. Histologically, the mass was determined to be an intramuscular vascular malformation of the small vessel arteriovenous subtype. This represents one of a select few intramuscular vascular malformations of the left ventricle reported in children. Our patient remains completely asymptomatic and has had no change in the size and appearance of the mass after more than 30 months of follow-up.

Cardiovascular Outcomes in Aortopathy: GenTAC Registry of Genetically Triggered Aortic Aneurysms and Related Conditions.

BACKGROUND: The GenTAC (Genetically Triggered Thoracic Aortic Aneurysm and Cardiovascular Conditions) Registry enrolled patients with genetic aortopathies between 2007 and 2016. OBJECTIVES: The purpose of this study was to compare age distribution and probability of elective surgery for proximal aortic aneurysm, any dissection surgery, and cardiovascular mortality among aortopathy etiologies. METHODS: The GenTAC study had a retrospective/prospective design. Participants with bicuspid aortic valve (BAV) with aneurysm (n = 879), Marfan syndrome (MFS) (n = 861), nonsyndromic heritable thoracic aortic disease (nsHTAD) (n = 378), Turner syndrome (TS) (n = 298), vascular Ehlers-Danlos syndrome (vEDS) (n = 149), and Loeys-Dietz syndrome (LDS) (n = 121) were analyzed. RESULTS: The 25% probability of elective proximal aortic aneurysm surgery was 30 years for LDS (95% CI: 18-37 years), followed by MFS (34 years; 95% CI: 32-36 years), nsHTAD (52 years; 95% CI: 48-56 years), and BAV (55 years; 95% CI: 53-58 years). Any dissection surgery 25% probability was highest in LDS (38 years; 95% CI: 33-53 years) followed by MFS (51 years; 95% CI: 46-57 years) and nsHTAD (54 years; 95% CI: 51-61 years). BAV experienced the largest relative frequency of elective surgery to any dissection surgery (254/33 = 7.7), compared with MFS (273/112 = 2.4), LDS (35/16 = 2.2), or nsHTAD (82/76 = 1.1). With MFS as the reference population, risk of any dissection surgery or cardiovascular mortality was lowest in BAV patients (HR: 0.13; 95% CI: 0.08-0.18; HR: 0.13; 95%: CI: 0.06-0.27, respectively). The greatest risk of mortality was seen in patients with vEDS. CONCLUSIONS: Marfan and LDS cohorts demonstrate age and event profiles congruent with the current understanding of syndromic aortopathies. BAV events weigh toward elective replacement with relatively few dissection surgeries. Nonsyndromic HTAD patients experience near equal probability of dissection vs prophylactic surgery, possibly because of failure of early diagnosis.

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome.

Cardiovascular abnormalities are important features of Costello syndrome and other Ras/MAPK pathway syndromes ("RASopathies"). We conducted clinical, pathological and molecular analyses of 146 patients with an HRAS mutation including 61 enrolled in an ongoing longitudinal study and 85 from the literature. In our study, the most common (84%) HRAS mutation was p.G12S. A congenital heart defect (CHD) was present in 27 of 61 patients (44%), usually non-progressive valvar pulmonary stenosis. Hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, was noted in 37 (61%), and 5 also had a CHD (14% of those with HCM). HCM was chronic or progressive in 14 (37%), stabilized in 10 (27%), and resolved in 5 (15%) patients with HCM; follow-up data was not available in 8 (22%). Atrial tachycardia occurred in 29 (48%). Valvar pulmonary stenosis rarely progressed and atrial septal defect was uncommon. Among those with HCM, the likelihood of progressing or remaining stable was similar (37%, 41% respectively). The observation of myocardial fiber disarray in 7 of 10 (70%) genotyped specimens with Costello syndrome is consistent with sarcomeric dysfunction. Multifocal atrial tachycardia may be distinctive for Costello syndrome. Potentially serious atrial tachycardia may present in the fetus, and may continue or worsen in about one-fourth of those with arrhythmia, but is generally self-limited in the remaining three-fourths of patients. Physicians should be aware of the potential for rapid development of severe HCM in infants with Costello syndrome, and the need for cardiovascular surveillance into adulthood as the natural history continues to be delineated.

Myocardial Perfusion in Hypoplastic Left Heart Syndrome.

BACKGROUND: The status of the systemic right ventricular coronary microcirculation in hypoplastic left heart syndrome (HLHS) is largely unknown. It is presumed that the systemic right ventricle's coronary microcirculation exhibits unique pathophysiological characteristics of HLHS in Fontan circulation. The present study sought to quantify myocardial blood flow by cardiac magnetic resonance imaging and evaluate the determinants of microvascular coronary dysfunction and myocardial ischemia in HLHS. METHODS: One hundred nineteen HLHS patients (median age, 4.80 years) and 34 healthy volunteers (median age, 5.50 years) underwent follow-up cardiac magnetic resonance imaging ≈1.8 years after total cavopulmonary connection. Right ventricle volumes and function, myocardial perfusion, diffuse fibrosis, and late gadolinium enhancement were assessed in 4 anatomic HLHS subtypes. Myocardial blood flow (MBF) was quantified at rest and during adenosine-induced hyperemia. Coronary conductance was estimated from MBF at rest and catheter-based measurements of mean aortic pressure (n=99). RESULTS: Hyperemic MBF in the systemic ventricle was lower in HLHS compared with controls (1.89±0.57 versus 2.70±0.84 mL/g per min; P<0.001), while MBF at rest normalized by the rate-pressure product, was similar (1.25±0.36 versus 1.19±0.33; P=0.446). Independent risk factors for a reduced hyperemic MBF were an HLHS subtype with mitral stenosis and aortic atresia (P=0.017), late gadolinium enhancement (P=0.042), right ventricular diastolic dysfunction (P=0.005), and increasing age at total cavopulmonary connection (P=0.022). The coronary conductance correlated negatively with systemic blood oxygen saturation (r, -0.29; P=0.02). The frequency of late gadolinium enhancement increased with age at total cavopulmonary connection (P=0.014). CONCLUSIONS: The coronary microcirculation of the systemic ventricle in young HLHS patients shows significant differences compared with controls. These hypothesis-generating findings on HLHS-specific risk factors for microvascular dysfunction suggest a potential benefit from early relief of frank cyanosis by total cavopulmonary connection.