The effects of pregnancy in subjects with repaired tetralogy of Fallot.

BACKGROUND: Previous reports reveal inconsistent findings of right ventricular (RV) changes following pregnancy in subjects with repaired tetralogy of Fallot (rTOF). METHODS: A two-center, retrospective cohort study which included women with rTOF who completed pregnancy that were matched to nulliparous women with rTOF by age at the time of baseline cardiac magnetic resonance (CMR), RV ejection fraction (RVEF), and indexed RV end-diastolic volume (RVEDVi). Pre-pregnancy and postpartum cardiac magnetic resonance (CMR) were analyzed and compared to sequential CMR of nulliparous subjects with rTOF. RESULTS: Thirty-six women with rTOF who completed pregnancy were matched to 72 nulliparous women with rTOF. Over a mean period of 3.1 years for the pregnancy group and 2.7 years for the comparison group, there was no significant change in the RVEDVi, RVEF, RV mass, pulmonary regurgitation severity, left ventricular (LV) volumes, LV ejection fraction (LVEF), or LV mass when comparing the baseline CMR and the follow-up CMR in either of the groups. There was a slight increase in RV indexed end-systolic volume (RVESVi) when comparing the baseline CMR and the follow-up CMR in the pregnancy group (68.93, SD 23.34 ml/m2 at baseline vs. 72.97, SD 25.24 mL/m2 at follow-up, P = .028). Using a mixed effects model for CMR parameters change over time; when adjusted for time between baseline and follow-up CMR there was no significant difference in rate of change between the pregnancy and comparison groups. CONCLUSIONS: Most ventricular remodeling parameters measured by CMR did not significantly change in subjects with rTOF who completed pregnancy or in nulliparous subjects with rTOF. In the pregnancy group, RVESVi is larger in those individuals who have undergone pregnancy without a significant change in ventricular function. These patients should be followed longitudinally to determine the long-term ventricular and clinical effects of pregnancy.

Prognostic value of myocardial deformation parameters for outcome prediction in tetralogy of Fallot.

INTRODUCTION: The prognostic value of myocardial deformation parameters in adults with repaired tetralogy of Fallot (rTOF) has not been well-elucidated. We therefore aimed to explore myocardial deformation parameters for outcome prediction in adults with rTOF using cardiovascular magnetic resonance imaging (CMR). METHODS: Adults with rTOF and at least moderate pulmonary regurgitation (PR) were identified from an institutional prospective CMR registry. Left (LV) and right ventricular (RV) global strain were recorded in longitudinal (GLS), circumferential (GCS) and radial (GRS) directions. Major adverse cardiovascular events (MACE) were defined as a composite of mortality, resuscitated sudden death, sustained ventricular tachycardia (>30seconds) or heart failure (hospital admission >24hours). In patients with pulmonary valve replacement (PVR), pre-and post-PVR CMR studies were analysed to assess for predictors of complete RV reverse remodelling, which we defined as RV end-diastolic volume indexed (RVEDVi) <110ml/m2. Logistic regression models were used to estimate the odds ratio (OR) per unit change in absolute strain value associated with clinical outcomes and receiver operator characteristic (ROC) curves were constructed with area under the curve (AUC) for select CMR variables. RESULTS: We included 307 patients (age 35±13 years, 59% male). During 6.1 years (3.3-8.8) of follow-up, pulmonary valve replacement (PVR) was performed in 142 (46%) and MACE occurred in 31 (10%). On univariate analysis, baseline biventricular ejection fraction (EF), mass and all strain parameters were associated with MACE. After adjustment for LVEF, only LVGLS remained independently predictive of MACE (OR 0.822 [0.693-0.976] p=0.025). Receiver operator curves identified an absolute LVGLS value less than 15 and LVEF <51% as thresholds for MACE prediction (AUC 0.759 [0.655-0.840] and 0.720 [0.608-0.810]). After adjusting for baseline RVEDVi, RVGCS (OR 1.323 [1.094-1.600] p=0.004), LVGCS (OR 1.276 [1.029-1.582] p=0.027) and LVGRS (OR 1.101 [1.0210-1.200], p=0.028) were independent predictors of complete remodelling post-PVR remodelling. CONCLUSIONS: Biventricular strain parameters predict clinical outcomes and post-PVR remodelling in rTOF. Further study will be necessary to establish the role of myocardial deformation parameters in clinical practice.

Feasibility of MRI assessment of maternal-fetal oxygen transport and consumption relative to maternal position in healthy late gestational pregnancies.

Late gestational supine positioning reduces maternal cardiac output due to inferior vena caval (IVC) compression, despite increased collateral venous return. However, little is known about the impact of maternal position on oxygen (O2 ) delivery and consumption of the gravid uterus, fetus, placenta and lower limbs. We studied the effects of maternal positioning on these parameters in 20 healthy pregnant subjects at 36 ± 2 weeks using magnetic resonance imaging (MRI); a follow-up MRI was performed 6-months postpartum (n = 16/20). MRI techniques included phase-contrast and T1/T2 relaxometry for blood flow and oximetry imaging, respectively. O2 transport was measured in the following vessels (bilateral where appropriate): maternal abdominal descending aorta (DAoabdo ), IVC, ovarian, paraspinal veins (PSV), uterine artery (UtA) and external iliacs, and umbilical. Maternal cardiac output was measured by summing DAothoracic and superior vena cava flows. Supine mothers (n = 6) had lower cardiac output and O2 delivery in the DAoabdo , UtA and external iliac arteries, and higher PSV flow than those in either the left (n = 8) or right (n = 6) lateral positions during MRI. However, O2 consumption in the gravid uterus, fetus, placenta and lower limbs was unaffected by maternal positioning. The ratio of IVC/PSV flow decreased in supine mothers while ovarian venous flow and O2 saturation were unaltered, suggesting a major route of pelvic venous return unaffected by maternal position. Placental-fetal O2 transport and consumption were similar between left and right lateral maternal positions. In comparison to non-pregnant findings, DAoabdo and UtA O2 delivery and pelvic O2 consumption increased, while lower-limb consumption remained constant , despite reduced external iliac artery O2 delivery in late gestation. KEY POINTS: Though sleeping supine during the third trimester is associated with an increased risk of antepartum stillbirth, the underlying biological mechanisms are not fully understood. Maternal cardiac output and uteroplacental flow are reduced in supine mothers due to inferior vena caval compression from the weight of the gravid uterus. This MRI study provides a comprehensive circulatory assessment, demonstrating reduced maternal cardiac output and O2 delivery (uteroplacental, lower body) in supine compared to lateral positioning; however, O2 consumption (gravid uterus, fetus, placenta, lower limbs) was preserved. Unlike other mammalian species, the ovarian veins conduct substantial venous return from the human pregnant uterus that is unaffected by maternal positioning. Lumbar paraspinal venous flow increased in supine mothers. These observations may have important considerations during major pelvic surgery in pregnancy (i.e. placenta percreta). Future studies should address the importance of maternal positioning as a potential tool to deliver improved perinatal outcomes in pregnancies with compromised uteroplacental O2 delivery.

Association of Pectus Excavatum With Ventricular Remodelling and Mitral Valve Abnormalities in Marfan Syndrome.

Background: Marfan syndrome (MFS) is an inherited connective tissue disorder. Pectus excavatum (PEX) is common in MFS. The purpose was to evaluate the association of PEX with cardiovascular manifestations of MFS, biventricular size and function. Methods: MFS adults undergoing cardiac MRI were retrospectively evaluated. Exclusion criteria were incomplete cardiac MRI, significant artifacts, co-existent ischaemic or congenital heart disease. Haller Index (HI) ≥3.25 classified patients as PEX positive (PEX+) and PEX negative (PEX-). Cardiac MRI analysis included assessment of mitral valve prolapse (MVP), mitral annular disjunction (MAD), biventricular volumetry and aortic dimensions. Results: 212 MFS patients were included, 76 PEX+ and 136 PEX- (HI 8.3 ± 15.2 vs 2.3 ± 0.5, P < .001). PEX+ were younger (33.4 ± 12.0 vs 38.1 ± 14.3 years, P = .02) and similar in sex distribution (55% vs 63% male, P = .26) compared to PEX-. MVP and MAD were more frequent in PEX+ vs PEX- (43/76 [57%] vs 37/136 [27%], P < .001; 44/76 [58%] vs 50/136[37%], P = .003, respectively). PEX+ had higher right ventricular end-diastolic and end-systolic volumes (RVEDVi 92 ± 17mL/m2 vs 84 ± 22mL/m2, P = .04; RVESVi 44 ± 10 mL/m2 vs 39 ± 14 mL/m2, P = .02), lower RV ejection fraction (RVEF 52 ± 5% vs 55 ± 6%, P = .01) compared to PEX-. Left ventricular (LV) volumes, LVEF and aortic dimensions were similar. Conclusion: MFS adults with PEX have higher frequency of cardiac manifestations including MV abnormalities, increased RV volumes and lower RVEF compared to those without PEX. Awareness of this association is important for all radiologists who interpret aortic CT or MRI, where HI can be easily measured. PEX in MFS may suggest more severe disease expression necessitating careful screening for MV abnormalities and outcomes surveillance.

Myocarditis Following COVID-19 Vaccination.

Myocarditis is an established but rare adverse event following administration of messenger RNA-based coronavirus disease 2019 (COVID-19) vaccines and is most common in male adolescents and young adults. Symptoms typically develop within a few days of vaccine administration. Most patients have mild abnormalities on cardiac imaging with rapid clinical improvement with standard treatment. However, longer term follow-up is needed to determine whether imaging abnormalities persist, to evaluate for adverse outcomes, and to understand the risk associated with subsequent vaccination. The purpose of the review is to evaluate the current literature related to myocarditis following COVID-19 vaccination, including the incidence, risk factors, clinical course, imaging findings, and proposed pathophysiologic mechanisms.

Myocardial Injury Pattern at MRI in COVID-19 Vaccine-Associated Myocarditis.

Background There are limited data on the pattern and severity of myocardial injury in patients with COVID-19 vaccination-associated myocarditis. Purpose To describe myocardial injury following COVID-19 vaccination and to compare these findings to other causes of myocarditis. Materials and Methods In this retrospective cohort study, consecutive adult patients with myocarditis with at least one T1-based and at least one T2-based abnormality at cardiac MRI performed at a tertiary referral hospital from December 2019 to November 2021 were included. Patients were classified into one of three groups: myocarditis following COVID-19 vaccination, myocarditis following COVID-19 illness, and other myocarditis not associated with COVID-19 vaccination or illness. Results Of the 92 included patients, 21 (23%) had myocarditis following COVID-19 vaccination (mean age, 31 years ± 14 [SD]; 17 men; messenger RNA-1273 in 12 [57%] and BNT162b2 in nine [43%]). Ten of 92 (11%) patients had myocarditis following COVID-19 illness (mean age, 51 years ± 14; three men) and 61 of 92 (66%) patients had other myocarditis (mean age, 44 years ± 18; 36 men). MRI findings in the 21 patients with vaccine-associated myocarditis included late gadolinium enhancement (LGE) in 17 patients (81%) and left ventricular dysfunction in six (29%). Compared with other causes of myocarditis, patients with vaccine-associated myocarditis had a higher left ventricular ejection fraction and less extensive LGE, even after controlling for age, sex, and time from symptom onset to MRI. The most frequent location of LGE in all groups was subepicardial at the basal inferolateral wall, although septal involvement was less common in vaccine-associated myocarditis. At short-term follow-up (median, 22 days [IQR, 7-48 days]), all patients with vaccine-associated myocarditis were asymptomatic with no adverse events. Conclusion Cardiac MRI demonstrated a similar pattern of myocardial injury in vaccine-associated myocarditis compared with other causes, although abnormalities were less severe, with less frequent septal involvement and no adverse events over the short-term follow-up. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Raman and Neubauer in this issue.

Clinical Impact of Cardiac MRI T1 and T2 Parametric Mapping in Patients with Suspected Cardiomyopathy.

Background There are limited data on the incremental value of parametric mapping compared with core cardiac MRI protocols for suspected cardiomyopathy in routine clinical practice. Purpose To evaluate the impact of cardiac MRI T1 and T2 mapping in routine clinical practice with respect to diagnostic accuracy, reader diagnostic confidence, and downstream cardiac imaging utilization. Materials and Methods In this retrospective single-center study, consecutive clinical cardiac MRI scans obtained with and without T1 and T2 mapping for evaluation of suspected cardiomyopathy between January 2017 and October 2019 were evaluated. Diagnostic accuracy and reader diagnostic confidence were evaluated in a random subset. Downstream cardiac imaging utilization was analyzed in patients with a minimum of 1 year of clinical follow-up ending before January 2020. Results A total of 1876 patients (mean age, 51 years ± 17 [SD]; 1113 men) were evaluated. Of these, 751 (40%) underwent cardiac MRI with the core protocol and 1125 (60%) with the core protocol plus T1 and T2 mapping. In the mapping group, T1 and T2 were high in 280 (25%) and 47 patients (4%), respectively. In the subset evaluated for diagnostic utility (n = 450), the addition of T1 and T2 maps to the core protocol resulted in an improvement in reader diagnostic confidence in 174 patients (39%). Diagnostic sensitivity was higher with the core protocol plus mapping compared with the core protocol alone for myocarditis (89% [31 of 35 patients] vs 69% [24 of 35]; P = .008), Fabry disease (93% [13 of 14 patients] vs 50% [seven of 14]; P = .01), and amyloidosis (100% [16 of 16 patients] vs 63% [10 of 16]; P = .01). In the subset evaluated for downstream imaging utilization (n = 903), 47% of patients with mapping had at least one subsequent cardiac imaging test compared with 55% of patients without mapping (P = .01). Conclusion In patients with suspected cardiomyopathy, cardiac MRI with T1 and T2 mapping had high diagnostic utility and was associated with lower downstream cardiac imaging utilization. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Jerosch-Herold and Coelho-Filho in this issue.

Cardiac MRI predictors of good long-term outcomes in patients with repaired TOF.

BACKGROUND: Risk stratification in patients with repaired tetralogy of Fallot (rTOF) have focused on poor clinical outcomes while predictors of a benign clinical course have not been characterized. OBJECTIVE: The goal of this study was to Identify cardiac magnetic resonance (CMR) markers of a good clinical course late after TOF repair. METHODS: Clinical and CMR data from the International Multicenter TOF Registry (INDICATOR) were analyzed. The primary outcome was time to the earliest occurrence of a composite of death, aborted sudden death, and sustained ventricular tachycardia (VT). The secondary outcome was time to the earliest occurrence of atrial arrhythmia, nonsustained VT, and NYHA class >II. Multinomial regression was used to identify predictors of the 3-category outcome: (a) good outcome, defined as freedom from the primary AND secondary outcomes at age 50 years; (b) poor outcome, defined as presence of the primary outcome before age 50 years; and (c) intermediate outcome, defined as not fulfilling criteria for good or poor outcomes. RESULTS: Among 1088 eligible patients, 96 had good outcome, 60 experienced poor outcome, and 932 had intermediate outcome. Patients were age 25.8±10.8 years at the time of the index CMR. Median follow-up was 5.8 years (IQR 3.0, 9.9) after CMR in event-free patients. By univariate analysis, smaller right ventricular (RV) end-systolic and end-diastolic volume index, smaller left ventricular end-systolic volume index, higher right and left ventricular ejection fraction, lower right and left ventricular mass index, and lower left ventricular mass/volume ratio were associated with good outcome. Multivariable modeling identified higher RV ejection fraction (OR 2.38 per 10% increase, P = .002) and lower RV mass index (OR 1.72, per 10 g/m2 decrease, P = .002) as independently associated with good outcome after adjusting for age at CMR. Classification and regression tree analysis identified important thresholds associated with good outcome that were specific to patients age ≥37 years at the time of CMR; these were RV ejection fraction ≥42% and RV mass index <39 g/m2. CONCLUSIONS: Adults with rTOF and no more than mild RV dysfunction combined with no significant RV hypertrophy are likely to be free from serious adverse clinical events into their sixth decade of life and may require less frequent cardiac testing.

An MRI approach to assess placental function in healthy humans and sheep.

KEY POINTS: Human placental function is evaluated using non-invasive Doppler ultrasound of umbilical and uterine artery pulsatility indices as measures of resistance in placental vascular beds, while measurement of placental oxygen consumption ( VO2 ) is only possible during Caesarean delivery. This study shows the feasibility of using magnetic resonance imaging (MRI) in utero to measure blood flow and oxygen content in uterine and umbilical vessels to calculate oxygen delivery to and VO2 by the gravid uterus, uteroplacenta and fetus. Normal late gestational human uteroplacental VO2 by MRI was ∼4 ml min-1  kg-1 fetal weight, which was similar to our MRI measurements in sheep and to those previously measured using invasive techniques. Our MRI approach can quantify uteroplacental VO2 , which involves the quantification of maternal- and fetal-placental blood flows, fetal oxygen delivery and VO2 , and the oxygen gradient between uterine- and umbilical-venous blood, providing a comprehensive assessment of placental function with clinical potential. ABSTRACT: It has not been feasible to perform routine clinical measurement of human placental oxygen consumption ( VO2 ) and in vitro studies do not reflect true metabolism in utero. Here we propose an MRI method to non-invasively quantify in utero placental and fetal oxygen delivery ( DO2 ) and VO2 in healthy humans and sheep. Women (n = 20) and Merino sheep (n = 10; 23 sets of measurements) with singleton pregnancies underwent an MRI in late gestation (36 ± 2 weeks and 128 ± 9 days, respectively; mean ± SD). Blood flow (phase-contrast) and oxygen content (T1 and T2 relaxometry) were measured in the major uterine- and umbilical-placental vessels, allowing calculation of uteroplacental and fetal DO2 and VO2 . Maternal DO2 (ml min-1  kg-1 fetus) to the gravid uterus was similar in humans and sheep (human = 54 ± 15, sheep = 53 ± 21, P = 0.854), while fetal DO2 (human = 25 ± 4, sheep = 22 ± 5, P = 0.049) was slightly lower in sheep. Uteroplacental and fetal VO2 (ml min-1  kg-1 fetus; uteroplacental: human = 4.1 ± 1.5, sheep = 3.5 ± 1.9, P = 0.281; fetus: human = 6.8 ± 1.3, sheep = 7.2 ± 1.7, P = 0.426) were similar between species. Late gestational uteroplacental:fetal VO2 ratio did not change with age (human, P = 0.256; sheep, P = 0.121). Human umbilical blood flow (ml min-1  kg-1 fetus) decreased with advancing age (P = 0.008), while fetal VO2 was preserved through an increase in oxygen extraction (P = 0.046). By contrast, sheep fetal VO2 was preserved through stable umbilical flow (ml min-1  kg-1 ; P = 0.443) and oxygen extraction (P = 0.582). MRI derived measurements of uteroplacental and fetal VO2 between humans and sheep were similar and in keeping with prior data obtained using invasive techniques. Taken together, these data confirm the reliability of our approach, which offers a novel clinical 'placental function test'.

Increased Spread of Native T1 Values Assessed With MRI as a Marker of Cardiac Involvement in Fabry Disease.

OBJECTIVE. Cardiac involvement is the leading cause of mortality in Fabry disease. Noninvasive markers of cardiac involvement are needed to identify patients at high risk. The purpose of this study was to evaluate the diagnostic potential of segmental native T1 spread as an imaging biomarker in Fabry disease. SUBJECTS AND METHODS. In this prospective study, 43 patients with confirmed Fabry disease (mean ± SD age, 46±14 years; 70% women) and 17 healthy control subjects (mean ± SD age, 44 ±13 years; 53% women) underwent 3-T cardiac MRI including modified Look-Locker inversion recovery T1 mapping. Segmental native T1 spread was calculated as the difference between maximum and minimum segmental native T1 values, expressed as an absolute value and as a relative percentage of global native T1. RESULTS. Absolute and relative segmental native T1 spreads were significantly higher in patients with Fabry disease than in healthy control subjects (absolute median, 115 vs 98 ms [p = 0.004]; relative median, 9.9% vs 8.0% [p < 0.001]) and correlated positively with quantitative late gadolinium enhancement (absolute, r = 0.434, p < 0.001; relative, r = 0.436, p < 0.001), indexed left ventricular mass (absolute, r = 0.316, p = 0.01; relative, r = 0.347, p = 0.007), and global longitudinal strain (absolute, r = 0.289, p = 0.03; relative, r = 0.277, p = 0.03). Relative segmental native T1 spread differentiated patients with Fabry disease from healthy control subjects (odds ratio, 1.44 [95% CI, 1.10-1.89]; p = 0.009). Interob-server agreement was excellent for both absolute (intraclass correlation coefficient, 0.932) and relative (intraclass correlation coefficient, 0.926) segmental native T1 spread. CONCLUSION. Increased native T1 spread is a reproducible imaging biomarker of cardiac involvement in Fabry disease and may be particularly useful in the evaluation of patients who cannot undergo late gadolinium enhancement imaging.

Calibration of an Electrical Analog Model of Liver Hemodynamics in Fontan Patients.

Fontan associated liver disease is a common complication in patients with Fontan circulation, who were born with a single functioning heart ventricle. The hepatic venous pressure gradient (HVPG) is used to assess liver health and is a surrogate measure of the pressure gradient across the entire liver (portal pressure gradient (PPG)). However, it is thought to be inaccurate in Fontan patients. The main objectives of this study were (1) to apply an existing detailed lumped parameter model (LPM) of the liver to Fontan patients using patient-specific clinical data and (2) to determine whether HVPG is a suitable measurement of PPGs in these patients. An existing LPM of the liver blood circulation was applied and tuned to simulate patient-specific liver hemodynamics. Geometries were collected from seven adult Fontan patients and used to evaluate model parameters. The model was solved and tuned using waveform measurements of flows, inlet and outlet pressures. The predicted ratio of portal to hepatic venous pressures is comparable to in vivo measurements. The results confirmed that HVPG is not suitable for Fontan patients, as it would underestimate the portal pressures gradient by a factor of 3 to 4. Our patient-specific liver model provides an estimate of the pressure drop across the liver, which differs from the clinically used metric HVPG. This work represents a first step toward models suitable to assess liver health in Fontan patients and improve its long-term management.

Left Ventricular Hypertrophy and Late Gadolinium Enhancement at Cardiac MRI Are Associated with Adverse Cardiac Events in Fabry Disease.

Background Cardiac involvement is the leading cause of mortality in patients with Fabry disease. Identification of imaging findings that predict adverse cardiac events is needed to enable identification of high-risk patients. Purpose To establish the prognostic value of cardiac MRI findings in men and women with Fabry disease. Materials and Methods Consecutive women and men with gene-positive Fabry disease who had undergone cardiac MRI at a single large tertiary referral hospital between March 2008 and January 2019 were included in this retrospective cohort study. Evaluators of cardiac MRI studies were blinded to all clinical information. Adverse cardiac events were assessed as a composite end point, defined as ventricular tachycardia, bradycardia requiring device implantation, severe heart failure, and cardiac death. Statistical analysis included Cox proportional hazard models adjusted for age and Mainz Severity Score Index (a measure of the severity of Fabry disease). Results Ninety patients (mean age, 44 years ± 15 [standard deviation]; 59 women) were evaluated. After a median follow-up period of 3.6 years, the composite end point was reached in 21 patients (incidence rate, 7.6% per year). Left ventricular hypertrophy (LVH) and late gadolinium enhancement (LGE) were independent predictors of the composite end point in adjusted analysis (LVH hazard ratio [HR], 3.0; 95% confidence interval [CI]: 1.1, 8.1; P = .03; and LGE HR, 7.2; 95% CI: 1.5, 34; P = .01). Patients with extensive LGE (≥15% of left ventricular mass) were at highest risk (HR, 12; 95% CI: 2.0, 67; P = .006). Sex did not modify the relationship between the composite end point and any of the cardiac MRI parameters, including LVH (P = .15 for interaction term) and LGE (P = .38 for interaction term). Conclusion Cardiac MRI findings of left ventricular hypertrophy and late gadolinium enhancement can be used to identify patients with Fabry disease who are at high risk of adverse cardiac events. © RSNA, 2019 See also the editorial by Zimmerman in this issue.

Preoperative Predictors of Death and Sustained Ventricular Tachycardia After Pulmonary Valve Replacement in Patients With Repaired Tetralogy of Fallot Enrolled in the INDICATOR Cohort.

BACKGROUND: Risk factors for adverse clinical outcomes have been identified in patients with repaired tetralogy of Fallot before pulmonary valve replacement (PVR). However, pre-PVR predictors for post-PVR sustained ventricular tachycardia and death have not been identified. METHODS: Patients with repaired tetralogy of Fallot enrolled in the INDICATOR cohort (International Multicenter TOF Registry), a 4-center international cohort study, who had a comprehensive preoperative evaluation and subsequently underwent PVR were included. Preprocedural clinical, ECG, cardiovascular magnetic resonance, and postoperative outcome data were analyzed. Cox proportional hazards multivariable regression analysis was used to evaluate factors associated with time from pre-PVR cardiovascular magnetic resonance until the primary outcome: death, aborted sudden cardiac death, or sustained ventricular tachycardia. RESULTS: Of the 452 eligible patients (median age at PVR, 25.8 years), 36 (8%) reached the primary outcome (27 deaths, 2 resuscitated death, and 7 sustained ventricular tachycardia) at a median time after PVR of 6.5 years. Cox proportional hazards regression identified pre-PVR right ventricular ejection fraction <40% (hazard ratio, 2.39; 95% CI, 1.18-4.85; P=0.02), right ventricular mass-to-volume ratio ≥0.45 g/mL (hazard ratio, 4.08; 95% CI, 1.57-10.6; P=0.004), and age at PVR ≥28 years (hazard ratio, 3.10; 95% CI, 1.42-6.78; P=0.005) as outcome predictors. In a subgroup analysis of 230 patients with Doppler data, predicted right ventricular systolic pressure ≥40 mm Hg was associated with the primary outcome (hazard ratio, 3.42; 95% CI, 1.09-10.7; P=0.04). Preoperative predictors of a composite secondary outcome, postoperative arrhythmias and heart failure, included older age at PVR, pre-PVR atrial tachyarrhythmias, and a higher left ventricular end-systolic volume index. CONCLUSIONS: In this observational investigation of patients with repaired tetralogy of Fallot, an older age at PVR and pre-PVR right ventricular hypertrophy and dysfunction were predictive of a shorter time to postoperative death and sustained ventricular tachycardia. These findings may inform the timing of PVR if confirmed by prospective clinical trials.

Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot.

PURPOSE: To determine disease-associated single-gene variants in conotruncal defects, particularly tetralogy of Fallot (TOF). METHODS: We analyzed for rare loss-of-function and deleterious variants in FLT4 (VEGFR3) and other genes in the vascular endothelial growth factor (VEGF) pathway, as part of a genome sequencing study involving 175 adults with TOF from a single site. RESULTS: We identified nine (5.1%) probands with novel FLT4 variants: seven loss-of-function, including an 8-kb deletion, and two predicted damaging. In ten other probands we found likely disruptive variants in VEGF-related genes: KDR (VEGFR2; two stopgain and two nonsynonymous variants), VEGFA, FGD5, BCAR1, IQGAP1, FOXO1, and PRDM1. Detection of VEGF-related variants (19/175, 10.9%) was associated with an increased prevalence of absent pulmonary valve (26.3% vs. 3.4%, p < 0.0001) and right aortic arch (52.6% vs. 29.1%, p = 0.029). Extracardiac anomalies were rare. In an attempt to replicate findings, we identified three loss-of-function or damaging variants in FLT4, KDR, and IQGAP1 in ten independent families with TOF. CONCLUSION: Loss-of-function variants in FLT4 and KDR contribute substantially to the genetic basis of TOF. The findings support dysregulated VEGF signaling as a novel mechanism contributing to the pathogenesis of TOF.

Left ventricular strain analysis using cardiac magnetic resonance imaging in patients undergoing in-centre nocturnal haemodialysis.

AIM: Intensified haemodialysis is associated with regression of left ventricular (LV) mass. Compared to LV ejection fraction, LV strain allows more direct assessment of LV function. We sought to assess the impact of in-centre nocturnal haemodialysis (INHD) on global LV strain (radial, circumferential, and longitudinal) and torsion by cardiac MRI (CMR). METHODS: In this prospective, two-centre cohort study, 37 participants on conventional haemodialysis (CHD, 3-4 h/session for three sessions/week) converted to INHD (7-8 h/session for three sessions/week) and 30 participants continued CHD. Participants underwent CMR using a standardized protocol and had biomarker measurements at baseline and 52 weeks. RESULTS: Among the 55 participants (mean age 55; 40% women) with complete CMR data, those who converted to INHD had a significant improvement in their global circumferential strain (GCS, P = 0.025), while those continuing CHD did not have any significant changes in LV strain. When the two groups were compared, there was significant improvement in torsion. LV strains were significantly correlated with each other, but not with troponin I, C-reactive protein, or brain natriuretic protein (NT-proBNP), except for global longitudinal strain (GLS) with troponin I (P = 0.001) and NT-proBNP (P = 0.038). CONCLUSION: Conversion to INHD was associated with significant improvement in GCS over one year of study, although comparisons with the CHD group were not significant. There was also a significant decrease in torsion in the INHD group compared with CHD. Improvement in LV regional function would support the notion that INHD has favourable effects on both LV structure and function.

Noninvasive hematocrit assessment for cardiovascular magnetic resonance extracellular volume quantification using a point-of-care device and synthetic derivation.

BACKGROUND: Calculation of cardiovascular magnetic resonance (CMR) extracellular volume (ECV) requires input of hematocrit, which may not be readily available. The purpose of this study was to evaluate the diagnostic accuracy of ECV calculated using various noninvasive measures of hematocrit compared to ECV calculated with input of laboratory hematocrit as the reference standard. METHODS: One hundred twenty three subjects (47.7 ± 14.1 years; 42% male) were prospectively recruited for CMR T1 mapping between August 2016 and April 2017. Laboratory hematocrit was assessed by venipuncture. Noninvasive hematocrit was assessed with a point-of-care (POC) device (Pronto-7® Pulse CO-Oximeter®, Masimo Personal Health, Irvine, California, USA) and by synthetic derivation based on the relationship with blood pool T1 values. Left ventricular ECV was calculated with input of laboratory hematocrit (Lab-ECV), POC hematocrit (POC-ECV), and synthetic hematocrit (synthetic-ECV), respectively. Statistical analysis included Wilcoxon signed-rank test, Bland-Altman analysis, receiver-operating curve analysis and intra-class correlation (ICC). RESULTS: There was no significant difference between Lab-ECV and POC-ECV (27.1 ± 4.7% vs. 27.3 ± 4.8%, p = 0.106), with minimal bias and modest precision (bias - 0.18%, 95%CI [- 2.85, 2.49]). There was no significant difference between Lab-ECV and synthetic-ECV (26.7 ± 4.4% vs. 26.5 ± 4.3%, p = 0.084) in subjects imaged at 1.5 T, although bias was slightly higher and limits of agreement were wider (bias 0.23%, 95%CI [- 2.82, 3.27]). For discrimination of abnormal Lab-ECV ≥30%, POC-ECV had good diagnostic performance (sensitivity 85%, specificity 96%, accuracy 94%, and AUC 0.902) and synthetic-ECV had moderate diagnostic performance (sensitivity 71%, specificity 98%, accuracy 93%, and AUC 0.849). POC-ECV had excellent test-retest (ICC 0.994, 95%CI[0.987, 0.997]) and inter-observer agreement (ICC 0.974, 95%CI[0.929, 0.991]). CONCLUSIONS: Myocardial ECV can be accurately and reproducibly calculated with input of hematocrit measured using a noninvasive POC device, potentially overcoming an important barrier to implementation of ECV. Further evaluation of synthetic ECV is required prior to clinical implementation.

Cardiovascular magnetic resonance left ventricular strain in end-stage renal disease patients after kidney transplantation.

BACKGROUND: Cardiovascular disease is a significant cause of morbidity and mortality in patients with end-stage renal disease (ESRD) and kidney transplant (KT) patients. Compared with left ventricular (LV) ejection fraction (LVEF), LV strain has emerged as an important marker of LV function as it is less load dependent. We sought to evaluate changes in LV strain using cardiovascular magnetic resonance imaging (CMR) in ESRD patients who received KT, to determine whether KT may improve LV function. METHODS: We conducted a prospective multi-centre longitudinal study of 79 ESRD patients (40 on dialysis, 39 underwent KT). CMR was performed at baseline and at 12 months after KT. RESULTS: Among 79 participants (mean age 55 years; 30% women), KT patients had significant improvement in global circumferential strain (GCS) (p = 0.007) and global radial strain (GRS) (p = 0.003), but a decline in global longitudinal strain (GLS) over 12 months (p = 0.026), while no significant change in any LV strain was observed in the ongoing dialysis group. For KT patients, the improvement in LV strain paralleled improvement in LVEF (57.4 ± 6.4% at baseline, 60.6% ± 6.9% at 12 months; p = 0.001). For entire cohort, over 12 months, change in LVEF was significantly correlated with change in GCS (Spearman's r = - 0.42, p < 0.001), GRS (Spearman's r = 0.64, p < 0.001), and GLS (Spearman's r = - 0.34, p = 0.002). Improvements in GCS and GRS over 12 months were significantly correlated with reductions in LV end-diastolic volume index and LV end-systolic volume index (all p < 0.05), but not with change in blood pressure (all p > 0.10). CONCLUSIONS: Compared with continuation of dialysis, KT was associated with significant improvements in LV strain metrics of GCS and GRS after 12 months, which did not correlate with blood pressure change. This supports the notion that KT has favorable effects on LV function beyond volume and blood pessure control. Larger studies with longer follow-up are needed to confirm these findings.

The Role of Cardiopulmonary Exercise Testing for Decision Making in Patients with Repaired Tetralogy of Fallot.

Tetralogy of Fallot is the most common form of cyanotic congenital heart disease. As a result of the surgical strategies employed at the time of initial repair, chronic pulmonary regurgitation (PR) is prevalent in this population. Despite sustained research efforts, patient selection and timing of pulmonary valve replacement (PVR) to address PR in young asymptomatic patients with repaired tetralogy of Fallot (rToF) remain a fundamental but as yet unanswered question in the field of congenital heart disease. The ability of the heart to compensate for the chronic volume overload imposed by PR is critical in the evaluation of the risks and benefits of PVR. The difficulty in clarifying the functional impact of PR on the cardiovascular capacity may be in part responsible for the uncertainty surrounding the timing of PVR. Cardiopulmonary exercise testing (CPET) may be used to assess abnormal cardiovascular response to increased physiologic demands. However, its use as a tool for risk stratification in asymptomatic adolescents and young adults with rToF is still ill-defined. In this paper, we review the role of CPET as a potentially valuable adjunct to current risk stratification strategies with a focus on asymptomatic rToF adolescents and young adults being considered for PVR. The role of maximal and submaximal exercise measurements to identify young patients with a decreased or borderline low peak VO2 resulting from impaired ventricular function is explored. Current knowledge gaps and research perspectives are highlighted.