Structural heart defects associated with ETB mutation, a cause of Hirschsprung disease

Background HSCR, a colonic neurocristopathy affecting 1/5000 births, is suggested to associate with cardiac septal defects and conotruncal malformations. However, we question subtle cardiac changes maybe more commonly present due to multi-regulations by HSCR candidate genes, in this instance, ETB. To investigate, we compared the cardiac morphology and quantitative measurements of sl/sl rat to those of the control group. Methods Eleven neonatal rats were generated from heterozygote (ETB+/−) crossbreeding. Age and bodyweight were recorded at time of sacrifice. Diffusion-staining protocols with 1.5% iodine solution was completed prior to micro-CT scanning. All rats were scanned using an in vivo micro-CT scanner, Caliper Quantum FX, followed by two quality-control scans using a custom-built ex vivo micro-CT system. All scans were reviewed for gross cardiac dysmorphology. Micro-CT data were segmented semi-automatically post-NLM filtering for: whole-heart, LV, RV, LA, RA, and aortic arch. Measurements were taken with Drishti. Following image analysis, PCR genotyping of rats was performed: five sl/sl rats, three wildtype, and three heterozygotes. Statistical comparisons on organ volume, growth rate, and organ volume/bodyweight ratios were made between sl/sl and the control group. Results Cardiac morphology and constituents were preserved. However, significant volumetric reductions were recorded in sl/sl rats with respect to the control: whole heart (38.70%, p value = 0.02); LV (41.22%, p value = 0.01), RV (46.15%, p value = 0.02), LA (44.93%, p value = 0.06), and RA (39.49%, p value = 0.02). Consistent trend was observed in growth rate (~ 20%) and organ-volume/bodyweight ratios (~ 25%). On the contrary, measurements on aortic arch demonstrated no significant difference among the two groups. Conclusion Despite the presence of normal morphology, significant cardiac growth retardation was detected in sl/sl rat, supporting the likely association of cardiac anomalies with HSCR, at least in ETB−/− subtype. Structural reduction was likely due to a combination of failure to thrive from enteric dysfunction, alterations to CaNCC colonization, and importantly coronary hypoperfusion from elevated ET-1/ETA-mediated hypervasoconstriction. Little correlation was detected between aortic arch development and sl/sl rat, supporting minor ETB role in large vessels. Although further clinical study is warranted, HSCR patients may likely require cardiac assessment in view of potential congenital cardiac defects.

Longitudinal changes in cardiac morphology and function in women with INOCA: results from repeat cardiac magnetic resonance imaging a median of 6 years apart

Background Women with signs and symptoms of ischemia but no obstructive coronary arteries (INOCA) are at increased risk of developing heart failure with preserved ejection fraction. The exact mechanism(s) driving disease progression, however, remains incompletely understood. Purpose To evaluate longitudinal changes in cardiac morphology and function across all four chambers of the heart, in women with INOCA. Methods To accomplish our goal, we leveraged 13 cases of repeat cardiac magnetic resonance imaging (cMRI), performed a median of 6 years apart (range: 3–11 years), in women with INOCA. Cardiac morphology and function were retrospectively assessed from conventional cine images using commercially available software (V5.11.1, CVI42, Circle Cardiovascular Imaging). Left and right ventricular (LV, RV, respectively) mass, volume, and ejection fraction were assessed using a series of short axis images spanning the base to apex. Left atrial (LA) volume was assessed using three orthogonal long-axis images, while right atrial (RA) area was assessed using a single horizontal long axis image. Concentricity was defined as the mass-to-end-diastolic volume ratio. Lastly, strain and strain rate were assessed in all four chambers by feature tracking analysis. Results Upon follow-up, LV and RV end-diastolic volume index (Figure 1A), LA volume index (from 36±5 to 32±5 mL/m2, P=0.02) and RA area index (from 11.3±1.6 to 9.6±2.0 cm2/m2, P=0.003) were significantly reduced. LV mass was preserved (Figure 1B), resulting in a significant increase in LV concentricity (from 0.59±0.07 to 0.64±0.09, P=0.02), together with an increase in LV ejection fraction (Figure 1C), and reduction in both longitudinal (Figure 1D) and circumferential (from 1.3±0.2 to 1.1±0.3 s-1, P=0.05) LV early diastolic strain rate. In contrast, RV mass was significantly reduced (Figure 1B), while RV concentricity (from 0.19±0.02 to 0.20±0.04) and ejection fraction (from 58±4 to 59±6) were preserved. Conclusions To our knowledge, this is the first study to evaluate long-term changes in cardiac morphology and function in women with INOCA. That LV early diastolic strain rate was reduced at follow-up, is consistent with a growing body of cross-sectional observations from our group and others, highlighting diastolic dysfunction as an important contributor of disease progression in this patient population. That we observed a discordant pattern of change between LV and RV concentricity is unique and warrants further consideration. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National heart, lung, and blood institute (NIH)

Investigating the Feasibility of Virtual Reality (VR) for Teaching Cardiac Morphology

Congenital heart disease (CHD) is the most common defect at birth. Effective training for clinical professionals is essential in order to provide a high standard of care for patients. Visual aids for teaching complex CHD have remained mostly unchanged in recent years, with traditional methods such as diagrams and specimens still essential for delivering educational content. Diagrams and other 2D visualisations for teaching are in most cases artistic illustrations with no direct relation to true, 3D medical data. Specimens are rare, difficult for students to access and are limited to specific institutions. Digital, patient-specific models could potentially address these problems within educational programmes. Virtual Reality (VR) can facilitate the access to digital models and enhance the educational experience. In this study, we recorded and analysed the sentiment of clinical professionals towards VR when learning about CHD. A VR application (VheaRts) containing a set of patient-specific models was developed in-house. The application was incorporated into a specialised cardiac morphology course to assess the feasibility of integrating such a tool, and to measure levels of acceptance. Attendees were clinical professionals from a diverse range of specialities. VR allowed users to interact with six different patient-derived models immersed within a 3D space. Feedback was recorded for 58 participants. The general response towards the use of VR was overwhelmingly positive, with 88% of attendees rating 4 or 5 for ‘helpfulness of VR in learning CHD’ (5-points Likert scale). Additionally, 70% of participants with no prior VR experience rated 4 or 5 for ‘intuitiveness and ease of use’. Our study indicates that VR has a high level of acceptance amongst clinical trainees when used as an effective aid for learning congenital heart disease. Additionally, we noted three specific use-cases where VR offered novel teaching experiences not possible with conventional methods.

Evaluation of prenatal changes in fetal cardiac morphology and function in maternal diabetes mellitus using a novel fetal speckle-tracking analysis: a prospective cohort study

Background Due to metabolic changes in the second trimester and the increasing number of pregnant women with obesity and advanced maternal age, the incidence of gestational diabetes mellitus (GDM) remains high. This study aimed to evaluate the effects of GDM on fetal cardiac morphology and function, and to determine whether these changes increase with increasing estimated fetal weight (EFW). Methods Fifty-eight women with GDM (GDM group) and 58 women with a healthy pregnancy (control group) were included in this prospective observational cohort study. Each group included subgroups of 31 pregnant women with a gestational age between 24+0 weeks and 27+6 weeks as well as 27 pregnant women with a gestational age between 28+0 weeks and 40+0 weeks. For all fetuses, a cine of 2–3 s in the four-chamber view was obtained, and online speckle-tracking analysis was performed using the GE Automatic Fetal Heart Assessment Tool (fetal HQ; General Electric Healthcare Ultrasound, Zipf, Austria) to measure the global sphericity index (GSI), global longitudinal strain (GLS), fractional area change (FAC), 24-segment sphericity index (SI), and 24-segment end-diastolic diameter of the left ventricle (LV) and right ventricle (RV). Data were analyzed using the independent t-test and Wilcoxon rank-sum test, as applicable. Results The GDM group (mean HbA1c value was 5.3 ± 0.57 mmol/L) showed a lower GSI value than the control group (1.21 vs. 1.27, P = 0.000), which indicated a rounder shape of the heart. In addition, fetuses in the GDM group demonstrated significant impairment in cardiac function compared to those in the control group (LV-GLS: -18.26% vs. -22.70%, RV-GLS: -18.52% vs. -22.74%, LV-FAC: 35.30% vs. 42.36%, RV-FAC: 30.89% vs. 36.80%; P = 0.000 for all). Subgroup analyses according to gestational age (24+0–27+6 weeks and 28+0–40+0 weeks) showed that the statistical differences were retained between the GDM and control groups in each subgroup. Conclusions Fetuses of women with GDM present with signs of biventricular systolic dysfunction according to deformation analysis using fetal HQ. Additionally, the heart had a rounder shape in the GDM group than in the control group. This study showed that fetal HQ can be used to assess fetal cardiac morphology and function easily and quickly, and the effects of GDM on fetal cardiac morphology and function appeared from the second trimester. Thus, whether earlier and stricter clinical intervention was necessary remained to be further studied. Furthermore, future studies will need to supplement the effects of blood glucose levels on GLS, FAC, GSI, and 24-segment SI. Additionally, the long-term follow-up after birth should also be improved to observe the influence of changes in the indicators on the prognosis.

Cardiac Morphology, Function, and Hemodynamics in Patients With Morbid Obesity and Nonalcoholic Steatohepatitis

Background The patients with nonalcoholic fatty liver disease demonstrate an increased cardiovascular risk. The adverse influence of liver abnormalities on cardiac function are among many postulated mechanisms behind this association. The aim of the study was to evaluate cardiac morphology and function in patients with morbid obesity referred for bariatric surgery with liver biopsy. Methods and Results We evaluated with echocardiography 171 consecutive patients without known cardiac disease (median age 42 [interquartile range, 37–48] years, median body mass index 43.7 [interquartile range, 41.0–47.5], 67% female patients. Based on the liver biopsy results, there were 44 patients with nonalcoholic steatohepatitis (NASH), 69 patients with isolated steatosis, and 58 patients without steatosis. Patients with NASH demonstrated signs of left ventricular concentric remodeling and hyperdynamic circulation, including indexed left ventricular end‐diastolic diameter [cm/m 2 ]: NASH 1.87 [0.22]; isolated steatosis 2.03 [0.33]; without steatosis 2.01 [0.19], P =0.001; relative wall thickness: NASH 0.49±0.05, isolated steatosis 0.47±0.06, without steatosis 0.46±0.06, P =0.011; cardiac index [L/m 2 ]: NASH 3.05±0.54, isolated steatosis 2.80±0.44, without steatosis 2.79±0.50, P =0.013. After adjustment for sex, age, blood pressure, and heart rate, most of the measures of the left ventricular systolic and diastolic function, left atrial size, right ventricular function, and right ventricular size did not differ between groups. Conclusions In a group of patients with extreme obesity, NASH was associated with left ventricular concentric remodeling and hyperdynamic circulation. Increased cardiac output in NASH may represent an additional risk factor for incident cardiovascular events in this population.

Recombinant Soluble Corin Improves Cardiac Function in Mouse Models of Heart Failure

Background Corin is a transmembrane protease that activates ANP and BNP (atrial and B‐type natriuretic peptides). Impaired corin expression and function are associated with heart failure. In this study, we characterized a soluble form of corin (sCorin) and examined its effects on cardiac morphology and function in mouse heart failure models. Methods and Results sCorin, consisting of the full‐length extracellular fragment of human corin with an engineered activation site, was expressed in Chinese hamster ovary cells, purified from the conditioned medium with affinity chromatography, and characterized in pro‐ANP processing assays in vitro and pharmacokinetic studies in mice. Effects of sCorin on mouse models of heart failure induced by left coronary artery ligation and transverse aortic constriction were assessed by ELISA analysis of plasma markers, histologic examination, and echocardiography. We showed that purified and activated sCorin converted pro‐ANP to ANP that stimulated cGMP production in cultured cells. In mice, intravenously and intraperitoneally administered sCorin had plasma half‐lives of 3.5±0.1 and 8.3±0.3 hour, respectively. In the mouse heart failure models, intraperitoneal injection of sCorin increased plasma ANP, BNP, and cGMP levels; lowered plasma levels of NT‐proANP (N‐terminal‐pro‐ANP), angiotensin II, and aldosterone; reduced cardiac hypertrophy and fibrosis; and improved cardiac function. Conclusions We show that sCorin treatment enhanced natriuretic peptide processing and activity, suppressed the renin‐angiotensin‐aldosterone system, and improved cardiac morphology and function in mice with failing hearts.

Age- and gender-related reference values of cardiac morphology and function in cardiovascular magnetic resonance

Cardiovascular magnetic resonance (CMR) is the reference standard for the quantitative assessment of cardiac morphology and function. The aim of the study was to determine age- and gender-related reference values for cardiac morphology and function according to current recommendations. 454 healthy volunteers (235 men, median age 52.0 (44.0–59.0) years) underwent a standard CMR scan and were divided into six groups of nearly equal size with regard to sex (male, female) and age (21–47 years, 48–57 years, 58–84 years). Left ventricular end-diastolic (LV-EDV) and end-systolic (LV-ESV) volumes and LV mass (LV-M) were measured at end-diastole and end-systole in steady-state free precession series with including papillary muscles and trabecular tissue in the LV-M. Absolute and indexed volumetric parameters were significantly different between gender groups with higher values in men compared to women (all p < 0.001). Furthermore, a significant age-dependent decline could be observed for left ventricular and right ventricular volumes (all p < 0.001), while LV-M did not show differences between the different age-groups. Parameters of longitudinal function for the left and right ventricle were higher in female compared to male subjects with a significant age-dependent decline. We provided normal values for cardiac volumes, function, and mass derived in accordance with current guidelines from a large population of healthy subjects, which can be implemented in clinical routine as a standard of reference.