Identifying novel data-driven subgroups in congenital heart disease using multi-modal measures of brain structure.

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.

Generalising XTRACT tractography protocols across common macaque brain templates.

Non-human primates are extensively used in neuroscience research as models of the human brain, with the rhesus macaque being a prominent example. We have previously introduced a set of tractography protocols (XTRACT) for reconstructing 42 corresponding white matter (WM) bundles in the human and the macaque brain and have shown cross-species comparisons using such bundles as WM landmarks. Our original XTRACT protocols were developed using the F99 macaque brain template. However, additional macaque template brains are becoming increasingly common. Here, we generalise the XTRACT tractography protocol definitions across five macaque brain templates, including the F99, D99, INIA, Yerkes and NMT. We demonstrate equivalence of such protocols in two ways: (a) Firstly by comparing the bodies of the tracts derived using protocols defined across the different templates considered, (b) Secondly by comparing the projection patterns of the reconstructed tracts across the different templates in two cross-species (human-macaque) comparison tasks. The results confirm similarity of all predictions regardless of the macaque brain template used, providing direct evidence for the generalisability of these tractography protocols across the five considered templates.

Genetic mouse models of autism spectrum disorder present subtle heterogenous cardiac abnormalities.

Autism spectrum disorder (ASD) and congenital heart disease (CHD) are linked on a functional and genetic level. Most work has investigated CHD-related neurodevelopmental abnormalities. Cardiac abnormalities in ASD have been less studied. We investigated the prevalence of cardiac comorbidities relative to ASD genetic contributors. Using high frequency ultrasound imaging, we screened 9 ASD-related genetic mouse models (Arid1b(+/-) , Chd8(+/-) , 16p11.2 (deletion), Sgsh(+/-) , Sgsh(-/-) , Shank3 Δexon 4-9(+/-) , Shank3 Δexon 4-9(-/-) , Fmr1(-/-) , Vps13b(+/-) ), and pooled wild-type littermates (WTs). We measured heart rate (HR), aorta diameter (AoD), thickness and thickening of the left-ventricular (LV) anterior and posterior walls, LV chamber diameter, fractional shortening, stroke volume and cardiac output, mitral inflow Peak E and A velocity ratio, ascending aorta velocity time integral (VTI). Mutant groups presented small-scale alterations in cardiac structure and function compared to WTs (LV anterior wall thickness and thickening, chamber diameter and fractional shortening, HR). A greater number of significant differences was observed among mutant groups than between mutant groups and WTs. Mutant groups differed primarily in structural measures (LV chamber diameter and anterior wall thickness, HR, AoD). The mutant groups with most differences to WTs were 16p11.2 (deletion), Fmr1(-/-) , Arid1b(+/-) . The mutant groups with most differences from other mutant groups were 16p11.2 (deletion), Sgsh(+/-) , Fmr1(-/-) . Our results recapitulate the associated clinical findings. The characteristic ASD heterogeneity was recapitulated in the cardiac phenotype. The type of abnormal measures (morphological, functional) can highlight common underlying mechanisms. Clinically, knowledge of cardiac abnormalities in ASD can be essential as even non-lethal abnormalities impact normal development. LAY SUMMARY: Autism spectrum disorder (ASD) and congenital heart disease (CHD) are linked functionally and genetically. ASD cardiac phenotyping is limited. We assessed the cardiac phenotype of 9 ASD-related mouse models. We found subtle heterogenous cardiac abnormalities compared to controls, with more differences within ASD than between ASD and controls, mirroring clinical findings. Clinically, knowing the cardiac abnormalities in ASD is vital as even non-lethal cardiac abnormalities can impact development.

Hemorrhage promotes chronic adverse remodeling in acute myocardial infarction: a T1 , T2 and BOLD study.

Hemorrhage is recognized as a new independent predictor of adverse outcomes following acute myocardial infarction. However, the mechanisms of its effects are less understood. The aim of our study was to probe the downstream impact of hemorrhage towards chronic remodeling, including inflammation, vasodilator function and matrix alterations in an experimental model of hemorrhage. Myocardial hemorrhage was induced in the porcine heart by intracoronary injection of collagenase. Animals (N = 18) were subjected to coronary occlusion followed by reperfusion in three groups (six/group): 8 min ischemia with hemorrhage (+HEM), 45 min infarction with no hemorrhage (I - HEM) and 45 min infarction with hemorrhage (I + HEM). MRI was performed up to 4 weeks after intervention. Cardiac function, edema (T2 , T1 ), hemorrhage (T2 *), vasodilator function (T2 BOLD), infarction and microvascular obstruction (MVO) and partition coefficient (pre- and post-contrast T1 ) were computed. Hemorrhage was induced only in the +HEM and I + HEM groups on Day 1 (low T2 * values). Infarct size was the greatest in the I + HEM group, while the +HEM group showed no observable infarct. MVO was seen only in the I + HEM group, with a 40% occurrence rate. Function was compromised and ventricular volume was enlarged only in the hemorrhage groups and not in the ischemia-alone group. In the infarct zone, edema and matrix expansion were the greatest in the I + HEM group. In the remote myocardium, T2 elevation and matrix expansion associated with a transient vasodilator dysfunction were observed in the hemorrhage groups but not in the ischemia-alone group. Our study demonstrates that the introduction of myocardial hemorrhage at reperfusion results in greater myocardial damage, upregulated inflammation, chronic adverse remodeling and remote myocardial alterations beyond the effects of the initial ischemic insult. A systematic understanding of the consequences of hemorrhage will potentially aid in the identification of novel therapeutics for high-risk patients progressing towards heart failure.

Clinical, Electrocardiographic, and Echocardiographic Features in Hospitalized Nonagenarians (90+): Comparison between the Genders.

OBJECTIVES: We investigated the clinical, electrocardiographic, and echocardiographic determinants of the cardiac status in nonagenarian patients. METHODS: We consecutively examined 654 Caucasian patients (232 males and 422 females) aged ≥90 years. All patients underwent clinical examination, ECG, and transthoracic echocardiography. RESULTS: Their average age was 92.5 ± 2.5 years. Patients were predominately female of older age (p < 0.0001 and p = 0.02, respectively). A history of cardiovascular disease was present in 78.4% of the participants. One third of the patients was hospitalized for cardiovascular causes, with females being twice as many (p < 0.0001). Females showed higher levels of serum cholesterol, triglycerides, and glycemia (p < 0.0001, p< 0.0001, and p = 0.04 respectively). Sinus rhythm was detected in 65%, and atrial fibrillation in 31% of the overall population. Heart rate, PR and corrected QT (QTc) intervals, right bundle branch block (RBBB) and RBBB associated with left anterior fascicular block (LAFB) were higher in males (p < 0.0001, p = 0.036, p = 0.009, p = 0.001, and p = 0.004, respectively). Aortic root dimension, left ventricular (LV) mass index, and indexed LV systolic-diastolic volumes were higher in males (p < 0.001, p < 0.0001, p < 0.001, and p < 0.0001, respectively). Women showed fewer LV segmental kinetic disorders (p = 0009) and higher LV ejection fraction (LVEF; p< 0.0001). Hyperuricemia was positively associated with a history of cardiovascular disease (r = 0.15), glycemia (r = 19), creatininemia (r = 0.50), uremia (r = 0.51), triglycerides (r = 0.19), PR interval (r = 0.14), and left bundle branch block (r = 0.11), and inversely associated with sinus rhythm (r = -0.14) and LVEF (r = -0.17). Diabetes was positively correlated with PR and QTc intervals (r = 0.14 and r = 0.10, respectively), and RBBB with LFAB (r = 0.10), and inversely correlated with LVEF (r = -0.10). CONCLUSIONS: We found a remarkable presence of cardiovascular risk factors, ECG, and structural alterations in hospitalized nonagenarians, which presents more commonly in males.

Electrocardiographic and echocardiographic features in patients with major arterial vascular disease assigned to surgical revascularization.

Background: We aimed to depict the electrocardiographic and echocardiographic aspects in patients before elective major vascular surgery.Methods: We evaluated through standard 12 lead electrocardiography and transthoracic echocardiography 469 patients with asymptomatic large abdominal aortic aneurysm (AAA), 334 with critical carotid stenosis (CAS), and 238 with advanced peripheral artery disease (PAD) before surgical revascularization.Results: Patients with AAA were predominantly males (p < .001) with normal sinus rhythm (p = .026), were more affected by atrioventricular block (p = .033) and left anterior fascicular block (p < .001). They also presented larger aortic root size (p < .001) and septal hypertrophy (p = .036), in addition, atrial fibrillation was less frequent in the same group (p = .023). Patients with CAS were of older age (p < .001) with a substantial number of females (p < .001). They presented less left ventricular segmental kinetic disorders and fewer dilated ventricles (p = .004 and p < .001 respectively). Finally, those with PAD had reduced septal and posterior wall thickness (p < .01, p = .009 respectively), greater mitral and aortic annular calcification (p < .001), and were more affected by previous myocardial infarction (p < .001). The PR interval, left anterior fascicular block and aortic root size were independently associated with aneurysm, previous myocardial infarction with PAD, while smaller left ventricular end systolic volumes with carotid artery stenosis.Conclusions: Patients with AAA were mostly affected by cardiac conduction disorders, septal hypertrophy, aortic root dilation and less affected by atrial fibrillation. Patients with CAS were older with more normal sized ventricles, whereas, previous myocardial infarction was most common amongst patients with peripheral artery disease.