Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.

Dysregulated transforming growth factor TGF-ß signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-ß-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-ß signaling, ipo8-/- zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8-/- zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-ß signaling during development and reinforces the existing link between TGF-ß signaling and connective tissue defects.

Wall Shear Stress Alteration: a Local Risk Factor of Atherosclerosis.

PURPOSE OF REVIEW: Wall shear stress describes the mechanical influence of blood flow on the arterial wall. In this review, we discuss the role of the wall shear stress in the development of atherosclerosis and its complications. RECENT FINDINGS: Areas with chronically low, oscillating wall shear stress are most prone to plaque development and include outer bifurcation walls and inner walls of arches. In some diseases, patients have lower wall shear stress even in straight arterial segments; also, these findings were associated with atherosclerosis. High wall shear stress develops in the distal part (shoulder) of a stenosis and contributes to plaque destabilization. Wall shear stress changes are involved in the development of atherosclerosis. They are not fully understood yet and act in concert with tangential wall stress.

Subclinical involvement of common carotid arteries in patients with fibromuscular dysplasia - a case-control study.

Background: Fibromuscular dysplasia (FMD) primarily involves medium-sized arteries, though the entire spectrum of vascular involvement is not fully understood. We hypothesized that larger arteries may also be affected, albeit sub-clinically. Patients and methods: We measured the cross-sectional diameter of the thoracic aorta, abdominal aorta, common iliac arteries (CIA) and common carotid arteries (CCA) in FMD subjects and compared them to matched controls. We retrospectively analyzed records of FMD subjects (n = 74) and of age- and sex- matched controls (n = 74) that underwent computed tomography of the neck, chest or abdomen. Cross-sectional diameters of the thoracic and abdominal aorta, CIA and CCA were measured in a standardized manner by two trained physicians. Results: The FMD group had a significantly greater diameter of the CIA and CCA bilaterally. The measurements (mm) in FMD and control groups were as follows: Right CIA: 10.85 + 1.75 vs. 10.23 + 1.36, p = 0.04, left CIA: 11.01 + 1.93 vs. 10.15 + 1.38, p = 0.007, right CCA: 7.70 + 0.81 vs. 6.80 + 1.10, p < 0.001 and left CCA: 7.70 + 1.10 vs. 6.80 + 1.0, p < 0.001). There was no difference in the diameter between the two groups in the ascending aorta, descending and the abdominal aorta. After adjusting for baseline differences, common carotid arteries (but not common iliac) were significantly larger in FMD group compared with controls. Conclusions: There is sub-clinical involvement of the common carotid arteries in patients with FMD and this manifests as a greater diameter of these arteries compared to age and sex matched controls.

Brain arterial dilatation and the risk of Alzheimer's disease.

INTRODUCTION: We tested the hypothesis that brain arterial dilatation increases the risk of Alzheimer's dementia (AD). METHODS: We studied dementia-free participants in the Washington Heights-Inwood Columbia Aging Project who had a brain MRI and post-MRI dementia adjudication. We measured the axial T2-proton density diameters of the intracranial carotids and basilar diameters and used Cox models to obtain AD hazard ratios and 95% intervals. RESULTS: Of 953 participants (mean age 77 ± 7 y, women 64%, 71% nonwhite) followed on average for 3 ± 3 years, 76 (8%) developed AD. In a model adjusted for demographics, vascular risks, apolipoprotein E (APOE)-ε4, and white matter hyperintensities, larger carotid diameters increased the risk of AD, defined categorically as ≥ 90th percentile (HR 4.34, 1.70-11.11) or continuously (HR 1.44 per SD, 1.07-1.94). DISCUSSION: Understanding the pathophysiology of the association between AD and brain arterial dilatation may reveal new clues to the vascular contributions to AD.

Brain Arterial Diameters and Cognitive Performance: The Northern Manhattan Study.

OBJECTIVES: To test the hypothesis that brain arterial diameters are associated with cognitive performance, particularly in arteries supplying domain-specific territories. METHODS: Stroke-free participants in the Northern Manhattan Study were invited to have a brain MRI from 2003-2008. The luminal diameters of 13 intracranial arterial segments were obtained using time-of-flight magnetic resonance angiogram (MRA), and then averaged and normalized into a global score and region-specific arterial diameters. Z-Scores for executive function, semantic memory, episodic memory and processing speed were obtained at MRI and during follow-up. Adjusted generalized additive models were used to assess for associations. RESULTS: Among the 1034 participants with neurocognitive testing and brain MRI, there were non-linear relationships between left anterior (ACA) and middle cerebral artery (MCA) diameter and semantic memory Z-scores (χ2=10.00; DF=3; p=.019), and left posterior cerebral artery (PCA) and posterior communicating artery (Pcomm) mean diameter and episodic memory Z-scores (χ2=9.88; DF=3; p=.020). Among the 745 participants who returned for 2nd neuropsychological testing, on average 5.0±0.4 years after their MRI, semantic memory change was associated non-linearly with the left PCA/Pcomm mean diameter (χ2=13.09; DF=3; p=.004) and with the right MCA/ACA mean diameter (χ2=8.43; DF=3; p=.03). In both cross-sectional and longitudinal analyses, participants with the larger brain arterial diameters had more consistently lower Z-scores and greater decline than the rest of the participants. CONCLUSIONS: Brain arterial diameters may have downstream effects in brain function presenting as poorer cognition. Identifying the mechanisms and the directionality of such interactions may increase the understanding of the vascular contribution to cognitive impairment and dementia. (JINS, 2018, 24, 335-346).

Echocardiographic reference intervals of the dimensions of the main pulmonary artery and the right pulmonary artery: a prospective study in 269 healthy dogs.

INTRODUCTION: No data are available on the echocardiographic reference intervals (RIs) for the main pulmonary artery (MPA) and right pulmonary artery (RPA) dimensions in a large sample of dogs. Therefore, we aimed to describe the echocardiographic RIs of the MPA and RPA dimensions in normal dogs. ANIMALS, MATERIALS, AND METHODS: Two hundred and sixty nine healthy dogs of different breeds, age and body weight (BW) were prospectively enrolled in this multicenter, observational study. The MPA diameter, RPA maximum diameter (RPAmax), and RPA minimum diameter (RPAmin) were measured from the right parasternal short axis view. Prediction intervals (PIs) for MPA, RPAmax and RPAmin were generated using allometric scales. Reference intervals (RI) of MPA indexed to the ascending aorta (MPA/AO), and RPAmax and RPAmin indexed to the aortic annulus (RPAmax/Aod and RPAmin/Aod), were defined. RESULTS: A positive linear relationship between MPA, RPAmax, RPAmin and BW was evident after logarithmic transformation (R2 = 0.859, R2 = 0.787 and R2 = 0.725, respectively; P<0.0001). According to allometric scales, the PI for the MPA normalized for BW (MPA_N) was between 5.50 and 8.07, the PI for the RPAmax normalized for BW (RPAmax_N) was between 3.23 and 5.62, while the PI for the RPAmin normalized for BW (RPAmin_N) was between 1.62 and 3.30. The median MPA/AO was 0.92 (RI, 0.78-1.01), the median RPAmax/Aod was 0.70 (RI, 0.53-0.98) and the median RPAmin/Aod was 0.40 (RI, 0.29-0.61). DISCUSSION AND CONCLUSIONS: The reported RIs of the MPA and RPA dimensions in normal dogs could increase the diagnostic accuracy of transthoracic echocardiography in the identification of pulmonary artery enlargement in dogs.

Imaging findings and pathological correlations of subacute encephalopathy with neuronal intranuclear inclusion disease-Case report.

Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease and may sometimes present with symptoms of subacute encephalopathy, including fever, headache, vomiting, and loss of consciousness. We present a case of adult-onset NIID with subacute encephalopathy, which is confirmed by skin and brain biopsied. The magnetic resonance imaging findings show cortical swelling and hyperintensities in the right temporooccipital lobes on T2-weighted images and magnetic resonance angiography demonstrates vasodilatations of the right middle cerebral artery and posterior cerebral artery. Abnormal enhancement is mainly observed in the gyral crowns (crown enhancement). Pathological examinations reveal new infarcts in the deep layers of the cortices. NIID should be considered in the presence of subacute encephalopathy with cortical swelling, contrast enhancement in the temporooccipital lobes, and vasodilation in adult patients. The encephalopathy targeted on the cortices, and the pathological background included infarctions.

Brain arterial dilatation modifies the association between extracranial pulsatile hemodynamics and brain perivascular spaces: the Northern Manhattan Study.

Pulsatile hemodynamics are associated with brain small perivascular spaces (SPVS). It is unknown whether the stiffness of intermediary arteries connecting the aorta and brain modifies this association. Participants from the Northern Manhattan Study were assessed for SPVS (defined as ≤3 mm T1 voids) and white matter hyperintensity volume (WMH) using MRI. Middle (MCA) and anterior cerebral arterial (ACA) diameters (measured on time-of-flight MRA) and CCA strain (assessed by ultrasound) were used as surrogates of stiffness. Brachial and aortic pulse pressure (PP) and aortic augmentation index (Aix, assessed by applanation tonometry) were used as markers of pulsatility. We tested whether stiffness in intermediary arteries modifies the association between extracranial pulsatility with SPVS and WMH. We found that among 941 participants (mean age 71 ± 9 years, 60% women, 66% Hispanic), the right MCA/ACA diameter was associated with right anterior SPVS (B = 0.177, P = 0.002). Brachial PP was associated with right anterior SPVS (B = 0.003, P = 0.02), and the effect size was bigger with right MCA/ACA diameter in the upper tertile (P = 0.001 for the interaction). The association between right CCA strain and ipsilateral SPVS was modified by MCA/ACA diameter, with the largest effect size in those with ipsilateral MCA/ACA diameter in the upper tertile (P = 0.001 for the interaction). Similar dose-effects and statistical interactions were replicated using aortic AIx or aortic PP. We found no evidence of effect modification between pulsatile measures and WMH by stiffness measures. In summary, pulsatile hemodynamics relate to brain SPVS, and the association is the strongest among individuals with dilated brain arteries.

Left main bronchus compression due to main pulmonary artery dilatation in pulmonary hypertension: two case reports.

Pulmonary arterial dilatation associated with pulmonary hypertension may result in significant compression of local structures. Left main coronary artery and left recurrent laryngeal nerve compression have been described. Tracheobronchial compression from pulmonary arterial dilatation is rare in adults, and there are no reports in the literature of its occurrence in idiopathic pulmonary arterial hypertension. Compression in infants with congenital heart disease has been well described. We report 2 cases of tracheobronchial compression: first, an adult patient with idiopathic pulmonary arterial hypertension who presents with symptomatic left main bronchus compression, and second, an adult patient with Eisenmenger ventricular septal defect and right-sided aortic arch, with progressive intermedius and right middle lobe bronchi compression in association with enlarged pulmonary arteries.

Massive dilatation of the pulmonary artery in association with pulmonic stenosis and pulmonary hypertension.

Congenital pulmonary valve stenosis has been associated with the development of massive pulmonary arterial (PA) dilatation. Over time, this dilatation may distort surrounding structures and lead to compression of the left main coronary artery (LMCA) or the left mainstem bronchus. In this report, we describe a patient with a history of chronic thromboembolic pulmonary hypertension (CTEPH) and congenital pulmonic stenosis with massive PA dilatation. He develops exertional chest pain, presenting an unusual differential diagnosis. Novel diagnostic testing was performed to help narrow the differential diagnosis, and the patient responded well to pulmonary vasodilator treatment for progressive pulmonary hypertension.