Association of Aortic Distensibility and Left Ventricular Function in Patients With Stenotic Bicuspid Aortic Valve and Preserved Ejection Fraction: A CMR study

To determine the relationship between aortic distensibility and left ventricular (LV) remodeling, myocardial strain and blood biomarkers in patients with stenotic bicuspid aortic valve (BAV) and preserved ejection fraction (EF) by cardiovascular magnetic resonance (CMR). 43 stenotic BAV patients were prospectively selected for 3.0T CMR. Patients were divided into LV remodeling group (LV mass /volume ≥ 1.15, n=21) and non-remodeling group (LV mass/volume < 1.15, n=22). Clinical characteristics, biochemical data including cardiac troponin T(cTNT), N-terminal pro-B type natriuretic peptide (NT-proBNP) and creatine kinase isoenzyme were noted. Distensibility of middle ascending aorta (mid-AA) and proximal descending aorta, LV structural and functional parameters, global and regional myocardial strain were measured. Compared to non-remodeling group, LV remodeling group had significantly decreased LV global strain (radial: 26.04±8.70 % vs. 32.92±7.81 %, P=0.009; circumferential: -17.20±3.38 % vs. -19.65±2.34 %, P=0.008; longitudinal: -9.13±2.34 % vs. -11.63±1.99 %, P＜0.001), while radial and circumferential strain were significantly reduced at the base (radial: 28.52±9.47 % vs. 39.65±10.33 %, P=0.001; circumferential: -14.45±2.97 % vs. -17.22±2.38 %, P=0.002), longitudinal strain was significantly reduced at all regions (basal: -5.79±3.43 % vs. -8.65±2.42 %, P=0.003; mid: -8.62±2.21 % vs. -11.33±2.58 %, P=0.001; apical : -12.79±2.49 % vs. -15.04±2.20 %, P=0.003). In addition, mid-AA distensibility was independently associated with LV remodeling (β=-0.282, P=0.003), and it was also significantly correlated with LV global strain (radial: r=0.392, P=0.009; circumferential: r=-0.348, P=0.022; longitudinal: r=-0.333, P=0.029), cTNT (r=-0.333, P=0.029) and NT-proBNP (r= -0.440, P=0.003). In this cohort with stenotic BAV and preserved EF, mid-AA distensibility is found significantly associated with LV dysfunction, which may be an important factor for predicting adverse cardiovascular events and a potential therapeutic target to prevent heart failure.

Evaluation of Aortic Distensibility in Patients with Nonalcoholic Fatty Liver using CT

Background: Nonalcoholic fatty liver disease has attracted considerable attention with continuously increasing morbidity. Objective: To evaluate the aortic distensibility in patients with non-diabetes and hypertension-type nonalcoholic fatty liver disease(NAFLD) through dual-source computed tomography(DSCT). Method: 120 patients with NAFLD (experimental group) and 30 healthy subjects (control group) were consecutively enrolled in the study. In the two groups, aortic distensibility was calculated as follows: D = △A/(A0 ×△p). Record fasting insulin, fasting blood glucose, fasting lipid status, age, heart rate, waist circumference, systolic blood pressure, and diastolic blood pressure. Calculate homeostasis model assessment of insulin resistance (HOMA-IR) and body mass index (BMI). A comparative analysis between the two groups was carried out, followed by correlation analysis between D value and risk factors. Results: D value and liver attenuation of the patients in the NAFLD group were significantly reduced relative to those in the control group (2.24±0.63×10-3mmHg-1 vs. 3.19±0.86×10-3mmHg-1, P＜0.001 and 41±6HU vs. 53±5HU, P＜0.001, respectively) and their fasting blood glucose, fasting insulin, triglyceride, low-density lipoprotein, aspartate aminotransferase, alanine transaminase, HOMA-IR, and BMI were higher than those in the control group. Liver attenuation, HOMA-IR, age, and BMI were significantly correlated with D value in the NAFLD group. The stepwise multiple linear regression analysis indicates that Liver attenuation and HOMA-IR were the significant risk factors for D value (β coefficient =0.43, P =0.001, and β coefficient =-0.33, P =0.02, respectively). Conclusion: Patients with NAFLD suffer from a reduction in aortic distensibility, and insulin resistance may play a significant role in the early atherosclerosis stage.

The Genetic Determinants of Aortic Distension

As the largest conduit vessel, the aorta is responsible for the conversion of phasic systolic inflow from ventricular ejection into more continuous blood delivery to peripheral arteries. Distension during systole and recoil during diastole conserves ventricular energy and is enabled by the specialized composition of the aortic extracellular matrix. Aortic distensibility decreases with age and prematurely in vascular disease. To discover genetic determinants of aortic distensibility we trained a deep learning model to quantify aortic size throughout the cardiac cycle and calculate aortic distensibility and aortic strain in 42,342 participants in the UK Biobank with available cardiac magnetic resonance imaging. In up to 40,028 participants with genetic data, common variant analysis identified 12 and 26 loci for ascending and 11 and 21 loci for descending aortic distensibility and strain, respectively. Of the newly identified loci, 22 were specific to strain or distensibility and were not identified in a thoracic aortic diameter GWAS within the same samples. Loci associated with both aortic diameter and aortic strain or distensibility demonstrated a consistent, inverse directionality. Transcriptome-wide analyses, rare-variant burden tests, and analyses of gene expression in single nucleus RNA sequencing of human aorta were performed to prioritize genes at individual loci. Loci highlighted multiple genes involved in elastogenesis, matrix degradation, and extracellular polysaccharide generation. Characterization of the genetic determinants of aortic function may provide novel targets for medical intervention in aortic disease.

Longitudinal changes in aortic distensibility in patients with Marfan syndrome

Background Patients with Marfan syndrome (MFS) may develop aortic dissection due to progressive dilatation in the entire aorta. Increased aortic stiffness, i.e.a. decreased distensibility has been shown to often precede these dismal sequelae. Therefore, we investigated longitudinal changes in aortic distensibility throughout the entire aorta by means of Cardiac Magnetic Resonance (CMR) imaging in patients with MFS. Methods This retrospective study included all MFS patients with four CMR examinations performed between 1996 and 2012. Aortic distensibility was measured and calculated by a single analyst, in the ascending, proximal- and distal descending, and abdominal aorta. Changes in distensibility were studied using linear mixed-effects regression models. Furthermore, we investigated the association between distensibility and age, sex, blood pressure, medication use, FBN1 mutation type, and previous aortic root surgery. Results In total, 35 MFS patients (age at inclusion 28 [IQR 23–32] years, 54% male) were included. Mean aortic distensibility was low in the ascending and proximal descending aorta (resp. 3.25±1.87, 3.91±1.73x10–3 mmHg–1) at the first scan. Distensibility decreased significantly over time at level 2, 3, and 4 (resp. p=0.021, p=0.002, p=0.038) (Figure 1). The rate of distensibility loss per year (x10–3 mmHg–1/year) was respectively 0.04 and 0.06 in the proximal- and distal descending aorta. Men seemed to have a lower but more stable distensibility, whereas women showed a higher distensibility at younger age, but a faster deterioration rate over time (difference in distensibility loss per year between men and women: 0.08, p=0.038). Distensibility did not correlate significantly with medication use, FBN1 mutation type or previous aortic root surgery. Conclusion Patients with MFS have low distensibility at all levels of the aorta at young age, which keeps decreasing over time. Men had lower distensibility at younger age than women. Distensibility was stably low in men, while still deteriorating over time in women. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): AMC FoundationHorstingstuit Foundation

Vascular stiffness in children born after frozen or fresh embryo transfer. A cardiac magnetic resonance imaging study of 8 to 9 year old children

Background Vascular stiffness increases during childhood, and increased vascular stiffness is associated with symptomatic cardiovascular disease in adults with metabolic syndrome. In comparison with naturally conceived children (NC), children conceived after in-vitro fertilization by frozen (FET) or fresh embryo transfer (Fresh ET) are at risk of being large- and small-for-gestational-age, respectively. Epigenetic modulation during assisted reproductive technologies (ART) is suggested to influence cardiovascular risk factors, and recent literature suggests that children conceived after ART are at increased risk of insulin resistance, endothelial dysfunction and arterial hypertension. Such changes may be associated with increased vascular stiffness, but it is not yet been examined directly. Purpose We investigated if ART children are at increased risk of aortic distensibility and pulse-wave velocity. Methods 150 children aged 8–9 years conceived after FET (n=50), Fresh ET (n=50) or by natural conception (NC, n=50) were studied with magnetic resonance imaging. Conductance artery stiffness was determined from aortic distensibility and aortic pulse-wave velocity (PWV). Data were analyzed with blinding according to treatment group. Based on a conservative estimate for the common SD for the difference between groups of 1.5 mm2/mmHg, 36 children were required in each group to detect a difference in aortic distensibility of 10%, which corresponds to a 5 year age difference, with an alpha of 0.05 (double-sided) and a beta of 0.80. We aimed for 50 children in each group to allow for dropouts and non-analyzable scans, and to allow for further determinations. The effects of potential confounders on the effect of conception method on ascending aorta distensibility and total aortic PWV were tested stepwise in four linear regression models (Figure 1). Results Child groups were comparable with respect to anthropometric measures (Table 1). No differences were observed in systolic or diastolic blood pressure, cardiac output, total peripheral resistance, or in aortic distensibility (Ascending aorta distensibility: FET, ascending aorta 11.12±3.55 10–3 mm2/mmHg; Fresh ET 11.77±2.97 10–3 mm2/mmHg; NC 11.43±2.82 10–3 mm2/mmHg) (ANOVA-p=0.58) or aortic PWV (PWV of total aorta: FET, 3.69±0.75 m/s; Fresh ET, 3.49±0.31 m/s; NC, 3.59±0.61 m/s) (ANOVA-p=0.26). The effect of ART remained non-significant after adjustment for child sex, maternal BMI at early pregnancy, and maternal educational level (Figure 1). Conclusion The effects of ART on aortic distensibility were not statistically significant, but in the direction of the hypothesis of stiffer conductance arteries from frozen embryo transfer. The confidence interval was relatively wide, and the results suggest that the difference between frozen and fresh embryo transfer may in fact correspond to an age difference of more than 5 years. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Novo Nordisk Foundation Table 1 Figure 1

The stiff male arterial system seems to establish itself well before puberty

Background Increased vascular stiffness in adults is associated with symptomatic cardiovascular disease independently of other risk factors. From puberty and onwards, men have higher aortic pulse-wave velocity than women explaining part of the male overrepresentation of early cardiovascular disease. It is not known if the stiff male arterial system is related to adult life-style or develops under the influence of male hormones, or if it is already present before puberty. According to the hyperbolic Bramwell-Hill relation, early changes must be expected to become detectable in aortic distensibility before influencing aortic pulse-wave velocity. Purpose The objective of this study was to quantitate sex-related differences in aortic distensibility and pulse-wave velocity in pre-pubertal children. Methods 150 children aged 8–9 years (75 girls and 75 boys) were recruited to a cardiovascular magnetic resonance imaging (CMR) study of the importance of in vitro fertilization (IVF) for aortic distensibility. Data did not show differences related to the mode of conception (natural vs. IVF), and pooled data are reported here. Conductance artery stiffness was determined from ascending, descending and abdominal aorta distensibility and from arch and abdominal aorta pulse-wave velocity (PWV). Data were analyzed blinded to child sex and mode of conception and related to left heart function as determined from flow and volumetric CMR data. The effects of sex on ascending aorta distensibility and total aortic PWV were examined in four linear regression models by stepwise adjustment for potential confounders. Results Systolic and diastolic blood pressures, cardiac output and total peripheral resistance did not differ between the sexes. Pulse pressure, however, was a mean of 2 mmHg lower and heart rate 7 bpm higher in girls (Table 1), and corresponding to the lower heart rate, left ventricle (LV) end-diastolic volume index and left ventricle stroke volume were 7 mL and 5 mL, respectively, higher in boys. LV peak-filling rate indexed to LV end-diastolic volume was 0.5 s-1 lower in boys, but in general LV filling and left atrium emptying parameters were equal. Distensibility of the ascending and descending aorta were both significantly higher in girls as compared to boys, whereas boys and girls had equal abdominal aortic distensibility and equal aortic pulse-wave velocities. Distensibility of the ascending aorta remained statistically significant after adjustment for potential confounders (Table 2). Conclusion Without yet significantly affecting pulse wave velocity or left ventricle function, pre-pubertal boys had significantly lower distensibility of the ascending aorta and the aortic arch than pre-pubertal girls. This is the part of the aorta primarily responsible for the aortic Windkessel function, and it seems that the stiffer arterial system seen in adult men as compared to adult women may already be present in childhood well before puberty. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Table 1 Table 2

GENOME-WIDE ASSOCIATIONS OF AORTIC DISTENSIBILITY SUGGEST CAUSAL RELATIONSHIPS WITH AORTIC ANEURYSMS AND BRAIN WHITE MATTER HYPERINTENSITIES

ABSTRACTAortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We tested genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identified 102 loci (including 31 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlighted four signalling pathways associated with aortic distensibility (TGF-β, IGF, VEGF and PDGF). We identified distinct sex-specific associations with aortic traits. We developed co-expression networks associated with aortic traits and applied phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggested a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.