Characteristics of pulmonary artery strain assessed by cardiovascular magnetic resonance imaging and associations with metabolomic pathways in human ageing.

Background: Pulmonary artery (PA) strain is associated with structural and functional alterations of the vessel and is an independent predictor of cardiovascular events. The relationship of PA strain to metabolomics in participants without cardiovascular disease is unknown. Methods: In the current study, community-based older adults, without known cardiovascular disease, underwent simultaneous cine cardiovascular magnetic resonance (CMR) imaging, clinical examination, and serum sampling. PA global longitudinal strain (GLS) analysis was performed by tracking the change in distance from the PA bifurcation to the pulmonary annular centroid, using standard cine CMR images. Circulating metabolites were measured by cross-sectional targeted metabolomics analysis. Results: Among n = 170 adults (mean age 71 ± 6.3 years old; 79 women), mean values of PA GLS were 16.2 ± 4.4%. PA GLS was significantly associated with age (ß = -0.13, P = 0.017), heart rate (ß = -0.08, P = 0.001), dyslipidemia (ß = -2.37, P = 0.005), and cardiovascular risk factors (ß = -2.49, P = 0.001). Alanine (ß = -0.007, P = 0.01) and proline (ß = -0.0009, P = 0.042) were significantly associated with PA GLS after adjustment for clinical risk factors. Medium and long-chain acylcarnitines were significantly associated with PA GLS (C12, P = 0.027; C12-OH/C10-DC, P = 0.018; C14:2, P = 0.036; C14:1, P = 0.006; C14, P = 0.006; C14-OH/C12-DC, P = 0.027; C16:3, P = 0.019; C16:2, P = 0.006; C16:1, P = 0.001; C16:2-OH, P = 0.016; C16:1-OH/C14:1-DC, P = 0.028; C18:1-OH/C16:1-DC, P = 0.032). Conclusion: By conventional CMR, PA GLS was associated with aging and vascular risk factors among a contemporary cohort of older adults. Metabolic pathways involved in PA stiffness may include gluconeogenesis, collagen synthesis, and fatty acid oxidation.

Longitudinal aortic strain, ventriculo-arterial coupling and fatty acid oxidation: novel insights into human cardiovascular aging.

Aging-induced aortic stiffness has been associated with altered fatty acid metabolism. We studied aortic stiffness using cardiac magnetic resonance (CMR)-assessed ventriculo-arterial coupling (VAC) and novel aortic (AO) global longitudinal strain (GLS) combined with targeted metabolomic profiling. Among community older adults without cardiovascular disease, VAC was calculated as aortic pulse wave velocity (PWV), a marker of arterial stiffness, divided by left ventricular (LV) GLS. AOGLS was the maximum absolute strain measured by tracking the phasic distance between brachiocephalic artery origin and aortic annulus. In 194 subjects (71 ± 8.6 years; 88 women), AOGLS (mean 5.6 ± 2.1%) was associated with PWV (R = -0.3644, p < 0.0001), LVGLS (R = 0.2756, p = 0.0001) and VAC (R = -0.3742, p <0.0001). Stiff aorta denoted by low AOGLS <4.26% (25th percentile) was associated with age (OR 1.13, 95% CI 1.04-1.24, p = 0.007), body mass index (OR 1.12, 95% CI 1.01-1.25, p = 0.03), heart rate (OR 1.04, 95% CI 1.01-1.06, p = 0.011) and metabolites of medium-chain fatty acid oxidation: C8 (OR 1.005, p = 0.026), C10 (OR 1.003, p = 0.036), C12 (OR 1.013, p = 0.028), C12:2-OH/C10:2-DC (OR 1.084, p = 0.032) and C16-OH (OR 0.82, p = 0.006). VAC was associated with changes in long-chain hydroxyl and dicarboxyl carnitines. Multivariable models that included acyl-carnitine metabolites, but not amino acids, significantly increased the discrimination over clinical risk factors for prediction of AOGLS (AUC [area-under-curve] 0.73 to 0.81, p = 0.037) and VAC (AUC 0.78 to 0.87, p = 0.0044). Low AO GLS and high VAC were associated with altered medium-chain and long-chain fatty acid oxidation, respectively, which may identify early metabolic perturbations in aging-associated aortic stiffening. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02791139.

Assessment of right ventricular diastolic function in pediatric patients with repaired tetralogy of Fallot by cardiovascular magnetic resonance and echocardiography.

OBJECTIVES: Cardiovascular magnetic resonance (CMR) imaging is routinely performed for assessing right ventricular (RV) systolic but not diastolic function. We aimed to investigate CMR-based assessment of RV diastolic function in pediatric patients with repaired tetralogy of Fallot (rTOF), compared to transthoracic echocardiography (TTE) measurements. METHODS: A total of 130 consecutive pediatric patients with rTOF who underwent clinically indicated CMR and same-day TTE were included. Forty-three controls were recruited. Phase-contrast images were used to measure trans-tricuspid valve flow velocities during early (E) and late diastolic (A) phases (measured in cm/s). Feature tracking of the tricuspid annulus was performed to derive early (e') and late diastolic (a') myocardial velocities (measured in cm/s). RV diastolic function was evaluated by E/A ratio, E/e' ratio, and E-wave deceleration time (measured in milliseconds). Regression analyses were utilized to identify potential variables associated with RV diastolic dysfunction (DD). The performance of CMR-derived parameters in diagnosing RV DD was assessed using receiver-operating characteristic analyses. RESULTS: Good agreement was found between CMR and TTE measurements (ICC 0.70-0.89). Patients with RV DD (n = 67) showed significantly different CMR-derived parameters including E and e' velocities, and E/A and E/e' ratio, compared to patients without DD (n = 63) (all p < 0.05). CMR-derived E and e' velocities and E/e' ratio were independent predictors of RV DD. E/e' of 5.8 demonstrated the highest discrimination of RV DD (AUC 0.76, sensitivity 70%, specificity 86%). CONCLUSIONS: CMR-derived parameters showed good agreement with TTE parameters in determining RV DD. CMR-derived E/e' was proved to be the most effective in identifying RV DD. CLINICAL RELEVANCE STATEMENT: This study demonstrated the feasibility and efficacy of CMR in assessing diastolic function in pediatric patients. RV DD was presented in over half of patients according to current TTE guidelines, highlighting the need for assessing RV diastolic function during follow-up. KEY POINTS: • Routinely acquired cine and phase-contrast cardiovascular magnetic resonance (CMR) images yielded right ventricular (RV) diastolic parameters which demonstrated good agreement with transthoracic echocardiography (TTE) measurements. • There was a high prevalence of RV diastolic function impairment in pediatric patients with repaired tetralogy of Fallot (rTOF). • CMR is a reliable complementary modality of TTE for RV diastolic function evaluation.

Heart-brain mapping: Cardiac atrial function is associated with distinct cerebral regions with high free water in older adults.

Left atrial (LA) dysfunction has been linked to cognitive impairment and cerebrovascular dysfunction. Higher brain free-water (FW) derived from diffusion-MRI was associated with early and subtle cerebrovascular dysfunction and more severe cognitive impairment. We hypothesized that LA dysfunction would correlate with higher brain free-water (FW) among healthy older adults. 56 community older adults (73.13 ± 3.56 years; 24 female) with normal cognition and without known cardiovascular disease who had undergone cardiac-MRI, brain-MRI, and neuropsychological assessments were included. Whole-brain voxel-level general linear models were constructed to correlate brain FW measures with LA indices. We found lower scores in LA function measures were related to higher grey matter (GM) FW in regions including orbital frontal and right temporal regions (p < 0.01, family-wise error corrected). In parallel, LA dysfunction was associated with higher FW in white matter (WM) fibres including superior longitudinal fasciculus, internal capsule, and superior corona radiata. However, LA dysfunction was not related to WM tissue reduction and GM cortical thinning. Moreover, these cardiac-related higher brain FW were associated with lower executive function and higher serum B-type natriuretic peptide (p < 0.05, Holm-Bonferroni corrected). These findings may have implications for anti-ageing preventive strategies targeting cardiac and cerebral vascular functions to improve heart and brain outcomes.

Age- and sex-specific reference values of biventricular flow components and kinetic energy by 4D flow cardiovascular magnetic resonance in healthy subjects.

BACKGROUND: Advances in four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) have allowed quantification of left ventricular (LV) and right ventricular (RV) blood flow. We aimed to (1) investigate age and sex differences of 4D flow CMR-derived LV and RV relative flow components and kinetic energy (KE) parameters indexed to end-diastolic volume (KEiEDV) in healthy subjects; and (2) assess the effects of age and sex on these parameters. METHODS: We performed 4D flow analysis in 163 healthy participants (42% female; mean age 43 ± 13 years) of a prospective registry study (NCT03217240) who were free of cardiovascular diseases. Relative flow components (direct flow, retained inflow, delayed ejection flow, residual volume) and multiple phasic KEiEDV (global, peak systolic, average systolic, average diastolic, peak E-wave, peak A-wave) for both LV and RV were analysed. RESULTS: Compared with men, women had lower median LV and RV residual volume, and LV peak and average systolic KEiEDV, and higher median values of RV direct flow, RV global KEiEDV, RV average diastolic KEiEDV, and RV peak E-wave KEiEDV. ANOVA analysis found there were no differences in flow components, peak and average systolic, average diastolic and global KEiEDV for both LV and RV across age groups. Peak A-wave KEiEDV increased significantly (r = 0.458 for LV and 0.341 for RV), whereas peak E-wave KEiEDV (r = - 0.355 for LV and - 0.318 for RV), and KEiEDV E/A ratio (r = - 0.475 for LV and - 0.504 for RV) decreased significantly, with age. CONCLUSION: These data using state-of-the-art 4D flow CMR show that biventricular flow components and kinetic energy parameters vary significantly by age and sex. Age and sex trends should be considered in the interpretation of quantitative measures of biventricular flow. Clinical trial registration  https://www. CLINICALTRIALS: gov . Unique identifier: NCT03217240.

Aortic flow is associated with aging and exercise capacity.

Aims: Increased blood flow eccentricity in the aorta has been associated with aortic (AO) pathology, however, its association with exercise capacity has not been investigated. This study aimed to assess the relationships between flow eccentricity parameters derived from 2-dimensional (2D) phase-contrast (PC) cardiovascular magnetic resonance (CMR) imaging and aging and cardiopulmonary exercise test (CPET) in a cohort of healthy subjects. Methods and Results: One hundred and sixty-nine healthy subjects (age 44 ± 13 years, M/F: 96/73) free of cardiovascular disease were recruited in a prospective study (NCT03217240) and underwent CMR, including 2D PC at an orthogonal plane just above the sinotubular junction, and CPET (cycle ergometer) within one week. The following AO flow parameters were derived: AO forward and backward flow indexed to body surface area (FFi, BFi), average flow displacement during systole (FDsavg), late systole (FDlsavg), diastole (FDdavg), systolic retrograde flow (SRF), systolic flow reversal ratio (sFRR), and pulse wave velocity (PWV). Exercise capacity was assessed by peak oxygen uptake (PVO2) from CPET. The mean values of FDsavg, FDlsavg, FDdavg, SRF, sFRR, and PWV were 17 ± 6%, 19 ± 8%, 29 ± 7%, 4.4 ± 4.2 mL, 5.9 ± 5.1%, and 4.3 ± 1.6 m/s, respectively. They all increased with age (r = 0.623, 0.628, 0.353, 0.590, 0.649, 0.598, all P < 0.0001), and decreased with PVO2 (r = -0.302, -0.270, -0.253, -0.149, -0.219, -0.161, all P < 0.05). A stepwise multivariable linear regression analysis using left ventricular ejection fraction (LVEF), FFi, and FDsavg showed an area under the curve of 0.769 in differentiating healthy subjects with high-risk exercise capacity (PVO2 ≤ 14 mL/kg/min). Conclusion: AO flow haemodynamics change with aging and predict exercise capacity. Registration: NCT03217240.

The potential role of subseafloor fungi in driving the biogeochemical cycle of nitrogen under anaerobic conditions.

Fungi represent the dominant eukaryotic group of organisms in anoxic marine sedimentary ecosystems, ranging from a few centimeters to ~ 2.5 km below seafloor. However, little is known about how fungi can colonize anaerobic subseafloor environments for tens of millions of years and whether they play a role in elemental biogeochemical cycles. Based on metabolite detection, isotope tracer and gene analysis, we examined the anaerobic nitrogen conversion pathways of 19 fungal species (40 strains) isolated from1.3 to 2.5 km coal-bearing sediments below seafloor. Our results show for the first time that almost all fungi possess anaerobic denitrification, dissimilatory nitrate reduction to ammonium (DNRA), and nitrification pathways, but not anaerobic ammonium oxidation (anammox). Moreover, the distribution of fungi with different nitrogen-conversion abilities in subseafloor sediments was mainly determined by in situ temperature, CaCO3, and inorganic carbon contents. These findings suggest that fungi have multiple nitrogen transformation processes to cope with their requirements for a variety of nitrogen sources in nutrient deficient anaerobic subseafloor sedimentary environments.

Pulmonary Artery Strain Predicts Prognosis in Pulmonary Arterial Hypertension.

BACKGROUND: Current cardiac magnetic resonance (CMR) imaging in pulmonary arterial hypertension (PAH) focuses on measures of ventricular function and coupling. OBJECTIVES: The purpose of this study was to evaluate pulmonary artery (PA) global longitudinal strain (GLS) as a prognostic marker in patients with PAH. METHODS: The authors included 169 patients with PAH from the ASPIRE (Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre) and INITIATE (Integrated computatioNal modelIng of righT heart mechanIcs and blood flow dynAmics in congeniTal hEart disease) registries, and 82 normal controls with similar age and gender distributions. PA GLS was derived from CMR feature tracking. Right ventricular measurements including volumes, ejection fraction, and right ventricular GLS were also derived from CMR. Patients were followed up a median of 34 months with all-cause mortality as the primary endpoint. Other known risk scores were collected, including the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) 2.0 and COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) 2.0 scores. RESULTS: Of 169 patients (mean age: 57 ± 15 years; 80% female), 45 (26.6%) died (median follow-up: 34 months). Mean PA GLS was 23% ± 6% in normal controls and 10% ± 5% in patients with PAH (P < 0.0001). Patients with PA GLS <9% had a higher risk of mortality than those with PA GLS ≥9% (P < 0.001), and this was an independent predictor of mortality in PAH on multivariable analysis after adjustment for known risk factors (HR: 2.93; P = 0.010). Finally, in patients with PAH, PA GLS provided incremental prognostic value over the REVEAL 2.0 (global chi-square; P = 0.001; C statistic comparison; P = 0.030) and COMPERA 2.0 (global chi-square; P = 0.001; C statistic comparison; P = 0.048). CONCLUSIONS: PA GLS confers incremental prognostic utility over the established risk scores for identifying patients with PAH at higher risk of death, who may be targeted for closer monitoring and/or intensified therapy.

Left Atrial Phasic Function in Older Adults Is Associated with Fibrotic and Low-Grade Inflammatory Pathways.

INTRODUCTION: Concomitant risk factors challenge the mechanistic understanding of cardiac aging. We determined the degree to which the left atrial function could be distinguished by advanced cardiac magnetic resonance (CMR) imaging in older adults and assessed associations between the left atrial function and the plasma biomarkers related to biological aging and cardiovascular disease [serum monocyte chemoattractant protein-1 (MCP1), matrix metallopeptidase 9 (MMP-9), B-type natriuretic peptides (BNPs), galectin-3 (Gal-3), high-sensitivity cardiac troponin I (hsTn1), high-sensitivity C-reactive protein (hs-CRP), and soluble urokinase plasminogen activator receptor (sUPAR)]. METHODS: Among a cross-sectional population-based cohort of older adults, longitudinal LA strain including reservoir strain (εs), conduit strain (εe), and booster strain (εa) as well as peak strain rates (SRs, SRe, SRa) were determined using CMR and studied in association with blood biomarkers. RESULTS: We studied 243 community adults (42.8% female, mean age 70.3 ± 9.5 years). In bivariate analysis, εe and SRe were reduced in gradation with increasing risk factors (all p values <0.0001). Corresponding levels of sUPAR (ng/mL) were quantitatively higher in older adults with <2 risk factors (2.5 ± 1.6 vs. 1.7 ± 1.3, p = 0.0005), in those with ≥2 risk factors (3.3 ± 2.4 vs. 1.7 ± 1.3, p < 0.0001), compared to young adults; including between older adults with ≥2 risk factors and older adults with <2 risk factors (3.3 ± 2.4 vs. 2.5 ± 1.6, p = 0.017). Based on multivariate analysis, sUPAR was significantly associated with both εe (OR 1.52, p = 0.006) and SRe decline (OR 1.5, p = 0.019). The associations between Gal-3 and εe reduction (OR 1.2, p = 0.022) and between BNP and SRe decline were generally weaker (OR 1.03, p = 0.027). The addition of sUPAR to a model consisting of age, risk factors, Gal-3, and BNPs increased the area under the curve of εe from 0.72 to 0.77 (p = 0.015). CONCLUSION: By advanced CMR imaging, a panel of circulating biomarkers comprising galectin, MMP-9 and sUPAR were associated with left atrial dysfunction in older adults. Higher levels of Gal-3 and MMP-9 may be suggestive of fibrotic mechanisms in left atrial aging while impairments in left atrial strain seen in association with circulating sUPAR may be related to immune activation in the left atrium in response to left atrial remodeling and fibrotic processes.

Coronary CT Angiography-based Morphologic Index for Predicting Hemodynamically Significant Coronary Stenosis.

Purpose To develop a new coronary CT angiography (CCTA)-based index, α×LL/MLD4, that considers lesion entrance angle (α) in addition to lesion length (LL) and minimal lumen diameter (MLD) and to evaluate its efficacy in predicting hemodynamically significant coronary stenosis compared with invasive coronary angiography (ICA)-derived fractional flow reserve (FFR). Materials and Methods This prospective study enrolled participants (September 2016-March 2020) from two centers who underwent CCTA followed by ICA (ClinicalTrials.gov identifier: NCT03054324). CCTA images were processed semiautomatically to measure LL, MLD, and α for calculating α×LL/MLD4. Diagnostic performance and accuracy of α×LL/MLD4 and LL/MLD4 in detecting hemodynamically significant coronary stenosis were compared against the reference standard (invasive FFR ≤ 0.80). Results In total, 133 participants (mean age, 63 years ± 9 [SD]; 99 [74%] men) with 210 stenosed coronary arteries were analyzed. Median α×LL/MLD4 was 54.0 degree/mm3 (IQR, 25.3-128.7) in participants with invasive FFR of 0.80 or less and 6.7 degree/mm3 (IQR, 3.3-12.8) in participants with invasive FFR of more than 0.80 (P < .001). The per-vessel accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for discriminating ischemic lesions were 86.2%, 83.1%, 88.4%, 84.1%, and 87.7% for α×LL/MLD4 and 80.5%, 66.3%, 90.9%, 84.3%, and 78.6% for LL/MLD4, respectively. Area under the receiver operating characteristic curve for discriminating hemodynamically significant stenosis was 0.93 for α×LL/MLD4, which was significantly greater than the values of 0.84 for LL/MLD4 and 0.63 for diameter stenosis (both P < .001). Conclusion The new morphologic index, α×LL/MLD4, incorporating lesion entrance angle achieved higher diagnostic performance in detecting hemodynamically significant lesions compared with diameter stenosis and LL/MLD4. Keywords: CT Angiography, Cardiac, Coronary Arteries, Ischemia, Infarction, Technology Assessment Clinical trial registration no. NCT03054324 Supplemental material is available for this article. © RSNA, 2023 See also the commentary by Fairbairn and Nørgaard in this issue.

Right ventricular energetic biomarkers from 4D Flow CMR are associated with exertional capacity in pulmonary arterial hypertension.

BACKGROUND: Cardiovascular magnetic resonance (CMR) offers comprehensive right ventricular (RV) evaluation in pulmonary arterial hypertension (PAH). Emerging four-dimensional (4D) flow CMR allows visualization and quantification of intracardiac flow components and calculation of phasic blood kinetic energy (KE) parameters but it is unknown whether these parameters are associated with cardiopulmonary exercise test (CPET)-assessed exercise capacity, which is a surrogate measure of survival in PAH. We compared 4D flow CMR parameters in PAH with healthy controls, and investigated the association of these parameters with RV remodelling, RV functional and CPET outcomes. METHODS: PAH patients and healthy controls from two centers were prospectively enrolled to undergo on-site cine and 4D flow CMR, and CPET within one week. RV remodelling index was calculated as the ratio of RV to left ventricular (LV) end-diastolic volumes (EDV). Phasic (peak systolic, average systolic, and peak E-wave) LV and RV blood flow KE indexed to EDV (KEIEDV) and ventricular LV and RV flow components (direct flow, retained inflow, delayed ejection flow, and residual volume) were calculated. Oxygen uptake (VO2), carbon dioxide production (VCO2) and minute ventilation (VE) were measured and recorded. RESULTS: 45 PAH patients (46 ± 11 years; 7 M) and 51 healthy subjects (46 ± 14 years; 17 M) with no significant differences in age and gender were analyzed. Compared with healthy controls, PAH had significantly lower median RV direct flow, RV delayed ejection flow, RV peak E-wave KEIEDV, peak VO2, and percentage (%) predicted peak VO2, while significantly higher median RV residual volume and VE/VCO2 slope. RV direct flow and RV residual volume were significantly associated with RV remodelling, function, peak VO2, % predicted peak VO2 and VE/VCO2 slope (all P < 0.01). Multiple linear regression analyses showed RV direct flow to be an independent marker of RV function, remodelling and exercise capacity. CONCLUSION: In this 4D flow CMR and CPET study, RV direct flow provided incremental value over RVEF for discriminating adverse RV remodelling, impaired exercise capacity, and PAH with intermediate and high risk based on risk score. These data suggest that CMR with 4D flow CMR can provide comprehensive assessment of PAH severity, and may be used to monitor disease progression and therapeutic response. TRIAL REGISTRATION NUMBER: https://www. CLINICALTRIALS: gov . Unique identifier: NCT03217240.

Ventricular flow analysis and its association with exertional capacity in repaired tetralogy of Fallot: 4D flow cardiovascular magnetic resonance study.

BACKGROUND: Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) allows quantification of biventricular blood flow by flow components and kinetic energy (KE) analyses. However, it remains unclear whether 4D flow parameters can predict cardiopulmonary exercise testing (CPET) as a clinical outcome in repaired tetralogy of Fallot (rTOF). Current study aimed to (1) compare 4D flow CMR parameters in rTOF with age- and gender-matched healthy controls, (2) investigate associations of 4D flow parameters with functional and volumetric right ventricular (RV) remodelling markers, and CPET outcome. METHODS: Sixty-three rTOF patients (14 paediatric, 49 adult; 30 ± 15 years; 29 M) and 63 age- and gender-matched healthy controls (14 paediatric, 49 adult; 31 ± 15 years) were prospectively recruited at four centers. All underwent cine and 4D flow CMR, and all adults performed standardized CPET same day or within one week of CMR. RV remodelling index was calculated as the ratio of RV to left ventricular (LV) end-diastolic volumes. Four flow components were analyzed: direct flow, retained inflow, delayed ejection flow and residual volume. Additionally, three phasic KE parameters normalized to end-diastolic volume (KEiEDV), were analyzed for both LV and RV: peak systolic, average systolic and peak E-wave. RESULTS: In comparisons of rTOF vs. healthy controls, median LV retained inflow (18% vs. 16%, P = 0.005) and median peak E-wave KEiEDV (34.9 µJ/ml vs. 29.2 µJ/ml, P = 0.006) were higher in rTOF; median RV direct flow was lower in rTOF (25% vs. 35%, P < 0.001); median RV delayed ejection flow (21% vs. 17%, P < 0.001) and residual volume (39% vs. 31%, P < 0.001) were both greater in rTOF. RV KEiEDV parameters were all higher in rTOF than healthy controls (all P < 0.001). On multivariate analysis, RV direct flow was an independent predictor of RV function and CPET outcome. RV direct flow and RV peak E-wave KEiEDV were independent predictors of RV remodelling index. CONCLUSIONS: In this multi-scanner multicenter 4D flow CMR study, reduced RV direct flow was independently associated with RV dysfunction, remodelling and, to a lesser extent, exercise intolerance in rTOF patients. This supports its utility as an imaging parameter for monitoring disease progression and therapeutic response in rTOF. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifier: NCT03217240.

Sex differences in assessing stenosis severity between physician visual assessment and quantitative coronary angiography.

BACKGROUND: Physician visual assessment (PVA) in invasive coronary angiography (ICA) is the current clinical method to determine stenosis severity and guide percutaneous coronary intervention. This study sought to evaluate the effect of sex differences in assessing coronary stenosis severity between PVA and quantitative coronary angiography (QCA). METHODS: 209 patients with coronary artery disease (288 coronary lesions) underwent ICA and fractional flow reserve (FFR). ICA image processing including PVA and QCA was used to quantify diameter stenosis (DS). The difference of DS (ΔDS) between PVA and QCA was defined as DSPVA-DSQCA. DS ≥50% was considered anatomically obstructive. FFR ≤0.8 was defined as myocardial ischemia. RESULTS: Mean ± SD age was 63 ± 9 years. There were no significant differences in DSPVA (61.1 ± 16.3% vs 60.1 ± 18.9%) and DSQCA (53.1 ± 12.1% vs 55.4 ± 14.3%) between females and males. However, ΔDS between PVA and QCA was higher in females (8.0 ± 10.9%) than in males (4.7 ± 10.9%) (P = 0.03). Thirty-four of 72 vessels (47.2%) in female patients and 75 of 216 vessels (34.7%) in male patients were classified differently by at least one grade using PVA compared to QCA assessment. DSPVA and DSQCA were negatively correlated with FFR in females (rPVA = -0.397, rQCA = -0.448) with an even stronger negative correlation in males (rPVA = -0.607, rQCA = -0.607). ROC analysis demonstrated that DSQCA had better discrimination capability for myocardial ischemia (FFR ≤ 0.80) than DSPVA in both sexes (P < 0.05). CONCLUSIONS: A systematic bias was found in PVA (QCA reference) for overestimating severity of coronary artery disease in females compared to males.

Diagnostic Performance of Fractional Flow Reserve From CT Coronary Angiography With Analytical Method.

The aim of this study was to evaluate a new analytical method for calculating non-invasive fractional flow reserve (FFRAM) to diagnose ischemic coronary lesions. Patients with suspected or known coronary artery disease (CAD) who underwent computed tomography coronary angiography (CTCA) and invasive coronary angiography (ICA) with FFR measurements from two sites were prospectively recruited. Obstructive CAD was defined as diameter stenosis (DS) ≥50% on CTCA or ICA. FFRAM was derived from CTCA images and anatomical features using analytical method and was compared with computational fluid dynamics (CFD)-based FFR (FFRB) and invasive ICA-based FFR. FFRAM, FFRB, and invasive FFR ≤ 0.80 defined ischemia. A total of 108 participants (mean age 60, range: 30-83 years, 75% men) with 169 stenosed coronary arteries were analyzed. The per-vessel accuracy, sensitivity, specificity, and positive predictive and negative predictive values were, respectively, 81, 75, 86, 81, and 82% for FFRAM and 87, 88, 86, 83, and 90% for FFRB. The area under the receiver operating characteristics curve for FFRAM (0.89 and 0.87) and FFRB (0.90 and 0.86) were higher than both CTCA- and ICA-derived DS (all p < 0.0001) on per-vessel and per-patient bases for discriminating ischemic lesions. The computational time for FFRAM was much shorter than FFRB (2.2 ± 0.9 min vs. 48 ± 36 min, excluding image acquisition and segmentation). FFRAM calculated from a novel and expeditious non-CFD approach possesses a comparable diagnostic performance to CFD-derived FFRB, with a significantly shorter computational time.

Computed Tomography Coronary Angiography and Computational Fluid Dynamics Based Fractional Flow Reserve Before and After Percutaneous Coronary Intervention.

Invasive fractional flow reserve (FFR) is recommended to guide stent deployment. We previously introduced a non-invasive FFR calculation (FFRB) based on computed tomography coronary angiography (CTCA) with reduced-order computational fluid dynamics (CFD) and resistance boundary conditions. Current study aimed to assess the feasibility and accuracy of FFRB for predicting coronary hemodynamics before and after stenting, with invasive FFR as the reference. Twenty-five patients who had undergone CTCA were prospectively enrolled before invasive coronary angiography (ICA) and FFR-guided percutaneous coronary intervention (PCI) on 30 coronary vessels. Using reduced-order CFD with novel boundary conditions on three-dimensional (3D) patient-specific anatomic models reconstructed from CTCA, we calculated FFRB before and after virtual stenting. The latter simulated PCI by clipping stenotic segments from the 3D coronary models and replacing them with segments to mimic the deployed coronary stents. Pre- and post-virtual stenting FFRB were compared with FFR measured pre- and post-PCI by investigators blinded to FFRB results. Among 30 coronary lesions, pre-stenting FFRB (mean 0.69 ± 0.12) and FFR (mean 0.67 ± 0.13) exhibited good correlation (r = 0.86, p < 0.001) and agreement [mean difference 0.024, 95% limits of agreement (LoA): -0.11, 0.15]. Similarly, post-stenting FFRB (mean 0.84 ± 0.10) and FFR (mean 0.86 ± 0.08) exhibited fair correlation (r = 0.50, p < 0.001) and good agreement (mean difference 0.024, 95% LoA: -0.20, 0.16). The accuracy of FFRB for identifying post-stenting ischemic lesions (FFR ≤ 0.8) (residual ischemia) was 87% (sensitivity 80%, specificity 88%). Our novel FFRB, based on CTCA with reduced-order CFD and resistance boundary conditions, accurately predicts the hemodynamic effects of stenting which may serve as a tool in PCI planning.

Age- and Sex-Specific Changes in CMR Feature Tracking-Based Right Atrial and Ventricular Functional Parameters in Healthy Asians.

Cardiovascular magnetic resonance (CMR) is the reference standard for non-invasive assessment of right-sided heart function. Recent advances in CMR post-processing facilitate quantification of tricuspid annular (TA) dynamics and longitudinal strains of the right ventricle (RV) and right atrium (RA). We aimed to determine age- and sex-specific changes in CMR-derived TA dynamics, and RV and RA functional parameters in healthy Asian adults. We studied 360 healthy subjects aged 21-79 years, with 30 men and 30 women in each of the six age groups. Functional parameters of RV and RA were measured on standard four-chamber cine CMR using fast feature tracking: (1) TA peak velocities (systolic velocity S', early diastolic velocity E', late diastolic velocity A') and TA plane systolic excursion (TAPSE); (2) RV global longitudinal strain (GLS) and strain rates; and (3) RA phasic longitudinal strains and strain rates. S' and TAPSE exhibited negative correlations with age. RV GLS was significantly higher in females than in males but not associated with age in both sexes. Females had similar E', lower A', and higher E'/A' ratios compared to males. Positive associations of E' and E'/A', and negative association of A' with age were observed in both sexes. Females had higher RA reservoir and conduit strains compared to males. There were significantly negative and positive associations between RA conduit and booster strains, respectively, with age. Age- and sex-specific reference ranges were established, and associations revealed, for fast CMR feature tracking parameters of right heart function in a large normal Asian population.

Exacerbation of cardiovascular ageing by diabetes mellitus and its associations with acyl-carnitines.

OBJECTIVE: To demonstrate differences in cardiovascular structure and function between diabetic and non-diabetic older adults. To investigate associations between acyl-carnitines and cardiovascular function as indexed by imaging measurements. METHODS: A community-based cohort of older adults without cardiovascular disease underwent current cardiovascular imaging and metabolomics acyl-carnitines profiling based on current and archived sera obtained fifteen years prior to examination. RESULTS: A total of 933 participants (women 56%, n=521) with a mean age 63±13 years were studied. Old diabetics compared to old non-diabetics had lower myocardial relaxation (0.8±0.2 vs 0.9±0.3, p=0.0039); lower left atrial conduit strain (12±4.3 vs 14±4.1, p=0.045), lower left atrial conduit strain rate (-1.2±0.4 vs -1.3±0.5, p=0.042) and lower ratio of left atrial conduit strain to left atrial booster strain (0.5±0.2 vs 0.7±0.3, p=0.0029). Higher levels of archived short chain acyl-carnitine were associated with present-day impairments in myocardial relaxation (C5:1; OR 1.03, p=0.011), worse left atrial conduit strain function (C5:1; OR 1.03, p=0.037). Increases in hydroxylated acyl-carnitines were associated with worse left atrial conduit strain [(C4-OH; OR 1.05, p=0.0017), (C16:2-OH; OR 1.18, p=0.037)]. Current, archived and changes in long chain acyl-carnitines were associated with cardiovascular functions [(C16; OR 1.02, p=0.002), (C20:3; OR 1.01, p=0.014), (C14:3; OR 1.12, p=0.033), (C18:1; OR 1.01, p=0.018), (C18:2; OR 1.01, p=0.028), (C20:4; OR 1.10, p=0.038)] (all p<0.05). CONCLUSION: Older diabetic adults had significant impairments in left ventricular myocardial relaxation and left atrial strain, compared to older non-diabetic adults. Short chain and long chain, di-carboxyl and hydroxylated acyl-carnitines were associated with these cardiovascular functional differences.

Impact of age, sex and ethnicity on intra-cardiac flow components and left ventricular kinetic energy derived from 4D flow CMR.

BACKGROUND: Four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) allows quantification of left ventricular (LV) blood flow. We aimed to 1) establish reference ranges for 4D flow CMR-derived LV relative flow components and kinetic energy parameters indexed to end-diastolic volume (KEiEDV) among healthy Asian subjects, 2) assess effects of age and sex on these parameters, and 3) compare these parameters between Asian and Caucasian subjects. METHODS: 74 healthy Asian subjects underwent cine and 4D flow CMR. Relative flow components (direct flow, retained inflow, delayed ejection flow, residual volume) and multiple phasic KEiEDV (LV global, peak systolic, systolic, diastolic, peak E-wave, peak A-wave) were analyzed. Sex- and age-specific reference ranges were reported. RESULTS: Relative flow components and systolic phase KEiEDV did not vary with age. Women had higher retained inflow and peak E-wave KEiEDV, lower residual volume, peak systolic and systolic KEiEDV than men. Peak A-wave KEiEDV increased significantly (r = 0.474) whereas peak E-wave KEiEDV (r = -0.458) and E-wave/A-wave ratio (r = -0.528) decreased with age. A sub-population (n = 44) was compared with 44 sex- and age-matched Caucasian subjects: no significant group differences were observed for all 4D flow CMR parameters. CONCLUSION: Asian sex- and age-specific 4D flow CMR reference ranges were established. Sex differences in retained inflow, residual volume, peak systolic, systolic KEiEDV and peak E-wave KEiEDV were observed. Ageing influenced diastolic KEiEDV but not systolic phase KEiEDV or relative flow components. All studied parameters were similar between sex- and age-matched Asian and Caucasian subjects, implying generalizability of the ranges.

Amino acid differences between diabetic older adults and non-diabetic older adults and their associations with cardiovascular function.

BACKGROUND: Ageing and insulin resistant states such as diabetes mellitus frequently coexist and increase the risk of cardiovascular disease development among older adults. Here we investigate metabolic differences in amino acid profiles between ageing and diabetes mellitus, and their associations with cardiovascular function. METHODS: In a group of community older adults we performed echocardiography, cardiac magnetic resonance imaging as well as cross sectional and longitudinal metabolomics profiling based on current and archived sera obtained fifteen years prior to examination. RESULTS: We studied a total of 515 participants (women 50%, n = 255) with a mean age 73 (SD = 4.3) years. Diabetics had higher alanine (562 vs 448, p < 0.0001), higher glutamate (107 vs 95, p = 0.016), higher proline (264 vs 231, p = 0.008) and lower arginine (107 vs 117, p = 0.043), lower citrulline (30 vs 38, p = 0.006) levels (µM) compared to non-diabetics. Over time, changes in amino acid profiles differentiated diabetic older adults from non-diabetic older adults, with greater accumulation of alanine (p = 0.002), proline (p = 0.008) and (non-significant) trend towards greater accumulation of glycine (p = 0.057) among the older diabetics compared to the older non-diabetics. However, independent of diabetes status, amino acids were associated with cardiovascular functions in ageing, [archived valine (p = 0.011), leucine (p = 0.011), archived isoleucine (p = 0.0006), archived serine (p = 0.008), archived glycine (p = 0.006) methionine (p = 0.003)] which were associated with impairments in E/A ratio. CONCLUSION: Markers of branched chain amino acids and one ­carbon metabolism pathways were associated with changes in cardiovascular function in older adults regardless of diabetes status. However, nitrogen handling pathways were specifically altered among older adults with diabetes. These findings broaden our understanding into specific amino acid pathways that may be altered between diabetic and non-diabetic older adults, and their relevance to cardiovascular function in ageing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02791139.

Cardiovascular magnetic resonance-assessed fast global longitudinal strain parameters add diagnostic and prognostic insights in right ventricular volume and pressure loading disease conditions.

BACKGROUND: Parameters of myocardial deformation may provide improved insights into right ventricular (RV) dysfunction. We quantified RV longitudinal myocardial function using a fast, semi-automated method and investigated its diagnostic and prognostic values in patients with repaired tetralogy of Fallot (rTOF) and pulmonary arterial hypertension (PAH), who respectively exemplify patients with RV volume and pressure overload conditions. METHODS: The study enrolled 150 patients (rTOF, n = 75; PAH, n = 75) and 75 healthy controls. RV parameters of interest were fast global longitudinal strain (GLS) and strain rates during systole (GLSRs), early diastole (GLSRe) and late diastole (GLSRa), obtained by tracking the distance from the medial and lateral tricuspid valve insertions to the RV epicardial apex on cine cardiovascular magnetic resonance (CMR). RESULTS: The RV fast GLS exhibited good agreement with strain values obtained by conventional feature tracking approach (bias - 4.9%, error limits (± 2·standard deviation) ± 4.3%) with fast GLS achieving greater reproducibility and requiring reduced analysis time. Mean RV fast GLS was reduced in PAH and rTOF groups compared to healthy controls (PAH < rTOF < healthy controls: 15.1 ± 4.9 < 19.3 ± 2.4 < 24.4 ± 3.0%, all P < 0.001 in pairwise comparisons). In rTOF patients, RV fast GLS was significantly associated with metabolic equivalents, peak oxygen consumption (PVO2) and percentage of predicted PVO2 achieved during cardiopulmonary exercise testing. Lower RV fast GLS was associated with subnormal exercise capacity in rTOF (area under the curve (AUC) = 0.822, sensitivity = 72%, specificity = 91%, cut-off = 19.3%). In PAH patients, reduced RV fast GLS was associated with RV decompensated hemodynamics (AUC = 0.717, sensitivity = 75%, specificity = 58%, cut-off = 14.6%) and higher risk of clinical worsening (AUC = 0.808, sensitivity = 79%, specificity = 70 %, cut-off = 16.0%). CONCLUSIONS: Quantitative RV fast strain and strain rate parameters assessed from CMR identify abnormalities of RV function in rTOF and PAH and are predictive of exercise capacity, RV decompensation and clinical risks in these patients. Trial registry Clinicaltrials.gov: NCT03217240.