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.

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.

The application of exercise stress cardiovascular magnetic resonance in patients with suspected dilated cardiomyopathy.

OBJECTIVES: The imaging features of dilated cardiomyopathy (DCM) overlap with physiological exercise-induced cardiac remodeling in active and otherwise healthy individuals. Distinguishing the two conditions is challenging. This study examined the diagnostic and prognostic roles of exercise stress imaging in asymptomatic patients with suspected DCM. METHODS: Exercise stress cardiovascular magnetic resonance (CMR) was performed in 60 asymptomatic patients with suspected DCM (dilated left ventricle and/or impaired systolic function on CMR), who also underwent DNA sequencing for DCM-causing genetic variants. Confirmed DCM was defined as genotype- and phenotype-positive (G+P+). Another 100 healthy subjects were recruited to establish normal exercise capacities (peak exercise cardiac index; PeakCI). The primary outcome was a composite of all-cause mortality, cardiac decompensation and ventricular arrhythmic events. RESULTS: No patients with confirmed G+P+ DCM had PeakCI exceeding the 35th percentile specific for age and sex. Applying this threshold in G-P+ patients, those with PeakCI below 35th percentile had characteristics similar to confirmed DCM while patients with higher PeakCI were younger, more active and higher longitudinal strain. Adverse cardiovascular events occurred only in patients with low exercise capacity (P = 0.004). CONCLUSIONS: In individuals with suspected DCM, exercise stress CMR demonstrates diagnostic and prognostic potential in distinguishing between pathological DCM and physiological exercise-induced cardiac remodeling.

Elevated Right Atrial Pressure Associated with Alteration of Left Ventricular Contractility and Ventricular-Arterial Coupling in Pulmonary Artery Hypertension.

Pulmonary artery hypertension (PAH) is a progressive disorder which leads to heart failure and death. Development of dilated right ventricle (RV), progressive RV dysfunction and increased right atrial (RA) pressure make the RV transition from a compensated to a decompensated phase and eventually leads to heart failure. However, the relationship between elevated RA pressure and left ventricular contractility and ventricular arterial coupling (VAC) has not been well studied. 36 patients were recruited and underwent both right heart catheterization (RHC) and cardiac magnetic resonance (CMR). Left ventricular (LV) pressure-volume loops were reconstructed from RHC and CMR. LV contractility was assessed by end-systolic elastance (Ees) using single-beat method and arterial elastance (Ea) was estimated as the ratio of end-systolic pressure and stroke volume (SV). The VAC was calculated as the ratio of Ees and Ea (i.e. Ees/Ea). The results demonstrated a nonlinear relationship between RA pressure and Ees, RA pressure and VAC. Ees increased when RA pressure increased to 7 mmHg and then decreased when RA pressure exceeded 7 mmHg. Ees were 2.79 ± 1.61 mmHg/ml, 4.27 ±1 33 mmHg/ml, 2.69 ± 0.89 mmHg/ml and 2.36± 1.10 mmHg/ml at ascending quartiles of RA pressure, respectively (quartile 1: RAP≤5 mmHg; quartile 2: 5<; RAP≤7 mmHg; quartile 3: 7<; RAP 10 mmHg and quartile 4: RAP>10 mmHg). Similarly, VAC were 1.36 ± 0.61, 1.93±0.86, 1.16 ± 0.55 and 0.95± 0.27 the four quartiles (both ANOVA P <; 0.05). We found that there was a nonlinear relationship between RA pressure and LV contractility, and between RA pressure and ventricular-arterial coupling. A cut-off value of 7 mmHg of RAP may indicate a decompensated LV hemodynamics.

Fractal analysis of left ventricular trabeculations is associated with impaired myocardial deformation in healthy Chinese.

BACKGROUND: Left ventricular (LV) non-compaction (LVNC) is defined by extreme LV trabeculation, but is measured variably. Here we examined the relationship between quantitative measurement in LV trabeculation and myocardial deformation in health and disease and determined the clinical utility of semi-automated assessment of LV trabeculations. METHODS: Cardiovascular magnetic resonance (CMR) was performed in 180 healthy Singaporean Chinese (age 20-69 years; males, n = 91), using balanced steady state free precession cine imaging at 3T. The degree of LV trabeculation was assessed by fractal dimension (FD) as a robust measure of trabeculation complexity using a semi-automated technique. FD measures were determined in healthy men and women to derive normal reference ranges. Myocardial deformation was evaluated using feature tracking. We tested the utility of this algorithm and the normal ranges in 10 individuals with confirmed LVNC (non-compacted/compacted; NC/C ratio > 2.3 and ≥1 risk factor for LVNC) and 13 individuals with suspected disease (NC/C ratio > 2.3). RESULTS: Fractal analysis is a reproducible means of assessing LV trabeculation extent (intra-class correlation coefficient: intra-observer, 0.924, 95% CI [0.761-0.973]; inter-observer, 0.925, 95% CI [0.821-0.970]). The overall extent of LV trabeculation (global FD: 1.205 ± 0.031) was independently associated with increased indexed LV end-diastolic volume and mass (sß = 0.35; p < 0.001 and sß = 0.13; p < 0.01, respectively) after adjusting for age, sex and body mass index. Increased LV trabeculation was independently associated with reduced global circumferential strain (sß = 0.17, p = 0.013) and global diastolic circumferential and radial strain rates (sß = 0.25, p < 0.001 and sß = -0.15, p = 0.049, respectively). Abnormally high FD was observed in all patients with a confirmed diagnosis of LVNC. Five out of 13 individuals with suspected LVNC had normal FD, despite NC/C > 2.3. CONCLUSION: This study defines the normal range of LV trabeculation in healthy Chinese that can be used to make or refute a diagnosis of LVNC using the fractal analysis tool, which we make freely available. We also show that increased myocardial trabeculation is associated with higher LV volumes, mass and reduced myocardial strain.

Stress cardiovascular magnetic resonance imaging: current and future perspectives.

INTRODUCTION: Vasodilator and dobutamine are the main pharmacological agents used in current stress cardiovascular magnetic resonance (CMR). Exercise stress has well-established advantages and it is commonly used in other stress imaging, but the technical considerations have limited its use in stress CMR. In this review, we will describe the diagnostic performance, prognostic value, strengths and challenges of current stress CMR techniques. We will also discuss future perspectives of exercise stress CMR. Areas covered: Despite notable mechanistic differences, vasodilator and dobutamine stress CMR offer similar diagnostic and prognostic value in coronary artery disease. Combined perfusion and wall motion assessment has been explored with dobutamine stress CMR: diagnostic sensitivity improved at the expense of reduced specificity. However, a combined assessment may provide additional prognostic value in selected patients. There is emerging interest and promising data in exercise stress CMR because of the availability of CMR-compatible stress equipment and development of novel real-time sequences that allow imaging during exercise with adequate spatiotemporal resolution. Expert commentary: Exercise stress CMR is able to assess wall motion abnormalities, perfusion defects, exercise capacity and viability in a single examination. This holds important clinical potential in a variety of cardiovascular conditions.

Assessing exercise cardiac reserve using real-time cardiovascular magnetic resonance.

BACKGROUND: Exercise cardiovascular magnetic resonance (ExCMR) has great potential for clinical use but its development has been limited by a lack of compatible equipment and robust real-time imaging techniques. We developed an exCMR protocol using an in-scanner cycle ergometer and assessed its performance in differentiating athletes from non-athletes. METHODS: Free-breathing real-time CMR (1.5T Aera, Siemens) was performed in 11 athletes (5 males; median age 29 [IQR: 28-39] years) and 16 age- and sex-matched healthy volunteers (7 males; median age 26 [interquartile range (IQR): 25-33] years). All participants underwent an in-scanner exercise protocol on a CMR compatible cycle ergometer (Lode BV, the Netherlands), with an initial workload of 25W followed by 25W-increment every minute. In 20 individuals, exercise capacity was also evaluated by cardiopulmonary exercise test (CPET). Scan-rescan reproducibility was assessed in 10 individuals, at least 7 days apart. RESULTS: The exCMR protocol demonstrated excellent scan-rescan (cardiac index (CI): 0.2 ± 0.5L/min/m2) and inter-observer (ventricular volumes: 1.2 ± 5.3mL) reproducibility. CI derived from exCMR and CPET had excellent correlation (r = 0.83, p < 0.001) and agreement (1.7 ± 1.8L/min/m2). Despite similar values at rest (P = 0.87), athletes had increased exercise CI compared to healthy individuals (at peak exercise: 12.2 [IQR: 10.2-13.5] L/min/m2 versus 8.9 [IQR: 7.5-10.1] L/min/m2, respectively; P < 0.001). Peak exercise CI, where image acquisition lasted 13-17 s, outperformed that at rest (c-statistics = 0.95 [95% confidence interval: 0.87-1.00] versus 0.48 [95% confidence interval: 0.23-0.72], respectively; P < 0.0001 for comparison) in differentiating athletes from healthy volunteers; and had similar performance as VO2max (c-statistics = 0.84 [95% confidence interval = 0.62-1.00]; P = 0.29 for comparison). CONCLUSIONS: We have developed a novel in-scanner exCMR protocol using real-time CMR that is highly reproducible. It may now be developed for clinical use for physiological studies of the heart and circulation.