Deep Learning-Enabled Quantification of 99mTc-Pyrophosphate SPECT/CT for Cardiac Amyloidosis.

Transthyretin cardiac amyloidosis (ATTR CA) is increasingly recognized as a cause of heart failure in older patients, with 99mTc-pyrophosphate imaging frequently used to establish the diagnosis. Visual interpretation of SPECT images is the gold standard for interpretation but is inherently subjective. Manual quantitation of SPECT myocardial 99mTc-pyrophosphate activity is time-consuming and not performed clinically. We evaluated a deep learning approach for fully automated volumetric quantitation of 99mTc-pyrophosphate using segmentation of coregistered anatomic structures from CT attenuation maps. Methods: Patients who underwent SPECT/CT 99mTc-pyrophosphate imaging for suspected ATTR CA were included. Diagnosis of ATTR CA was determined using standard criteria. Cardiac chambers and myocardium were segmented from CT attenuation maps using a foundational deep learning model and then applied to attenuation-corrected SPECT images to quantify radiotracer activity. We evaluated the diagnostic accuracy of target-to-background ratio (TBR), cardiac pyrophosphate activity (CPA), and volume of involvement (VOI) using the area under the receiver operating characteristic curve (AUC). We then evaluated associations with the composite outcome of cardiovascular death or heart failure hospitalization. Results: In total, 299 patients were included (median age, 76 y), with ATTR CA diagnosed in 83 (27.8%) patients. CPA (AUC, 0.989; 95% CI, 0.974-1.00) and VOI (AUC, 0.988; 95% CI, 0.973-1.00) had the highest prediction performance for ATTR CA. The next highest AUC was for TBR (AUC, 0.979; 95% CI, 0.964-0.995). The AUC for CPA was significantly higher than that for heart-to-contralateral ratio (AUC, 0.975; 95% CI, 0.952-0.998; P = 0.046). Twenty-three patients with ATTR CA experienced cardiovascular death or heart failure hospitalization. All methods for establishing TBR, CPA, and VOI were associated with an increased risk of events after adjustment for age, with hazard ratios ranging from 1.41 to 1.84 per SD increase. Conclusion: Deep learning segmentation of coregistered CT attenuation maps is not affected by the pattern of radiotracer uptake and allows for fully automatic quantification of hot-spot SPECT imaging such as 99mTc-pyrophosphate. This approach can be used to accurately identify patients with ATTR CA and may play a role in risk prediction.

Sex-based differences in the phenotypic expression and prognosis of idiopathic non-ischaemic cardiomyopathy: a cardiovascular magnetic resonance study.

AIMS: We sought to characterize sex-related differences in cardiovascular magnetic resonance-based cardiovascular phenotypes and prognosis in patients with idiopathic non-ischaemic cardiomyopathy (NICM). METHODS AND RESULTS: Patients with NICM enrolled in the Cardiovascular Imaging Registry of Calgary (CIROC) between 2015 and 2021 were identified. Z-score values for chamber volumes and function were calculated as standard deviation from mean values of 157 sex-matched healthy volunteers, ensuring reported differences were independent of known sex-dependencies. Patients were followed for the composite outcome of all-cause mortality, heart failure admission, or ventricular arrhythmia. A total of 747 patients were studied, 531 (71%) males. By Z-score values, females showed significantly higher left ventricular (LV) ejection fraction (EF; median difference 1 SD) and right ventricular (RV) EF (difference 0.6 SD) with greater LV mass (difference 2.1 SD; P < 0.01 for all) vs. males despite similar chamber volumes. Females had a significantly lower prevalence of mid-wall striae (MWS) fibrosis (22% vs. 34%; P < 0.001). Over a median follow-up of 4.7 years, 173 patients (23%) developed the composite outcome, with equal distribution in males and females. LV EF and MWS were significant independent predictors of the outcome (respective HR [95% CI] 0.97 [0.95-0.99] and 1.6 [1.2-2.3]; P = 0.003 and 0.005). There was no association of sex with the outcome. CONCLUSION: In a large contemporary cohort, NICM was uniquely expressed in females vs. males. Despite similar chamber dilation, females demonstrated greater concentric remodelling, lower reductions in bi-ventricular function, and a lower burden of replacement fibrosis. Overall, their prognosis remained similar to male patients with NICM.

Resolution of Cardiac Infiltration Following Autologous Stem Cell Transplantation for AL Amyloidosis.

A 43-year-old man presented with severe heart failure secondary to high-risk light chain cardiac amyloidosis. He underwent chemotherapy and autologous stem cell transplantation with complete hematologic response. Serial cardiac magnetic resonance imaging post-transplant demonstrated gradual normalization of biventricular function and myocardial T1, a surrogate measure of disease burden.

The Cardiac Amyloidosis Registry Study (CARS): Rationale, Design and Methodology.

BACKGROUND: CARS (Cardiac Amyloidosis Registry Study) is a multicenter registry established in 2019 that includes patients with transthyretin (ATTR, wild-type and variant) and light chain (AL) cardiac amyloidosis (CA) evaluated at major amyloidosis centers between 1997 and 2025. CARS aims to describe the natural history of CA with attention to clinical and diagnostic variables at the time of diagnosis, real-world treatment patterns, and associated outcomes of patients in a diverse cohort that is more representative of the at-risk population than that described in CA clinical trials. METHODS AND RESULTS: This article describes the design and methodology of CARS, including procedures for data collection and preliminary results. As of February 2023, 20 centers in the United States enrolled 1415 patients, including 1155 (82%) with ATTR and 260 (18%) with AL CA. Among those with ATTR, wild-type is the most common ATTR (71%), and most of the 305 patients with variant ATTR have the p.V142I mutation (68%). A quarter of the total population identifies as Black. More individuals with AL are female (39%) compared to those with ATTR (13%). CONCLUSIONS: CARS will answer crucial clinical questions about CA natural history and permit comparison of different therapeutics not possible through current clinical trials. Future international collaboration will further strengthen the validity of observations of this increasingly recognized condition.

Right Ventricular Systolic Pressure Trajectory as a Predictor of Hospitalization and Mortality in Patients With Chronic Heart Failure.

Background: Pulmonary hypertension is common among patients with heart failure (HF). Right ventricular systolic pressure (RVSP) is frequently used to assess its presence and severity. Although RVSP has been associated with adverse outcomes, the importance of serial measurements has not been studied. We evaluated associations between serial RVSP measurements and cardiovascular events in patients with HF. Methods: Patients with HF and 2 echocardiograms performed ≥ 6 months apart were included. RVSP was categorized, using the second echocardiogram, as follows: normal (< 40 mm Hg); severely elevated (≥ 60 mm Hg); moderately elevated (50-59 mm Hg); or mildly elevated (40-49 mm Hg). Patients also were classified according to change in RVSP categories between echocardiograms. The primary outcome was time to HF hospitalization (HFH) or all-cause mortality (ACM) after the second echocardiogram. Results: In total, 4319 patients were included (median age: 78 years; 52.1% female). During a median follow-up period of 19.4 months, HFH/ACM occurred in 2714 patients (62.8%). In multivariable analysis, baseline RSVP that was mildly elevated (1069 patients, hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.12-1.54), moderately elevated (797 patients, HR 1.54, 95% CI 1.30-1.82), or severely elevated (837 patients, HR 1.92, 95% CI 1.60-2.31) was independently associated with HFH/ACM. Additionally, improving RVSP was associated with increased HFH/ACM in both categorical (HR 1.16, 95% CI 1.01-1.33) and continuous analyses. Conclusions: RVSP measurements identify patients at increased risk who may require more-aggressive monitoring and medical therapy. Our study raises the hypothesis that, in addition to the absolute value of RVSP, improving RVSP category may identify higher-risk patients, but further study is needed to elucidate the underlying reasons.

Contexte: L'hypertension pulmonaire est fréquente chez les patients atteints d'insuffisance cardiaque. La pression systolique ventriculaire droite (PSVD) est souvent utilisée pour évaluer la présence et la gravité de l'hypertension pulmonaire. Bien que la PSVD ait été associée à des complications, l'importance de mesures répétitives n'a pas été étudiée. Nous avons évalué les liens entre des mesures répétitives de la PSVD et des événements cardiovasculaires chez des patients atteints d'insuffisance cardiaque. Méthodologie: Ont été inclus des patients atteints d'insuffisance cardiaque pour lesquels on disposait de deux échocardiogrammes réalisés dans un intervalle ≥ 6 mois. La PSVD a été catégorisée comme suit, au moyen du deuxième échocardiogramme : normale (< 40 mmHg); gravement élevée (≥ 60 mmHg); modérément élevée (50 à 59 mmHg) ou légèrement élevée (40 à 49 mmHg). Les patients ont également été classés dans des catégories en fonction de la variation de la PSVD d'un échocardiogramme à l'autre. Le paramètre d'évaluation principal était le temps écoulé avant une hospitalisation pour insuffisance cardiaque ou un décès, toutes causes confondues, après le second échocardiogramme. Résultats: Au total, 4 319 patients ont été inclus (âge médian de 78 ans; 52,1 % de sexe féminin). Pendant une période de suivi médian de 19,4 mois, une hospitalisation pour insuffisance cardiaque ou un décès, toutes causes confondues, se sont produits chez 2 714 patients (62,8 %). Une analyse multivariée a déterminé qu'une PSVD initiale légèrement élevée (1 069 patients, rapport de risques instantanés [RRI] de 1,31, intervalle de confiance [IC] à 95 % de 1,12 à 1,54), modérément élevée (797 patients, RRI de 1,54, IC à 95 % de 1,30 à 1,82) ou gravement élevée (837 patients, RRI de 1,92, IC à 95 % de 1,60 à 2,31) était indépendamment associée à une hospitalisation pour insuffisance cardiaque ou à un décès, toutes causes confondues. En outre, l'amélioration de la PSVD était associée à une hausse des hospitalisations pour insuffisance cardiaque ou des décès, toutes causes confondues, dans les analyses des catégories (RRI de 1,16, IC à 95 % de 1,01 à 1,33) et continues. Conclusions: Les mesures de la PSVD ont permis de repérer les patients présentant un risque accru qui pourraient nécessiter une surveillance et un traitement médical plus intenses. Notre étude incite à poser l'hypothèse voulant qu'en plus de la valeur absolue de la PSVD, l'amélioration des catégories de PSVD puisse permettre de repérer les patients présentant un risque accru, mais des études plus approfondies sont nécessaires pour élucider les raisons sous-jacentes.

Characteristics of Carpal Tunnel Syndrome in Wild-Type Transthyretin Amyloidosis.

BACKGROUND: Carpal tunnel syndrome (CTS) is one of the most common extra-cardiac manifestations of wild-type transthyretin amyloidosis (wtATTR); however, the characteristics of CTS in this population remain poorly understood. METHODS: This retrospective cohort study reports findings from a single-centre experience of comprehensive neurological screening at the time of wtATTR diagnosis by nerve conduction studies (NCS) and neurologist assessment. RESULTS: Seventy-nine patients underwent neurological screening, 73 (92%) males, mean age 79.2 ± 7.5 years. Seventy-four (94%) had electrodiagnostic findings of median neuropathy at the wrist (MNW), 37 (50%) of which had a prior diagnosis of CTS and 37 (50%) had a new diagnosis of MNW. Over half of wtATTR patients (42, 53%) had bilateral MNW on screening. Most with pre-existing CTS had bilateral disease (28, 76%) and underwent bilateral carpal tunnel release (CTR) (23, 62%) prior to screening. Twenty-one (19%) wrists had mild MNW, 43 (38%) moderate and 49 (43%) severe. Twenty-one (28%) wtATTR patients with MNW were asymptomatic, 10 of which (48%) had moderate disease. Nineteen (36%) wtATTR patients with symptomatic MNW had recurrent disease despite previous CTR. As a result of screening, 36 (68%) patients with symptomatic MNW were referred for CTR. CONCLUSIONS: MNW is exceptionally common at the time of wtATTR diagnosis, affecting 94% of our patients. Most had severe, bilateral MNW on NCS. Some were asymptomatic, despite having moderate disease. The rate of recurrence following CTR was observed to be higher in wtATTR patients than the general population.

Anderson-Fabry disease cardiomyopathy: an update on epidemiology, diagnostic approach, management and monitoring strategies.

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by deficient activity of the enzyme alpha-galactosidase. While AFD is recognized as a progressive multi-system disorder, infiltrative cardiomyopathy causing a number of cardiovascular manifestations is recognized as an important complication of this disease. AFD affects both men and women, although the clinical presentation typically varies by sex, with men presenting at a younger age with more neurologic and renal phenotype and women developing a later onset variant with more cardiovascular manifestations. AFD is an important cause of increased myocardial wall thickness, and advances in imaging, in particular cardiac magnetic resonance imaging and T1 mapping techniques, have improved the ability to identify this disease non-invasively. Diagnosis is confirmed by the presence of low alpha-galactosidase activity and identification of a mutation in the GLA gene. Enzyme replacement therapy remains the mainstay of disease modifying therapy, with two formulations currently approved. In addition, newer treatments such as oral chaperone therapy are now available for select patients, with a number of other investigational therapies in development. The availability of these therapies has significantly improved outcomes for AFD patients. Improved survival and the availability of multiple agents has presented new clinical dilemmas regarding disease monitoring and surveillance using clinical, imaging and laboratory biomarkers, in addition to improved approaches to managing cardiovascular risk factors and AFD complications. This review will provide an update on clinical recognition and diagnostic approaches including differentiation from other causes of increased ventricular wall thickness, in addition to modern strategies for management and follow-up.

Prevalence, incidence and clinical outcomes of epicardial coronary artery disease among transthyretin amyloidosis cardiomyopathy patients.

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) patients are often older and may be at risk for obstructive epicardial coronary artery disease (oeCAD). While ATTR-CM may cause small vessel coronary disease, the prevalence and clinical significance of oeCAD is not well described. METHODS AND RESULTS: The prevalence and incidence of oeCAD and its association with all-cause mortality and hospitalization among 133 ATTR-CM patients with ≥ 1-year follow-up was evaluated. The mean age was 78 ± 9 years, 119 (89%) were male, 116 (87%) had wild-type and 17 (13%) had hereditary subtypes. Seventy-two (54%) patients underwent oeCAD investigations, with 30 (42%) receiving a positive diagnosis. Among patients with a positive oeCAD diagnosis, 23 (77%) were diagnosed prior to ATTR-CM diagnosis, 6 (20%) at the time of ATTR-CM diagnosis, and 1 (3%) after ATTR-CM diagnosis. Baseline characteristics between patients with and without oeCAD were similar. Among patients with oeCAD, only 2 (7%) required additional investigations, intervention or hospitalization after ATTR-CM diagnosis. After a median follow-up of 27 months there were 37 (28%) deaths in the study population, including 5 patients with oeCAD (17%). Fifty-six (42%) patients in the study population required hospitalization, including 10 patients with oeCAD (33%). There was no significant difference in the rates of death or hospitalization among ATTR-CM patients with and without oeCAD, and oeCAD was not significantly associated with either outcome by univariable regression analysis. CONCLUSIONS: While oeCAD is prevalent in ATTR-CM patients, this diagnosis is frequently known at time of ATTR-CM diagnosis and characteristics are similar to patients without oeCAD.

Cost-effectiveness of immediate initiation of dapagliflozin in patients with a history of heart failure.

AIMS: To compare the cost-effectiveness of immediate and 12-month delayed initiation of dapagliflozin treatment in patients with a history of hospitalization for heart failure (HHF) from the UK, Canadian, German, and Spanish healthcare perspectives. METHODS AND RESULTS: A cost-utility analysis was conducted using a decision-analytic Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire scores, type 2 diabetes mellitus status and incidence of heart failure (HF) events. Patient-level data for patients with prior HHF from the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial were used to inform the model inputs on clinical events and utility values. Healthcare costs were sourced from the relevant national reference databases and the published literature. Compared to standard therapy, immediate initiation of dapagliflozin decreased HHF (187 events), urgent HF visits (32 events) and cardiovascular mortality (18 events). Standard therapy was associated with lifetime costs of £13 224 and 4.02 quality-adjusted life years (QALYs). Twelve-month delayed initiation of dapagliflozin was associated with total discounted lifetime costs and QALYs of £16 660 and 4.61, respectively, compared to £16 912 and 4.66, respectively, for immediate initiation. Compared to standard therapy, immediate and 12-month delayed initiation of dapagliflozin yielded an incremental cost-effectiveness ratio (ICER) of £5779 and £5821, respectively. Compared to 12-month delayed initiation, immediate initiation of dapagliflozin had an ICER of £5263. Results were similar from the Canadian, German, and Spanish healthcare perspectives. CONCLUSION: Both immediate and 12-month delayed initiation of dapagliflozin are cost-effective. However, immediate initiation provides greater clinical benefits, with almost 10% additional QALYs gain, compared to 12-month delayed initiation of dapagliflozin and should be considered standard of care.

Normative healthy reference values for global and segmental 3D principal and geometry dependent strain from cine cardiac magnetic resonance imaging.

3-Dimensional (3D) myocardial deformation analysis (3D-MDA) enables novel descriptions of geometry-independent principal strain (PS). Applied to routine 2D cine cardiovascular magnetic resonance (CMR), this provides unique measures of myocardial biomechanics for disease diagnosis and prognostication. However, healthy reference values remain undefined. This study describes age- and sex-stratified reference values from CMR-based 3D-MDA, including 3D PS. One hundred healthy volunteers were prospectively recruited following institutional ethics approval and underwent CMR imaging. 3D-MDA was performed using validated software. Age- and sex-stratified global and segmental strain measures were derived for conventional geometry-dependent [circumferential (CS), longitudinal (LS), and radial (RS)] and geometry-independent [minimum (minPS) and maximum principal (maxPS)] directions of deformation. Layer-specific contraction angle interactions were determined using local minPS vectors. The average age was 43 ± 15 years and 55% were women. Strain measures were higher in women versus men. 3D PS-based assessment of maximum tissue shortening (minPS) and maximum tissue thickening (maxPS) were greater than corresponding geometry-dependent markers of LS and RS, consistent with improved representation of local tissue deformations. Global maxPS amplitude best discriminated both age and sex. Segmental analyses showed greater strain amplitudes in apical segments. Transmural PS contraction angles were higher in females and showed a heterogeneous distribution across segments. In this study we provided age and sex-based reference values for 3D strain from CMR imaging, demonstrating improved capacity for 3D PS to document maximal local tissue deformations and to discriminate age and sex phenotypes. Novel markers of layer-specific strain angles from 3D PS were also described.

Amyloidosis and Carpal Tunnel Syndrome: Surgical Technique for Extended Carpal Tunnel Release with Tenosynovium and Transverse Carpal Ligament Biopsies.

Carpal tunnel syndrome (CTS) is common in patients with transthyretin amyloidosis (ATTR), and many experience residual symptoms and/or develop recurrent disease following routine carpal tunnel release (CTR). An extended CTR with median nerve neurolysis is recommended for thorough nerve decompression. Tissue confirmation of amyloidosis can be performed at the time of CTR with biopsies of the transverse carpal ligament and/or tenosynovium. Methods: We describe a retrospective, single-center experience performing an extended CTR technique including unilateral and bilateral cases for 13 consecutive patients (18 wrists) with ATTR and symptomatic median neuropathy at the wrist. Results: The mean patient age was 83 (range 67-90) years and 11 (85%) were men. Notable intraoperative findings in all cases included thickened tenosynovium and median nerve epineurium, and adherence of the median nerve to the deep surface of transverse carpal ligament. Pathology findings were positive for amyloidosis from both the transverse carpal ligament and the tenosynovium biopsies in all patients. Conclusions: Extended CTR with simultaneous wrist tissue biopsy can be safely performed for ATTR patients with CTS. Characteristic intraoperative findings should increase clinical suspicion for undiagnosed ATTR and prompt performance of biopsy for diagnostic confirmation. Volar wrist tenosynovial biopsy is our preferred tissue for confirmation of ATTR, for patients with and without CTS, given its safety profile and 100% pathological yield in our series.

Blood flow restriction during high-intensity interval cycling exacerbates psychophysiological responses to a greater extent in females than males.

This study aimed to characterize neuromuscular, perceptual, and cardiorespiratory responses to high-intensity interval training (HIIT) with superimposed blood flow restriction in males and females. Twenty-four, healthy individuals (n = 12 females) completed two cycling HIIT protocols to task failure (1-min work phases at 90% of peak power output interspersed by 1-min rest phases). The blood flow restriction (BFR) and control (CON) protocols were identical except for the presence and absence of BFR during rest phases, respectively. The interpolated twitch technique, including maximal voluntary isometric knee extension (MVC) and femoral nerve electrical stimuli, was performed at baseline, every six intervals, and task failure. Perceptual and cardiorespiratory responses were recorded every three intervals and continuously during exercise, respectively. Bayesian inference was used to obtain the joint posterior distribution for all parameters and evidence of an effect was determined via the marginal posterior probability (PP). The BFR shortened task duration by 57.3% compared with CON (PP > 0.99), without a sex difference. The application of BFR exacerbated the rate of decline in neuromuscular measures (MVC and twitch force output), increase of perceptual responses (perceived effort, pain, dyspnea, fatigue), and development of cardiorespiratory parameters (minute ventilation and heart rate), compared with CON (PP > 0.95). In addition, BFR exacerbated the neuromuscular, perceptual, and cardiorespiratory responses to a greater extent in females than males (PP > 0.99). Our results suggest that superimposition of blood flow restriction exacerbates psychophysiological responses to a HIIT protocol to a greater extent in females than males.NEW & NOTEWORTHY To our knowledge, no study has explored sex differences in the neuromuscular, perceptual, and cardiorespiratory indices characterizing exercise tolerance during high-intensity interval training (HIIT) with blood flow restriction (BFR) applied only during rest periods. Our results suggest that BFR elicited a decline in exercise performance that could be attributed to integration of psychophysiological responses. However, this integration was sex-dependent where females demonstrated an exacerbated rate of change in these responses compared with males.

Integrating Cardiac MRI Imaging and Multidisciplinary Clinical Care is Associated With Improved Outcomes in Patients With Fabry Disease.

Given the inherent complexities of Fabry disease (FD) and evolving landscape of cardiovascular clinical management, there is no established ideal clinical care model for these patients. We identified clinical factors predictive of increased risk of major adverse cardiac events (MACE) in patients with FD targeted to improve clinical outcomes. Ninety-five patients studied over a median follow-up time of 6.3 years, and 26 patients reached the composite endpoint with a high prevalence of heart failure and cerebrovascular events and no cardiac-related mortality. Patients with MACE had worse health-related quality of life scores. Hypertrophy and presence of myocardial fibrosis increase risk of MACE by 4-5 times, and dyslipidemia increases risk of MACE by 3 times. Early Fabry-specific treatment and close monitoring of comorbidities reduce cardiac complications and mortality. These findings highlight the importance of comprehensive multidisciplinary management to help improve outcomes in FD patients.

Right ventricular systolic strain in patients with pulmonary hypertension: clinical feasibility, reproducibility, and correlation with ejection fraction.

BACKGROUND: Right ventricular (RV) systolic function is the major determinant of prognosis in patients with pulmonary hypertension (PH) with quantitative assessment by speckle-tracking strain echocardiography emerging as a viable candidate measure. METHOD: We evaluated a prospective cohort of 231 patients with known or suspected PH referred for clinical echocardiography. All underwent measurement of RV free-wall systolic strain by sonographer staff. Digital images were recorded for blinded offline assessment by an expert echocardiographer. Reproducibility was assessed using the analysis methods of Bland-Altman and the Cohen's-Kappa coefficient. RESULTS: RV strain was feasible in 213 (92%). The average RV systolic pressure was 59 ± 22 mmHg. RV systolic strain correlated with functional class, NT-proBNP, and the degree of RV enlargement. The average free-wall systolic strain was - 20 ± 7% (range - 2 to - 37%). The RV strain measures (clinical practice versus blinded expert) had an excellent correlation with a normal distribution (R2 0.87, p < 0.0001). By Bland-Altman analysis, the mean difference in measurement was - 1.7% (95% CI - 1.4 to - 2.1) with a correlation of 0.93, p value of < 0.0001. The reproducibility of RV strain for clinically relevant thresholds was also excellent (Kappa coefficients 0.68-0.83). There was no effect on the variability of strain measures across body mass, pulmonary pressures, or rhythm. RV strain correlated with RV diastolic volumes and ejection fraction with RV free wall strain being the best echo predictor for a reduction in ejection fraction. CONCLUSION: Here RV systolic strain was found to be highly feasible and reproducible in clinical practice with excellent levels of agreement for clinically relevant thresholds.