Molecular Imaging of Heart Failure: An Update and Future Trends.

Molecular imaging can detect and quantify pathophysiological processes underlying heart failure, complementing evaluation of cardiac structure and function with other imaging modalities. Targeted tracers have enabled assessment of various cellular and subcellular mechanisms of heart failure aiming for improved phenotyping, risk stratification, and personalized therapy. This review outlines the current status of molecular imaging in heart failure, accompanied with discussion on novel developments. The focus is on radionuclide methods with data from clinical studies. Imaging of myocardial metabolism can identify left ventricle dysfunction caused by myocardial ischemia that may be reversible after revascularization in the presence of viable myocardium. In vivo imaging of active inflammation and amyloid deposition have an established role in the detection of cardiac sarcoidosis and transthyretin amyloidosis. Innervation imaging has well documented prognostic value in predicting heart failure progression and arrhythmias. Tracers specific for inflammation, angiogenesis and myocardial fibrotic activity are in earlier stages of development, but have demonstrated potential value in early characterization of the response to myocardial injury and prediction of cardiac function over time. Early detection of disease activity is a key for transition from medical treatment of clinically overt heart failure towards a personalized approach aimed at supporting repair and preventing progressive cardiac dysfunction.

Smartphone-Based Recognition of Heart Failure by Means of Microelectromechanical Sensors.

BACKGROUND: Heart failure (HF) is the leading cause of hospitalization in individuals over 65 years of age. Identifying noninvasive methods to detect HF may address the epidemic of HF. Seismocardiography which measures cardiac vibrations transmitted to the chest wall has recently emerged as a promising technology to detect HF. OBJECTIVES: In this multicenter study, the authors examined whether seismocardiography using commercially available smartphones can differentiate control subjects from patients with stage C HF. METHODS: Both inpatients and outpatients with HF were enrolled from Finland and the United States. Inpatients with HF were assessed within 2 days of admission, and outpatients were assessed in the ambulatory setting. In a prespecified pooled data analysis, algorithms were derived using logistic regression and then validated using a bootstrap aggregation method. RESULTS: A total of 217 participants with HF (174 inpatients and 172 outpatients) and 786 control subjects from cardiovascular clinics were enrolled. The mean age of participants with acute HF was 64 ± 13 years, 64.9% were male, left ventricular ejection fraction was 39 ± 15%, and median N-terminal pro-B-type natriuretic peptide was 5,778 ng/L (Q1-Q3: 1,933-6,703). The majority (74%) of participants with HF had reduced EF, and 38% had atrial fibrillation. Across both HF cohorts, the algorithms had an area under the receiver operating characteristic curve of 0.95 with a sensitivity of 85%, specificity of 90%, and accuracy of 89% for the detection of HF, with a decision threshold of 0.5. The positive and negative likelihood ratios were 8.50 and 0.17, respectively. The accuracy of the algorithms was not significantly different in subgroups based on age, sex, body mass index, and atrial fibrillation. CONCLUSIONS: Smartphone-based assessment of cardiac function using seismocardiography is feasible and differentiates patients with HF from control subjects with high diagnostic accuracy. (Recognition of Heart Failure With Micro Electro-mechanical Sensors FI [NCT04444583]; Recognition of Heart Failure With Micro Electro-mechanical Sensors [NCT04378179]; Detection of Coronary Artery Disease With Micro Electro-mechanical Sensors [NCT04290091]).

Tiredness after work associates with less leisure-time physical activity.

Physical activities and sedentary behaviors take place in different contexts. This study aimed to determine if the context, total score, and leisure-time MET-index assessed by the Baecke questionnaire associate with each other or with sedentary behavior and physical activity outcomes from a 4-week accelerometer measurement in physically inactive adults with overweight. The item "After working I am tired" correlated negatively with items related to leisure-time physical activity and sports participation. The total Baecke Score showed weak but significant correlations with accelerometer-measured sedentary behavior, physical activity, daily steps, and mean activity intensity of the day (r = - 0.33, 0.41, 0.35, and 0.41, respectively). The associations strengthened when the Sport Index was omitted from the Score. The leisure-time MET-Index did not correlate with accelerometer-measured sedentary behavior or physical activity. Tiredness after working associated with less self-reported physical activity during leisure time. This suggests that better recovery from work-related stress could increase leisure-time physical activity, or increasing leisure-time physical activity could reduce tiredness after working. Moreover, among self-reportedly inactive adults with overweight, focusing the questionnaire on work and non-sport leisure time instead of total time might give more accurate estimates of sedentary behavior and physical activity when compared to accelerometry.The study is registered at ClinicalTrials.gov (NCT03101228, 05/04/2017).

Coronary Artery Calcium Score Predicts Major Adverse Cardiovascular Events in Stable Chest Pain.

Background Coronary artery calcium (CAC) has prognostic value for major adverse cardiovascular events (MACE) in asymptomatic individuals, whereas its role in symptomatic patients is less clear. Purpose To assess the prognostic value of CAC scoring for MACE in participants with stable chest pain initially referred for invasive coronary angiography (ICA). Materials and Methods This prespecified subgroup analysis from the Diagnostic Imaging Strategies for Patients With Stable Chest Pain and Intermediate Risk of Coronary Artery Disease (DISCHARGE) trial, conducted between October 2015 and April 2019 across 26 centers in 16 countries, focused on adult patients with stable chest pain referred for ICA. Participants were randomly assigned to undergo either ICA or coronary CT. CAC scores from noncontrast CT scans were categorized into low, intermediate, and high groups based on scores of 0, 1-399, and 400 or higher, respectively. The end point of the study was the occurrence of MACE (myocardial infarction, stroke, and cardiovascular death) over a median 3.5-year follow-up, analyzed using Cox proportional hazard regression tests. Results The study involved 1749 participants (mean age, 60 years ± 10 [SD]; 992 female). The prevalence of obstructive coronary artery disease (CAD) at CT angiography rose from 4.1% (95% CI: 2.8, 5.8) in the CAC score 0 group to 76.1% (95% CI: 70.3, 81.2) in the CAC score 400 or higher group. Revascularization rates increased from 1.7% to 46.2% across the same groups (P < .001). The CAC score 0 group had a lower MACE risk (0.5%; HR, 0.08 [95% CI: 0.02, 0.30]; P < .001), as did the 1-399 CAC score group (1.9%; HR, 0.27 [95% CI: 0.13, 0.59]; P = .001), compared with the 400 or higher CAC score group (6.8%). No significant difference in MACE between sexes was observed (P = .68). Conclusion In participants with stable chest pain initially referred for ICA, a CAC score of 0 showed very low risk of MACE, and higher CAC scores showed increasing risk of obstructive CAD, revascularization, and MACE at follow-up. Clinical trial registration no. NCT02400229 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Hanneman and Gulsin in this issue.

Plasma Lipidomics and Coronary Plaque Changes: A Substudy of the SMARTool Clinical Trial.

AIMS: To date, no studies have investigated the association between lipid species and coronary plaque changes over time, quantitatively assessed by serial imaging. We aimed to prospectively determine the association between lipid species quantified by plasma lipidomic analysis, with coronary plaque changes according to composition assessed by quantitative serial analysis of coronary computed tomography angiography (CTA). METHODS AND RESULTS: Patients with suspected coronary artery disease (CAD) undergoing baseline coronary CTA were prospectively enrolled by 7 EU Centers in the SMARTool study and submitted to clinical, molecular and coronary CTA re-evaluation at follow-up (interscan period 6.39 ± 1.17 years). From the 202 patients that were analysed in the SMARTool main clinical study, lipidomic analysis was performed in 154 patients before the baseline coronary CTA, and this group was included in the present study. Quantitative CTA analysis was performed by a separate core laboratory blinded from clinical data. In univariable analysis, no lipid species were significantly associated with annual total and calcified plaque changes. After adjusting for clinical variables at baseline and statin use, 3 lipid species were significantly associated with non-calcified plaque progression. In detail, cholesteryl ester (CE)(20:3), sphingomyelin (SM)(40:3) and SM(41:1) were found positively related to non-calcified plaque progression (Bonferroni adjusted P-value = 0.005, 0.016 and 0.004, respectively). CONCLUSION: The current study showed an independent relationship between specific lipid species determined by plasma lipidomic analysis, and non-calcified coronary plaque progression assessed by serial, quantitative coronary CTA analysis.

Effect of Body Mass Index on Effectiveness of CT versus Invasive Coronary Angiography in Stable Chest Pain: The DISCHARGE Trial.

Background Recent trials support the role of cardiac CT in the evaluation of symptomatic patients suspected of having coronary artery disease (CAD); however, body mass index (BMI) has been reported to negatively impact CT image quality. Purpose To compare initial use of CT versus invasive coronary angiography (ICA) on clinical outcomes in patients with stable chest pain stratified by BMI category. Materials and Methods This prospective study represents a prespecified BMI subgroup analysis of the multicenter Diagnostic Imaging Strategies for Patients with Stable Chest Pain and Intermediate Risk of Coronary Artery Disease (DISCHARGE) trial conducted between October 2015 and April 2019. Adult patients with stable chest pain and a CAD pretest probability of 10%-60% were randomly assigned to undergo initial CT or ICA. The primary end point was major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal myocardial infarction, or stroke. The secondary end point was an expanded MACE composite, including transient ischemic attack, and major procedure-related complications. Competing risk analyses were performed using the Fine and Gray subdistribution Cox proportional hazard model to assess the impact of the relationship between BMI and initial management with CT or ICA on the study outcomes, whereas noncardiovascular death and unknown causes of death were considered competing risk events. Results Among the 3457 participants included, 831 (24.0%), 1358 (39.3%), and 1268 (36.7%) had a BMI of less than 25, between 25 and 30, and greater than 30 kg/m2, respectively. No interaction was found between CT or ICA and BMI for MACE (P = .29), the expanded MACE composite (P = .38), or major procedure-related complications (P = .49). Across all BMI subgroups, expanded MACE composite events (CT, 10 of 409 [2.4%] to 23 of 697 [3.3%]; ICA, 26 of 661 [3.9%] to 21 of 422 [5.1%]) and major procedure-related complications during initial management (CT, one of 638 [0.2%] to five of 697 [0.7%]; ICA, nine of 630 [1.4%] to 12 of 422 [2.9%]) were less frequent in the CT versus ICA group. Participants with a BMI exceeding 30 kg/m² exhibited a higher nondiagnostic CT rate (7.1%, P = .044) compared to participants with lower BMI. Conclusion There was no evidence of a difference in outcomes between CT and ICA across the three BMI subgroups. Clinical trial registration no. NCT02400229 © RSNA, 2024 Supplemental material is available for this article.

Polygenic Risk Scores in Predicting Coronary Artery Disease in Symptomatic Patients. A Validation Study.

AIM: Clinical risk scores for coronary artery disease (CAD) are used in clinical practice to select patients for diagnostic testing and therapy. Several studies have proposed that polygenic risk scores (PRSs) can improve the prediction of CAD, but the scores need to be validated in clinical populations with accurately characterized phenotypes. We assessed the predictive power of the three most promising PRSs for the prediction of coronary atherosclerosis and obstructive CAD. METHODS: This study was conducted on 943 symptomatic patients with suspected CAD for whom the phenotype was accurately characterized using anatomic and functional imaging. Previously published genome-wide polygenic scores were generated to compare a genetic model based on PRSs with a model based on clinical data. The test and PRS cohorts were predominantly Caucasian of northern European ancestry. RESULTS: All three PRSs predicted coronary atherosclerosis and obstructive CAD statistically significantly. The predictive accuracy of the models combining clinical data and different PRSs varied between 0.778 and 0.805 in terms of the area under the receiver operating characteristic (AUROC), being close to the model including only clinical variables (AUROC 0.769). The difference between the clinical model and combined clinical + PRS model was not significant for PRS1 (p=0.627) and PRS3 (p=0.061). Only PRS2 slightly improved the predictive power of the model (p=0.04). The likelihood ratios showed the very weak diagnostic power of all PRSs. CONCLUSION: The addition of PRSs to conventional risk factors did not clinically significantly improve the predictive accuracy for either coronary atherosclerosis or obstructive CAD, showing that current PRSs are not justified for routine clinical use in CAD.

Age and Computed Tomography and Invasive Coronary Angiography in Stable Chest Pain: A Prespecified Secondary Analysis of the DISCHARGE Randomized Clinical Trial.

Importance: The effectiveness and safety of computed tomography (CT) and invasive coronary angiography (ICA) in different age groups is unknown. Objective: To determine the association of age with outcomes of CT and ICA in patients with stable chest pain. Design, Setting, and Participants: The assessor-blinded Diagnostic Imaging Strategies for Patients With Stable Chest Pain and Intermediate Risk of Coronary Artery Disease (DISCHARGE) randomized clinical trial was conducted between October 2015 and April 2019 in 26 European centers. Patients referred for ICA with stable chest pain and an intermediate probability of obstructive coronary artery disease were analyzed in an intention-to-treat analysis. Data were analyzed from July 2022 to January 2023. Interventions: Patients were randomly assigned to a CT-first strategy or a direct-to-ICA strategy. Main Outcomes and Measures: MACE (ie, cardiovascular death, nonfatal myocardial infarction, or stroke) and major procedure-related complications. The primary prespecified outcome of this secondary analysis of age was major adverse cardiovascular events (MACE) at a median follow-up of 3.5 years. Results: Among 3561 patients (mean [SD] age, 60.1 [10.1] years; 2002 female [56.2%]), 2360 (66.3%) were younger than 65 years, 982 (27.6%) were between ages 65 to 75 years, and 219 (6.1%) were older than 75 years. The primary outcome was MACE at a median (IQR) follow-up of 3.5 (2.9-4.2) years for 3523 patients (99%). Modeling age as a continuous variable, age, and randomization group were not associated with MACE (hazard ratio, 1.02; 95% CI, 0.98-1.07; P for interaction = .31). Age and randomization group were associated with major procedure-related complications (odds ratio, 1.15; 95% CI, 1.05-1.27; P for interaction = .005), which were lower in younger patients. Conclusions and Relevance: Age did not modify the effect of randomization group on the primary outcome of MACE but did modify the effect on major procedure-related complications. Results suggest that CT was associated with a lower risk of major procedure-related complications in younger patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02400229.

Sedentary time associates detrimentally and physical activity beneficially with metabolic flexibility in adults with metabolic syndrome.

Metabolic flexibility (MetFlex) describes the ability to respond and adapt to changes in metabolic demand and substrate availability. The relationship between physical (in)activity and MetFlex is unclear. This study aimed to determine whether sedentary time, physical activity (PA), and cardiorespiratory fitness associate with MetFlex. Sedentary time, standing, and PA were measured with accelerometers for 4 weeks in 64 sedentary adults with metabolic syndrome [37 women, 27 men; 58.3 (SD 6.8) years]. Fitness (V̇o2max; mL·kg-1·min-1) was measured with graded maximal cycle ergometry. MetFlex was assessed with indirect calorimetry as the change in respiratory exchange ratio (ΔRER) from fasting to insulin stimulation with hyperinsulinemic-euglycemic clamp and from low-intensity to maximal exercise. Carbohydrate (CHOox) and fat oxidation (FATox) were calculated from respiratory gases. High sedentary time associated with higher fasting RER [ß = 0.35 (95% confidence interval: 0.04, 0.67)], impaired insulin-stimulated MetFlex (ΔRER) [ß=-0.41 (-0.72, -0.09)], and lower fasting FATox [ß=-0.36 (-0.67, -0.04)]. Standing associated with lower fasting RER [ß=-0.32 (-0.62, -0.02)]. Higher standing time and steps/day associated with higher fasting FATox [ß = 0.31 (0.01, 0.61), and ß = 0.26 (0.00, 0.53)]. Light-intensity and total PA associated with better insulin-stimulated MetFlex [ß = 0.33 (0.05, 0.61)], and ß = 0.33 (0.05, 0.60)]. Higher V̇o2max associated with higher CHOox during maximal exercise [ß = 0.81 (0.62, 1.00)], as well as during insulin stimulation [ß = 0.43 (0.13, 0.73)]. P values are less than 0.05 for all associations. Sedentary time and PA associate with MetFlex. Reducing sitting and increasing PA of even light intensity might aid in the prevention of metabolic diseases in risk populations through their potential effects on energy metabolism.NEW & NOTEWORTHY High accelerometer-assessed sedentary time associates with metabolic inflexibility measured during hyperinsulinemic-euglycemic clamp in adults with metabolic syndrome, and more light-intensity and total physical activity associate with more metabolic flexibility. Physical activity behaviors may thus play an important role in the regulation of fuel metabolism. This highlights the potential of reduced sedentary time and increased physical activity of any intensity to induce metabolic health benefits and help in disease prevention in risk populations.

Effects of reduced sedentary time on resting, exercise and post-exercise blood pressure in inactive adults with metabolic syndrome - a six-month exploratory RCT.

Evidence on the long-term effects of reducing sedentary behaviour (SB) on blood pressure (BP) is scarce. Therefore, we performed a sub-analysis of the BP effects of a six-month intervention that aimed at reducing SB by 1 h/day and replacing it with non-exercise activities. Sixty-four physically inactive and sedentary adults with metabolic syndrome (58% female, 58 [SD 7] years, BP 143/88 [16/9] mmHg, SB 10 [1] h/day) were randomised into intervention (INT, n = 33) and control (CON, n = 31) groups. Resting BP and BP at each stage during and after a graded maximal bicycle ergometer test were measured before and after the intervention. SB, standing, moderate-to-vigorous physical activity (MVPA), and light physical activity (LPA) were measured in six-second intervals at baseline and during the whole six-month intervention using hip-worn accelerometers. The analyses were adjusted for BP medication status. The intervention resulted in a 40 min/day reduction in SB and concomitant 20 min/day increase in MVPA. Resting systolic BP was lower in the CON group before and after the intervention. No group x time interactions were observed in resting BP or BP during exercise at submaximal or maximal intensities, or during recovery. The changes in LPA and MVPA were inversely correlated with the changes in BP during light-to-moderate intensity exercise. An intervention that resulted in a 40 min/day reduction in SB for six months was not sufficient at influencing BP at rest, during or after exercise in adults with metabolic syndrome. However, successfully increasing LPA or MVPA might lower BP during light-to-moderate-intensity activities.

Calcium Scoring Improves Clinical Management in Patients With Low Clinical Likelihood of Coronary Artery Disease.

BACKGROUND: Coronary artery calcium scoring (CACS) improves management of chest pain patients. However, it is unknown whether the benefit of CACS is dependent on the clinical likelihood (CL). OBJECTIVES: This study aims to investigate for which patients CACS has the greatest benefit when added to a CL model. METHODS: Based on data from a clinical database, the CL of obstructive coronary artery disease (CAD) was calculated for 39,837 patients referred for cardiac imaging due to symptoms suggestive of obstructive CAD. Patients were categorized according to the risk factor-weighted (RF-CL) model (very low, ≤5%; low, >5 to ≤15%; moderate >15 to ≤50%; high, >50%). CL was then recalculated incorporating the CACS result (CACS-CL). Reclassification rates and the number needed to test with CACS to reclassify patients were calculated and validated in 3 independent cohorts (n = 9,635). RESULTS: In total, 15,358 (39%) patients were down- or upclassified after including CACS. Reclassification rates were 8%, 75%, 53%, and 30% in the very low, low, moderate, and high RF-CL categories, respectively. Reclassification to very low CACS-CL occurred in 48% of reclassified patients. The number needed to test to reclassify 1 patient from low RF-CL to very low CACS-CL was 2.1 with consistency across age, sex, and cohorts. CACS-CL correlated better to obstructive CAD prevalence than RF-CL. CONCLUSIONS: Added to an RF-CL model for obstructive CAD, CACS identifies more patients unlikely to benefit from further testing. The number needed to test with CACS to reclassify patients depends on the pretest RF-CL and is lowest in patients with low (>5% to ≤15%) likelihood of CAD.

Impact of Absolute Myocardial Blood Flow Quantification on the Diagnostic Performance of PET-Based Perfusion Scans Using 82Rubidium.

BACKGROUND: Guidelines propose the inclusion of quantitative measurements from 82Rubidium positron emission tomography (RbPET) to discriminate obstructive coronary artery disease (CAD). However, the effect on diagnostic accuracy is unknown. The aim was to investigate the optimal RbPET reading algorithm for improved identification of obstructive CAD. METHODS: Prospectively enrolled patients (N=400) underwent RbPET and invasive coronary angiography with fractional flow reserve and quantitative coronary angiography. Quantitative measurements (myocardial blood flow (MBF), MBF reserve, transient ischemic dilatation) by RbPET were step-wisely added to a qualitative assessment by the summed stress score based on their diagnostic accuracy of obstructive CAD by invasive coronary angiography-fractional flow reserve. Prespecified cutoffs were summed stress score ≥4, hyperemic MBF 2.00 mL/g per min, and MBF reserve 1.80, respectively. Hemodynamically obstructive CAD was defined as >90% diameter stenosis or invasive coronary angiography-fractional flow reserve ≤0.80, and sensitivity analyses included a clinically relevant reference of anatomically severe CAD (>70% diameter stenosis by invasive coronary angiography-quantitative coronary angiography). RESULTS: Hemodynamically obstructive CAD was present in 170/400 (42.5%) patients. Stand-alone summed stress score showed a sensitivity and specificity of 57% and 93%, respectively, while hyperemic MBF showed similar sensitivity (61%, P=0.57) but lower specificity (85%, P=0.008). With increased discrimination by receiver-operating characteristic curves (0.78 versus 0.85; P<0.001), combining summed stress score, MBF and MBF reserve showed the highest sensitivity of 77% but lower specificity of 74% (P<0.001 for both comparisons). Against anatomically severe CAD, all measures independently yielded high discrimination ≥0.90 with increased sensitivity and lower specificity by additional quantification. CONCLUSIONS: The inclusion of quantitative measurements to a RbPET read increases in the identification of obstructive CAD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481712.

Short-term effects of sacubitril/valsartan therapy on myocardial oxygen consumption and energetic efficiency of cardiac work in heart failure with reduced ejection fraction: A randomized controlled study.

AIMS: We sought to evaluate the mechanism of angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan therapy and compare it with a valsartan-only control group in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: The study was a phase IV, prospective, randomized, double-blind, parallel-group study in patients with New York Heart Association class II-III heart failure and left ventricular ejection fraction (LVEF) ≤35%. During a 6-week run-in period, all patients received valsartan therapy, which was up-titrated to the highest tolerated dose level (80 mg bid or 160 mg bid) and then randomized to either valsartan or sacubitril/valsartan. Myocardial oxygen consumption, energetic efficiency of cardiac work, cardiac and systemic haemodynamics were quantified using echocardiography and 11 C-acetate positron emission tomography before and after 6 weeks of therapy (on stable dose) in 55 patients (ARNI group: n = 27, mean age 63 ± 10 years, LVEF 29.2 ± 10.4%; and valsartan-only control group: n = 28, mean age 64 ± 8 years, LVEF 29.0 ± 7.3%; all p = NS). The energetic efficiency of cardiac work remained unchanged in both treatment arms. However, both diastolic (-4.5 mmHg; p = 0.026) and systolic blood pressure (-9.8 mmHg; p = 0.0007), myocardial perfusion (-0.054 ml/g/min; p = 0.045), and left ventricular mechanical work (-296; p = 0.038) decreased significantly in the ARNI group compared to the control group. Although myocardial oxygen consumption decreased in the ARNI group (-5.4%) compared with the run-in period and remained unchanged in the control group (+0.5%), the between-treatment group difference was not significant (p = 0.088). CONCLUSIONS: We found no differences in the energetic efficiency of cardiac work between ARNI and valsartan-only groups in HFrEF patients. However, ARNI appears to have haemodynamic and cardiac mechanical effects over valsartan in heart failure patients.

Imaging of Myocardial αvß3 Integrin Expression for Evaluation of Myocardial Injury After Acute Myocardial Infarction.

[68Ga]Ga-NODAGA-Arg-Gly-Asp (RGD) is a PET tracer targeting αvß3 integrin, which is upregulated during angiogenesis soon after acute myocardial infarction (AMI). We prospectively evaluated determinants of myocardial uptake of [68Ga]Ga-NODAGA-RGD and its associations with left ventricular (LV) function in patients after AMI. Methods: Myocardial blood flow and [68Ga]Ga-NODAGA-RGD uptake (60 min after injection) were evaluated by PET in 31 patients 7.7 ± 3.8 d after primary percutaneous coronary intervention for ST-elevation AMI. Transthoracic echocardiography of LV function was performed on the day of PET and at the 6-mo follow-up. Results: PET images showed increased uptake of [68Ga]Ga-NODAGA-RGD in the ischemic area at risk (AAR), predominantly in injured myocardial segments. The SUV in the segment with the highest uptake (SUVmax) in the ischemic AAR was higher than the SUVmean of the remote myocardium (0.73 ± 0.16 vs. 0.51 ± 0.11, P < 0.001). Multivariable predictors of [68Ga]Ga-NODAGA-RGD uptake in the AAR included high peak N-terminal pro-B-type natriuretic peptide (P < 0.001), low LV ejection fraction, low global longitudinal strain (P = 0.01), and low longitudinal strain in the AAR (P = 0.01). [68Ga]Ga-NODAGA-RGD uptake corrected for myocardial blood flow and perfusable tissue fraction in the AAR predicted improvement in global longitudinal strain at follow-up (P = 0.002), independent of peak troponin, N-terminal pro-B-type natriuretic peptide, and LV ejection fraction. Conclusion: [68Ga]Ga-NODAGA-RGD uptake shows increased αvß3 integrin expression in the ischemic AAR early after AMI that is associated with regional and global systolic dysfunction, as well as increased LV filling pressure. Increased [68Ga]Ga-NODAGA-RGD uptake predicts improvement of global LV function 6 mo after AMI.

Critical limb-threatening ischaemia and microvascular transformation: clinical implications.

BACKGROUND AND AIMS: Clinical management of critical limb-threatening ischaemia (CLTI) is focused on prevention and treatment of atherosclerotic arterial occlusions. The role of microvascular pathology in disease progression is still largely unspecified and more importantly not utilized for treatment. The aim of this explorative study was to characterize the role of the microvasculature in CLTI pathology. METHODS: Clinical high-resolution imaging of CLTI patients (n = 50) and muscle samples from amputated CLTI limbs (n = 40) were used to describe microvascular pathology of CLTI at the level of resting muscle blood flow and microvascular structure, respectively. Furthermore, a chronic, low arterial driving pressure-simulating ischaemia model in rabbits (n = 24) was used together with adenoviral vascular endothelial growth factor A gene transfers to study the effect of microvascular alterations on muscle outcome. RESULTS: Resting microvascular blood flow was not depleted but displayed decreased capillary transit time (P < .01) in CLTI muscles. Critical limb-threatening ischaemia muscle microvasculature also exhibited capillary enlargement (P < .001) and further arterialization along worsening of myofibre atrophy and detaching of capillaries from myofibres. Furthermore, CLTI-like capillary transformation was shown to worsen calf muscle force production (P < .05) and tissue outcome (P < .01) under chronic ischaemia in rabbits and in healthy, normal rabbit muscle. CONCLUSIONS: These findings depict a progressive, hypoxia-driven transformation of the microvasculature in CLTI muscles, which pathologically alters blood flow dynamics and aggravates tissue damage under low arterial driving pressure. Hypoxia-driven capillary enlargement can be highly important for CLTI outcomes and should therefore be considered in further development of diagnostics and treatment of CLTI.

Exercise electrocardiography for pre-test assessment of the likelihood of coronary artery disease.

OBJECTIVES: To develop a tool including exercise electrocardiography (ExECG) for patient-specific clinical likelihood estimation of patients with suspected obstructive coronary artery disease (CAD). METHODS: An ExECG-weighted clinical likelihood (ExECG-CL) model was developed in a training cohort of patients with suspected obstructive CAD undergoing ExECG. Next, the ExECG-CL model was applied in a CAD validation cohort undergoing ExECG and clinically driven invasive coronary angiography and a prognosis validation cohort and compared with the risk factor-weighted clinical likelihood (RF-CL) model for obstructive CAD discrimination and prognostication, respectively.In the CAD validation cohort, obstructive CAD was defined as >50% diameter stenosis on invasive coronary angiography. For prognosis, the endpoint was non-fatal myocardial infarction and death. RESULTS: The training cohort consisted of 1214 patients (mean age 57 years, 57% males). In the CAD (N=408; mean age 55 years, 53% males) and prognosis validation (N=3283; mean age 57 years, 57% males) cohorts, 11.8% patients had obstructive CAD and 4.4% met the endpoint. In the CAD validation cohort, discrimination of obstructive CAD was similar between the ExECG-CL and RF-CL models: area under the receiver-operating characteristic curves 83.1% (95% CIs 77.5% to 88.7%) versus 80.7% (95% CI 74.6% to 86.8%), p=0.14. In the ExECG-CL model, more patients had very low (≤5%) clinical likelihood of obstructive CAD compared with the RF-CL (42.2% vs 36.0%, p<0.01) where obstructive CAD prevalence and event risk remained low. CONCLUSIONS: ExECG incorporated into a clinical likelihood model improves reclassification of patients to a very low clinical likelihood group with very low prevalence of obstructive CAD and favourable prognosis.

Incremental prognostic value of downstream positron emission tomography perfusion imaging after coronary computed tomography angiography: a study using machine learning.

AIMS: To evaluate the incremental value of positron emission tomography (PET) myocardial perfusion imaging (MPI) over coronary computed tomography angiography (CCTA) in predicting short- and long-term outcome using machine learning (ML) approaches. METHODS AND RESULTS: A total of 2411 patients with clinically suspected coronary artery disease (CAD) underwent CCTA, out of whom 891 patients were admitted to downstream PET MPI for haemodynamic evaluation of obstructive coronary stenosis. Two sets of Extreme Gradient Boosting (XGBoost) ML models were trained, one with all the clinical and imaging variables (including PET) and the other with only clinical and CCTA-based variables. Difference in the performance of the two sets was analysed by means of area under the receiver operating characteristic curve (AUC). After the removal of incomplete data entries, 2284 patients remained for further analysis. During the 8-year follow-up, 210 adverse events occurred including 59 myocardial infarctions, 35 unstable angina pectoris, and 116 deaths. The PET MPI data improved the outcome prediction over CCTA during the first 4 years of the observation time and the highest AUC was at the observation time of Year 1 (0.82, 95% confidence interval 0.804-0.827). After that, there was no significant incremental prognostic value by PET MPI. CONCLUSION: PET MPI variables improve the prediction of adverse events beyond CCTA imaging alone for the first 4 years of follow-up. This illustrates the complementary nature of anatomic and functional information in predicting the outcome of patients with suspected CAD.

Prognostic Value of a Novel Artificial Intelligence-Based Coronary Computed Tomography Angiography-Derived Ischemia Algorithm for Patients with Suspected Coronary Artery Disease.

AIMS: Coronary computed tomography angiography (CTA) imaging is used to diagnose patients with suspected coronary artery disease (CAD). A novel artificial-intelligence-guided quantitative computed tomography ischemia algorithm (AI-QCTischemia) aims to identify myocardial ischemia directly from CTA images and may be helpful to improve risk stratification. The aims were 1) the prognostic value of AI-QCTischemia among symptomatic patients with suspected CAD entering diagnostic imaging with coronary CTA, and 2) the prognostic value of AI-QCTischemia separately among patients with no/non-obstructive CAD (≤50% visual diameter stenosis) and obstructive CAD (>50% visual diameter stenosis). METHODS AND RESULTS: For this cohort study, AI-QCTischemia was calculated by blinded analysts among patients with suspected CAD undergoing coronary CTA. The primary endpoint was the composite of death, myocardial infarction (MI), or unstable angina pectoris (uAP) (median follow-up 6.9 years). 1880/2271 (83%) patients were analyzable by AI-QCTischemia. Patients with an abnormal AI-QCTischemia result (n = 509/1880) vs. patients with a normal AI-QCTischemia result (n = 1371/1880) had significantly higher crude and adjusted rates of the primary endpoint (HRadj 1.96,95% CI 1.46-2.63, p < 0.001; covariates: age/sex/hypertension/diabetes/smoking/typical angina). An abnormal AI-QCTischemia result was associated with significantly higher crude and adjusted rates of the primary endpoint among patients with no/non-obstructive CAD (n = 1373/1847) (HRadj 1.81,95% CI 1.09-3.00, p = 0.022), but not among those with obstructive CAD (n = 474/1847) (HRadj 1.26,95% CI 0.75-2.12, p = 0.386) (p-interaction = 0.032). CONCLUSION: Among patients with suspected CAD, an abnormal AI-QCTischemia result was associated with a 2-fold increased adjusted rate of long-term death, MI, or uAP. AI-QCTischemia may be useful to improve risk stratification, especially among patients with no/non-obstructive CAD on coronary CTA.

Screening for Coronary Artery Disease in Patients with Diabetes.

PURPOSE OF REVIEW: The study aims to describe methods for detecting subclinical coronary artery disease (CAD) and their potential implications in asymptomatic patients with diabetes. RECENT FINDINGS: Imaging tools can assess non-invasively the presence and severity of CAD, based on myocardial ischemia, coronary artery calcium score, and coronary computed tomography coronary angiography. Subclinical CAD is common in the general population ageing 50 to 64 years with any coronary atherosclerosis present in 42.1% and obstructive CAD in 5.2%. In patients with diabetes, an even higher prevalence has been noted. The presence of myocardial ischemia, obstructive CAD, and the extent of coronary atherosclerosis provide powerful risk stratification regarding the risk of cardiovascular events. However, randomized trials evaluating systematic screening in the general population or patients with diabetes have demonstrated only moderate impact on management and no significant impact on patient outcomes. Despite providing improved risk stratification, systematic screening of CAD is not recommended in patients with diabetes.