Determining Hemodynamically Significant Coronary Artery Disease: Patient-Specific Cutoffs in Quantitative Myocardial Blood Flow Using [15O]H2O PET Imaging.

Currently, cutoffs of quantitative [15O]H2O PET to detect fractional flow reserve (FFR)-defined coronary artery disease (CAD) were derived from a single cohort that included patients without prior CAD. However, prior CAD, sex, and age can influence myocardial blood flow (MBF). Therefore, the present study determined the influence of prior CAD, sex, and age on optimal cutoffs of hyperemic MBF (hMBF) and coronary flow reserve (CFR) and evaluated whether cutoff optimization enhanced diagnostic performance of quantitative [15O]H2O PET against an FFR reference standard. Methods: Patients with chronic coronary symptoms underwent [15O]H2O PET and invasive coronary angiography with FFR. Optimal cutoffs for patients with and without prior CAD and subpopulations based on sex and age were determined. Results: This multicenter study included 560 patients. Optimal cutoffs were similar for patients with (n = 186) and without prior CAD (hMBF, 2.3 vs. 2.3 mL·min-1·g-1; CFR, 2.7 vs. 2.6). Females (n = 190) had higher hMBF cutoffs than males (2.8 vs. 2.3 mL·min-1·g-1), whereas CFRs were comparable (2.6 vs. 2.7). However, female sex-specific hMBF cutoff implementation decreased diagnostic accuracy as compared with the cutoff of 2.3 mL·min-1·g-1 (72% vs. 82%, P < 0.001). Patients aged more than 70 y (n = 79) had lower hMBF (1.7 mL·min-1·g-1) and CFR (2.3) cutoffs than did patients aged 50 y or less, 51-60 y, and 61-70 y (hMBF, 2.3-2.4 mL·min-1·g-1; CFR, 2.7). Age-specific cutoffs in patients aged more than 70 y yielded comparable accuracy to the previously established cutoffs (hMBF, 72% vs. 76%, P = 0.664; CFR, 80% vs. 75%, P = 0.289). Conclusion: Patients with and without prior CAD had similar [15O]H2O PET cutoffs for detecting FFR-defined significant CAD. Stratifying patients according to sex and age led to different optimal cutoffs; however, these values did not translate into an increased overall accuracy as compared with previously established thresholds for MBF.

Natural History of Myocardial αvß3 Integrin Expression After Acute Myocardial Infarction: Correlation with Changes in Myocardial Blood Flow.

Angiogenesis is an essential part of the cardiac repair process after myocardial infarction, but its spatiotemporal dynamics remain to be fully deciphered.68Ga-NODAGA-Arg-Gly-Asp (RGD) is a PET tracer targeting αvß3 integrin expression, which is a marker of angiogenesis. Methods: In this prospective single-center trial, we aimed to monitor angiogenesis through myocardial integrin αvß3 expression in 20 patients with ST-segment elevation myocardial infarction (STEMI). In addition, the correlations between the expression levels of myocardial αvß3 integrin and the subsequent changes in 82Rb PET/CT parameters, including rest and stress myocardial blood flow (MBF), myocardial flow reserve (MFR), and wall motion abnormalities, were assessed. The patients underwent 68Ga-NODAGA-RGD PET/CT and rest and stress 82Rb-PET/CT at 1 wk, 1 mo, and 3 mo after STEMI. To assess 68Ga-NODAGA-RGD uptake, the summed rest 82Rb and 68Ga-NODAGA-RGD images were coregistered, and segmental SUVs were calculated (RGD SUV). Results: At 1 wk after STEMI, 19 participants (95%) presented increased 68Ga-NODAGA-RGD uptake in the infarcted myocardium. Seventeen participants completed the full imaging series. The values of the RGD SUV in the infarcted myocardium were stable 1 mo after STEMI (1 wk vs. 1 mo, 1.47 g/mL [interquartile range (IQR), 1.37-1.64 g/mL] vs. 1.47 g/mL [IQR, 1.30-1.66 g/mL]; P = 0.9), followed by a significant partial decrease at 3 mo (1.32 g/mL [IQR, 1.12-1.71 g/mL]; P = 0.011 vs. 1 wk and 0.018 vs. 1 mo). In segment-based analysis, positive correlations were found between RGD SUV at 1 wk and the subsequent changes in stress MBF (Spearman ρ: r = 0.17, P = 0.0033) and MFR (Spearman ρ: r = 0.31, P < 0.0001) at 1 mo. A negative correlation was found between RGD SUV at 1 wk and the subsequent changes in wall motion abnormalities at 3 mo (Spearman ρ: r = -0.12, P = 0.035). Conclusion: The present study found that αvß3 integrin expression is significantly increased in the infarcted myocardium 1 wk after STEMI. This expression remains stable after 1 mo and partially decreases after 3 mo. Initial αvß3 integrin expression at 1 wk is significantly weakly correlated with subsequent improvements in stress MBF, MFR, and wall motion analysis.

Prognostic value of a novel artificial intelligence-based coronary CTA-derived ischemia algorithm among patients with normal or abnormal myocardial perfusion.

BACKGROUND: Among patients with obstructive coronary artery disease (CAD) on coronary computed tomography angiography (CTA), downstream positron emission tomography (PET) perfusion imaging can be performed to assess the presence of myocardial ischemia. A novel artificial-intelligence-guided quantitative computed tomography ischemia algorithm (AI-QCTischemia) aims to predict ischemia directly from coronary CTA images. We aimed to study the prognostic value of AI-QCTischemia among patients with obstructive CAD on coronary CTA and normal or abnormal downstream PET perfusion. METHODS: AI-QCTischemia was calculated by blinded analysts among patients from the retrospective coronary CTA cohort at Turku University Hospital, Finland, with obstructive CAD on initial visual reading (diameter stenosis ≥50%) being referred for downstream 15O-H2O-PET adenosine stress perfusion imaging. All coronary arteries with their side branches were assessed by AI-QCTischemia. Absolute stress myocardial blood flow ≤2.3 â€‹ml/g/min in ≥2 adjacent segments was considered abnormal. The primary endpoint was death, myocardial infarction, or unstable angina pectoris. The median follow-up was 6.2 [IQR 4.4-8.3] years. RESULTS: 662 of 768 (86%) patients had conclusive AI-QCTischemia result. In patients with normal 15O-H2O-PET perfusion, an abnormal AI-QCTischemia result (n â€‹= â€‹147/331) vs. normal AI-QCTischemia result (n â€‹= â€‹184/331) was associated with a significantly higher crude and adjusted rates of the primary endpoint (adjusted HR 2.47, 95% CI 1.17-5.21, p â€‹= â€‹0.018). This did not pertain to patients with abnormal 15O-H2O-PET perfusion (abnormal AI-QCTischemia result (n â€‹= â€‹269/331) vs. normal AI-QCTischemia result (n â€‹= â€‹62/331); adjusted HR 1.09, 95% CI 0.58-2.02, p â€‹= â€‹0.794) (p-interaction â€‹= â€‹0.039). CONCLUSION: Among patients with obstructive CAD on coronary CTA referred for downstream 15O-H2O-PET perfusion imaging, AI-QCTischemia showed incremental prognostic value among patients with preserved perfusion by 15O-H2O-PET imaging, but not among those with reduced perfusion.

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]).

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.

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.

Macrophage mannose receptor CD206 targeting of fluoride-18 labeled mannosylated dextran: A validation study in mice.

PURPOSE: Aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated mannosylated dextran derivative (Al[18F]F-NOTA-D10CM) is a new tracer for PET imaging. We report here on in vitro and in vivo validation of the tracer's ability to target the macrophage mannose receptor CD206. METHODS: First, the uptake of intravenously (i.v.) administered Al[18F]F-NOTA-D10CM was compared between wild-type (WT) and CD206-/- knockout (KO) mice. C57BL/6N mice were injected with complete Freund's adjuvant (CFA) in the left hind leg and the uptake of Al[18F]F-NOTA-D10CM after i.v. or intradermal (i.d.) injection was studied at 5 and 14 days after CFA induction of inflammation. Healthy C57BL/6N mice were studied as controls. Mice underwent PET/CT on consecutive days with [18F]FDG, i.v. Al[18F]F-NOTA-D10CM, and i.d. Al[18F]F-NOTA-D10CM. After the last imaging, Al[18F]F-NOTA-D10CM was i.v. injected for an ex vivo biodistribution study and autoradiography of inflamed tissues. Blood plasma samples were analyzed using high-performance liquid chromatography. To evaluate the specificity of Al[18F]F-NOTA-D10CM binding, an in vitro competitive displacement study was performed on inflamed tissue sections using autoradiography. CD206 expression was assessed by immunohistochemical staining. RESULTS: Compared with WT mice, the uptake of Al[18F]F-NOTA-D10CM was significantly lower in several CD206-/- KO mice tissues, including liver (SUV 8.21 ± 2.51 vs. 1.06 ± 0.16, P < 0.001) and bone marrow (SUV 1.63 ± 0.37 vs. 0.22 ± 0.05, P < 0.0001). The uptake of i.v. injected Al[18F]F-NOTA-D10CM was significantly higher in inflamed ankle joint (SUV 0.48 ± 0.13 vs. 0.18 ± 0.05, P < 0.0001) and inflamed foot pad skin (SUV 0.41 ± 0.10 vs. 0.04 ± 0.01, P < 0.0001) than in the corresponding tissues in healthy mice. The i.d.-injected Al[18F]F-NOTA-D10CM revealed differences between CFA-induced lymph node activation and lymph nodes in healthy mice. Ex vivo γ-counting, autoradiography, and immunohistochemistry supported the results, and a decrease of ~ 80% in the binding of Al[18F]F-NOTA-D10CM in the displacement study with excess NOTA-D10CM confirmed that tracer binding was specific. At 60 min after i.v. injection, an average 96.70% of plasma radioactivity was derived from intact Al[18F]F-NOTA-D10CM, indicating good in vivo stability. The uptake of Al[18F]F-NOTA-D10CM into inflamed tissues was positively associated with the area percentage of CD206-positive staining. CONCLUSION: The uptake of mannosylated dextran derivative Al[18F]F-NOTA-D10CM correlated with CD206 expression and the tracer appears promising for inflammation imaging.

PET imaging of unruptured intracranial aneurysm inflammation (PET-IA) study: a feasibility study protocol.

INTRODUCTION: Positron emission tomography (PET) imaging can be used to evaluate arterial wall inflammation in extracranial vascular diseases. However, the application of PET imaging in unruptured intracranial aneurysms (UIA) remains unexplored. Our objective is to investigate feasibility of PET imaging using 18F-FDG and 68Ga-DOTANOC tracers to evaluate arterial wall inflammation in UIA. METHODS AND ANALYSIS: This PET imaging feasibility study will enrol patients scheduled for surgical treatment of UIA. The study subjects will undergo PET imaging of the intracranial arteries within 1 month before planned surgery. The imaging protocol includes 18F-FDG PET MRI, MRA with gadolinium enhancement, and 68Ga-DOTANOC PET CT. The study will also involve preoperative blood samples, intraoperative cerebrospinal fluid (CSF) samples, and aneurysm sac biopsy. Planned sample size is at least 18 patients. Primary outcome is uptake of 18F-FDG or 68Ga-DOTANOC in intracranial arterial aneurysms compared with contralateral normal vessel as maximum standardised uptake value or target-to-blood pool ratio and correlation of uptake of 18F-FDG or 68Ga-DOTANOC to aneurysm histological findings. Secondary outcomes include estimating the correlations between uptake of 18F-FDG or 68Ga-DOTANOC and histological findings with blood and CSF miRNA-levels, arterial wall enhancement in gadolinium enhanced MRA, aneurysm size and shape, smoking, hypertension, and location of the aneurysm. ETHICS AND DISSEMINATION: This study is approved by the Human Research Ethics Committee of the Hospital District of Southwest Finland, Finnish Medicines Agency Fimea, and Turku University Hospital. Findings will be disseminated through peer-reviewed journal articles and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04715503.

Total-Body PET/CT Applications in Cardiovascular Diseases: A Perspective Document of the SNMMI Cardiovascular Council.

Digital PET/CT systems with a long axial field of view have become available and are emerging as the current state of the art. These new camera systems provide wider anatomic coverage, leading to major increases in system sensitivity. Preliminary results have demonstrated improvements in image quality and quantification, as well as substantial advantages in tracer kinetic modeling from dynamic imaging. These systems also potentially allow for low-dose examinations and major reductions in acquisition time. Thereby, they hold great promise to improve PET-based interrogation of cardiac physiology and biology. Additionally, the whole-body coverage enables simultaneous assessment of multiple organs and the large vascular structures of the body, opening new opportunities for imaging systemic mechanisms, disorders, or treatments and their interactions with the cardiovascular system as a whole. The aim of this perspective document is to debate the potential applications, challenges, opportunities, and remaining challenges of applying PET/CT with a long axial field of view to the field of cardiovascular disease.

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.

External validation of a deep learning algorithm for automated echocardiographic strain measurements.

Aims: Echocardiographic strain imaging reflects myocardial deformation and is a sensitive measure of cardiac function and wall-motion abnormalities. Deep learning (DL) algorithms could automate the interpretation of echocardiographic strain imaging. Methods and results: We developed and trained an automated DL-based algorithm for left ventricular (LV) strain measurements in an internal dataset. Global longitudinal strain (GLS) was validated externally in (i) a real-world Taiwanese cohort of participants with and without heart failure (HF), (ii) a core-lab measured dataset from the multinational prevalence of microvascular dysfunction-HF and preserved ejection fraction (PROMIS-HFpEF) study, and regional strain in (iii) the HMC-QU-MI study of patients with suspected myocardial infarction. Outcomes included measures of agreement [bias, mean absolute difference (MAD), root-mean-squared-error (RMSE), and Pearson's correlation (R)] and area under the curve (AUC) to identify HF and regional wall-motion abnormalities. The DL workflow successfully analysed 3741 (89%) studies in the Taiwanese cohort, 176 (96%) in PROMIS-HFpEF, and 158 (98%) in HMC-QU-MI. Automated GLS showed good agreement with manual measurements (mean ± SD): -18.9 ± 4.5% vs. -18.2 ± 4.4%, respectively, bias 0.68 ± 2.52%, MAD 2.0 ± 1.67, RMSE = 2.61, R = 0.84 in the Taiwanese cohort; and -15.4 ± 4.1% vs. -15.9 ± 3.6%, respectively, bias -0.65 ± 2.71%, MAD 2.19 ± 1.71, RMSE = 2.78, R = 0.76 in PROMIS-HFpEF. In the Taiwanese cohort, automated GLS accurately identified patients with HF (AUC = 0.89 for total HF and AUC = 0.98 for HF with reduced ejection fraction). In HMC-QU-MI, automated regional strain identified regional wall-motion abnormalities with an average AUC = 0.80. Conclusion: DL algorithms can interpret echocardiographic strain images with similar accuracy as conventional measurements. These results highlight the potential of DL algorithms to democratize the use of cardiac strain measurements and reduce time-spent and costs for echo labs globally.

A systematic review for the evidence of recommendations and guidelines in hybrid nuclear cardiovascular imaging.

OBJECTIVES: This study aimed to evaluate the level of evidence of expert recommendations and guidelines for clinical indications and procedurals in hybrid nuclear cardiovascular imaging. METHODS: From inception to August 2023, a PubMed literature analysis of the latest version of guidelines for clinical hybrid cardiovascular imaging techniques including SPECT(/CT), PET(/CT), and PET(/MRI) was performed in two categories: (1) for clinical indications for all-in primary diagnosis; subgroup in prognosis and therapy evaluation; and for (2) imaging procedurals. We surveyed to what degree these followed a standard methodology to collect the data and provide levels of evidence, and for which topic systematic review evidence was executed. RESULTS: A total of 76 guidelines, published between 2013 and 2023, were included. The evidence of guidelines was based on systematic reviews in 7.9% of cases, non-systematic reviews in 47.4% of cases, a mix of systematic and non-systematic reviews in 19.7%, and 25% of guidelines did not report any evidence. Search strategy was reported in 36.8% of cases. Strengths of recommendation were clearly reported in 25% of guidelines. The notion of external review was explicitly reported in 23.7% of cases. Finally, the support of a methodologist was reported in 11.8% of the included guidelines. CONCLUSION: The use of evidence procedures for developing for evidence-based cardiovascular hybrid imaging recommendations and guidelines is currently suboptimal, highlighting the need for more standardized methodological procedures.

Myeloperoxidase Inhibition in Heart Failure With Preserved or Mildly Reduced Ejection Fraction: SATELLITE Trial Results.

BACKGROUND: Inflammation is a key driver of heart failure with preserved left ventricular ejection fraction. AZD4831 inhibits extracellular myeloperoxidase, decreases inflammation, and improves microvascular function in preclinical disease models. METHODS AND RESULTS: In this double-blind phase 2a study (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure [SATELLITE]; NCT03756285), patients with symptomatic heart failure, left ventricular ejection fraction of ≥40%, and elevated B-type natriuretic peptides were randomized 2:1 to once-daily oral AZD4831 5 mg or placebo for 90 days. We aimed to assess target engagement (primary end point: myeloperoxidase specific activity) and safety of AZD4831. Owing to coronavirus disease 2019, the study was terminated early after randomizing 41 patients (median age 74.0 years, 53.7% male). Myeloperoxidase activity was decreased by more than 50% from baseline to day 30 and day 90 in the AZD4831 group, with a placebo-adjusted decreased of 75% (95% confidence interval, 48, 88, nominal P < .001). No improvements were noted in secondary or exploratory end points, apart from a trend in Kansas City Cardiomyopathy Questionnaire overall summary score. No deaths or treatment-related serious adverse events occurred. AZD4831 treatment-related adverse events were generalized maculopapular rash, pruritus, and diarrhea (all n = 1). CONCLUSIONS: AZD4831 inhibited myeloperoxidase and was well tolerated in patients with heart failure and left ventricular ejection fraction of 40% or greater. Efficacy findings were exploratory owing to early termination, but warrant further clinical investigation of AZD4831. LAY SUMMARY: Few treatments are available for patients with the forms of heart failure known as heart failure with preserved or mildly reduced ejection fraction. Current treatments do not target inflammation, which may play an important role in this condition. We tested a new drug called AZD4831 (mitiperstat), which decreases inflammation by inhibiting the enzyme myeloperoxidase. Among the 41 patients in our clinical trial, AZD4831 had a good safety profile and inhibited myeloperoxidase by the expected amount. Results mean we can conduct further trials to see whether AZD4831 decreases the symptoms of heart failure and improves patients' ability to participate in physical exercise.

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.

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.

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.

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.

Regional differences and coronary microvascular dysfunction in heart failure with preserved ejection fraction.

AIMS: In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF. METHODS AND RESULTS: We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction ≥40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS-HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine-induced vs. resting flow) < 2.5. Patients from Singapore had the lowest body mass index yet highest prevalence of hypertension, dyslipidaemia, and diabetes; patients from Finland and Sweden were oldest, with the most atrial fibrillation, chronic kidney disease, and high smoking rates; and those from United States were youngest and most obese. The prevalence of CMD was 88% in Finland, 80% in Singapore, 77% in Sweden, and 59% in the United States; however, non-significant after adjustment for age, sex, N-terminal pro-brain natriuretic peptide, smoking, left atrial reservoir strain, and atrial fibrillation. Associations between CMD and clinical characteristics did not differ based on region (interaction analysis). CONCLUSIONS: Despite regional differences in clinical characteristics, CMD was present in the majority of patients with HFpEF across different regions of the world with the lowest prevalence in the United States. This difference was explained by differences in patient characteristics. CMD could be a common therapeutic target across regions.

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.