Lemley, M A R K

Abstract Purpose Spatial distribution of coronary artery calcium (CAC) may provide additional prognostic value in patients undergoing SPECT and PET myocardial perfusion imaging (MPI). We aimed to automatically identify CAC in proximal segments from attenuation correction CT (CTAC) scans using artificial intelligence (AI) and to evaluate prognostic significance in two large international multicenter registries. Methods From hybrid MPI/CT imaging (N=43,099) across 15 sites, we included 4,552 most relevant patients with 1) no prior coronary artery disease; 2) AI-derived mild CAC scores (1-99); and 3) normal perfusion (stress total perfusion deficit <5%). The independent associations between AI-identified proximal CAC and major adverse cardiovascular events (MACE) and all-cause mortality (ACM) were evaluated using multivariable Cox regression, likelihood ratio test (LRT), and continuous net reclassification index (NRI). Results Among the patients with mild CAC and normal perfusion (mean age 65±12 years, 51% male), 1,730 (38%) had proximal CAC. Over 3.6 (inter-quartile interval 2.1, 5.2) years follow-up, 599 (13%) and 444 (10%) patients had MACE or ACM, respectively. Proximal CAC was associated with an increased risk of MACE (adjusted hazard ratio [HR] 1.24, 95% CI 1.03–1.48, P=0.02) and ACM (adjusted HR 1.25, 95% CI 1.01–1.53, P=0.04) after the adjustment of CAC score and density, clinical risk factors, and perfusion deficit. Proximal CAC improved the risk stratification of MACE (LRT P=0.02; NRI 12%) and ACM (LRT P=0.04; NRI 12%). Conclusion In patients with mild CAC and normal perfusion, AI detection of proximal CAC identified a higher-risk group for adverse outcomes, highlighting its prognostic utility. Graphical Abstract From patients who underwent hybrid myocardial perfusion imaging (MPI) from 15 sites, we analyzed those without prior coronary artery disease (CAD), mild coronary artery calcium (CAC) scores (1-99), and normal perfusion (stress total perfusion deficit <5%). A previously developed AI model was used to identify CAC lesions in proximal coronary segments on CT attenuation correction maps (CTAC). We evaluated associations with major adverse cardiovascular events (MACE) and all-cause mortality (ACM), showing risk stratification of proximal CAC and improvement by net reclassification index (NRI). CAC lesion color: green, left anterior descending artery (LAD) with left main artery; red, left circumflex artery (LCX); yellow, right coronary artery (RCA). Adjusted hazard ratios (HRs) are shown with 95% confidence intervals.

Abstract Aims Left bundle branch block (LBBB) is associated with mechanical dyssynchrony, heterogeneous perfusion, and adverse left ventricular (LV) remodelling. However, not all patients with LBBB develop cardiomyopathy, and dyssynchrony can occur without conduction defects. The role of microvascular dysfunction remains uncertain. We aimed to assess how mechanical dyssynchrony and perfusion heterogeneity relate to LV remodelling and function in patients with and without LBBB. Methods and results We analysed 233 patients with LBBB and 932 matched controls who underwent PET myocardial perfusion imaging, assessing mechanical dyssynchrony (phase entropy), LV volumes, and ejection fraction (EF); coronary vascular resistance (CVR), myocardial blood flow (MBF), myocardial flow reserve (MFR) as markers of microvascular function; and septal-to-lateral MBF ratio (SLR) as a measure of regional perfusion heterogeneity. Compared with controls, LBBB patients had greater dyssynchrony (56% vs. 40%), larger LV volumes, and lower EF (54% vs. 67%) (all P &lt; 0.001), as well as higher stress CVR (37 vs. 34 mmHg/mL·min−1·g−1), and lower MBF (2.4 vs. 2.6 mL/min/g), MFR (2.4 vs. 2.6), and SLR (0.95 vs. 1.00) (all P &lt; 0.05). Among patients with dyssynchrony, SLR &lt;1.0 identified greater remodelling. In multivariable regression, phase entropy and SLR independently predicted LV volumes and EF, with adverse effects of SLR reduction amplified in LBBB (interaction P &lt; 0.01). In Cox analysis, phase entropy (HR:1.02, P = 0.01), MFR (HR:0.62, P &lt; 0.001), and LVEF (HR:0.97, P &lt; 0.001) were independently associated with death or heart failure hospitalization, whereas LBBB was not. Conclusion Mechanical dyssynchrony and perfusion heterogeneity independently predict adverse LV remodelling, irrespective of LBBB. Integrated imaging improves cardiomyopathy stratification.

ABSTRACT Introduction Positron emission tomography (PET) myocardial flow reserve (MFR) is a robust indicator of coronary vascular health and a strong predictor of cardiovascular risk. Clinical guidelines typically use fixed MFR thresholds (e.g., <2.0) to stratify risk, yet this approach overlooks individual variation, particularly by age and sex. We aimed to establish age- and sex-adjusted MFR percentiles and to evaluate their prognostic and predictive performance for cardiovascular risk assessment, in comparison with conventional fixed-threshold MFR approach. Methods Using data from the REFINE PET registry (24,820 patients from 12 sites), we measured PET MFR and derived age- and sex-adjusted MFR reference percentiles using quantile regression in patients without known coronary artery disease. All patients were categorized into percentile-based quartile groups. The primary outcome for prognostic and prediction analyses was major adverse cardiovascular events (MACE), defined as all-cause mortality, myocardial infarction, or heart-failure hospitalization. Time-to-event associations were evaluated using covariate-adjusted survival models, with cumulative incidence and hazard ratios (HR) estimated at 1 and 5 years in the derivation dataset, an independent but similar validation dataset A, and a high-risk validation dataset B. Predictive performance for MACE was assessed using discrimination, calibration, and reclassification metrics, comparing percentile-based models with models using a fixed MFR threshold (<2.0). Results Among participants (mean age 66.5 years; median follow-up 3.6 years), age- and sex-adjusted MFR quartile groups were strong independent predictors of MACE, with adjusted HR increasing stepwise across quartile groups at both early and later follow-up. At 1 year, HR (95% CI) comparing the lowest to the highest quartile group were 4.06 (3.41–4.82) in the derivation cohort, 3.31 (2.32–4.71) in validation cohort A, and 2.35 (2.05–2.70) in validation cohort B. At 5 years, the corresponding HR were 2.18 (1.86–2.56), 1.77 (1.31–2.40), and 1.59 (1.36–1.86). Percentile-based models demonstrated consistently higher discrimination, better calibration, and greater net reclassification for MACE at both time points compared with fixed-threshold MFR models. Although 67.2% of patients had preserved MFR (>2.0), cardiovascular risk increased steadily across MFR percentiles even within this range. Conclusion Age- and sex-adjusted MFR percentiles provide a reliable, clinically actionable measure of vascular health, improving cardiovascular risk stratification by better capturing age- and sex-related heterogeneity in vascular risk. Compared with traditional fixed-threshold approaches, MFR percentiles demonstrate improved predictive performance for cardiovascular risk assessment across diverse patient populations. CLINICAL PERSPECTIVE What is new? In a large, multinational real-world registry of more than 24,000 patients undergoing PET MPI, we derived age- and sex-adjusted myocardial flow reserve (MFR) percentiles, establishing a lifespan-based reference framework with age-specific reference values. Age- and sex-adjusted MFR percentiles showed a strong, graded association with 1- and 5-year cardiovascular risk and demonstrated improved prognostic and predictive performance compared with fixed MFR thresholds and models without MFR across independent derivation and validation datasets, including a higher-risk cohort. Lower adjusted MFR percentiles were consistently associated with higher risk of major adverse cardiovascular events, including all-cause mortality, myocardial infarction, and heart-failure hospitalization. What are the clinical implications? Age- and sex-adjusted MFR percentiles provide a personalized, dynamic measure of coronary vascular health that improves cardiovascular risk stratification by accounting for age- and sex-related heterogeneity. A percentile-based approach may help clinicians better identify patients at elevated cardiovascular risk who may warrant closer monitoring or intensified preventive strategies, while avoiding unnecessary intervention in lower-risk individuals. By integrating macrovascular and microvascular dysfunction, age- and sex-adjusted MFR percentiles offer a clinically interpretable marker of vascular aging that may inform future research on aging biomarkers, novel therapeutics and cardiovascular risk assessment across the spectrum of atherosclerotic and microvascular disease.