Blankstein, Ron

BACKGROUND: Although the prognostic utility of positron emission tomography (PET) myocardial flow reserve (MFR) is well established, emerging data suggest that reduced subendocardial flows also predict adverse outcomes. However, the incremental value of subendocardial MFR (MFR SE ) beyond transmural MFR (MFR TM ) remains unclear. METHODS: We studied patients in a multicenter PET registry with normal perfusion on stress/rest Rb-82 PET, excluding those with a previous history of coronary artery bypass surgery, heart transplantation, or left ventricular ejection fraction <40%. The optimal MFR SE cutoff for predicting major adverse cardiovascular events (MACEs; death, myocardial infarction [MI], revascularization, or heart failure [HF] hospitalization) was determined using Youden’s index. Patients were stratified into 3 groups: concordant-normal (MFR TM ≥2.0; MFR SE ≥2.1), discordant (low-MFR SE , normal MFR TM ), and abnormal MFR TM . Clinical outcomes were compared by MFR groups. RESULTS: Among 6603 patients (normal N=4103; discordant N=885; abnormal N=1615) the mean age was 66.3±12.4 years, and 54% were women. Compared with the concordant-normal group, patients with discordant low-MFR SE were older and more likely to have hypertension, diabetes, peripheral artery disease, and previous percutaneous coronary intervention. The median MFR TM for normal, discordant, and abnormal groups were 2.86, 2.15, and 1.72, respectively. Over a median follow-up of 4.9 years, 1661 MACE events occurred. Discordant low-MFR SE patients had a higher risk of MACE (hazard ratio [HR], 1.41; 95% CI, 1.22–1.64) and all-cause mortality (HR, 1.36; 95% CI, 1.14–1.61) compared with concordant-normal patients. The discordant group had an intermediate absolute risk of MACE, with an adjusted annualized event rate of 5.79% (95% CI, 5.10–6.49) compared with 3.99% (95% CI, 3.67–4.30; P <0.001) in the concordant-normal group and 8.35% (95% CI, 7.71–9.00; P <0.001) in the abnormal MFR TM group. CONCLUSIONS: Subendocardial MFR reveals clinically meaningful risk heterogeneity among patients with preserved transmural flow reserve, helping refine risk stratification beyond traditional PET metrics.

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 Aims Left bundle branch block (LBBB) is associated with mechanical dyssynchrony, heterogeneous perfusion, and adverse left ventricular (LV) remodeling. 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 remodeling and function in patients with and without LBBB. Methods and results We retrospectively analyzed 233 patients with isolated LBBB and 932 matched controls who underwent PET myocardial perfusion imaging, assessing mechanical dyssynchrony (phase entropy), myocardial blood flow (MBF), coronary vascular resistance (CVR), myocardial flow reserve (MFR), septal-to-lateral MBF ratio (SLR) for perfusion heterogeneity, LV volumes, and ejection fraction (EF). Compared to controls, patients with LBBB had greater dyssynchrony (56% vs. 40%), larger LV volumes, and lower EF (54% vs. 67%) (all p <0.001), and had higher stress CVR (37 vs. 34 mmHg/mL·min⁻¹·g⁻¹), lower stress MBF (2.4 vs. 2.6 mL/min/g), reduced MFR (2.4 vs. 2.6), and lower SLR (0.95 vs. 1.00) (all p <0.05). Among patients with dyssynchrony, SLR<1.0 identified those with more adverse remodeling. In multivariable regression, phase entropy and SLR independently predicted LV volumes and EF, with adverse effects of SLR reduction amplified in LBBB (interaction p <0.01). In the Cox proportional hazards analysis, phase entropy (HR:1.02, p =0.01), MFR (HR:0.62, p <0.001), and LVEF (HR:0.97, p <0.001) were independently associated with mortality and heart failure hospitalization, whereas LBBB was not. Conclusions Mechanical dyssynchrony and perfusion heterogeneity independently predict adverse LV remodeling, irrespective of LBBB. Integrated imaging enhances 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.

Innovations in cardiac imaging have fundamentally advanced the understanding and treatment of cardiovascular disease. These advances in noninvasive cardiac imaging have also expanded the role of the cardiac imager and dramatically increased the demand for imagers who are cross-trained in multiple modalities. However, we hypothesize that there is significant variation in the availability of cardiac imaging expertise and a disparity in the adoption of advanced imaging technologies across the United States. To evaluate this, we have brought together the leaders of cardiovascular imaging societies, imaging trainees, as well as collaborated with national imaging accreditation commissions and imaging certification boards to assess the state of cardiac imaging and the diversity of the imaging workforce in the United States. Aggregate data confirm the presence of critical gaps, such as limited access to imaging and imaging expertise in rural communities, as well as disparities in the imaging workforce, notably among women and underrepresented minorities. Based on these results, we have proposed solutions to promote and maintain a robust and diverse community of cardiac imagers and improve equity and accessibility for cardiac imaging technologies.

Abstract Introduction Sarcoidosis is a multisystem disorder characterized by an autoimmune response to an unidentified antigen in genetically susceptible persons. Despite clinically detectable cardiac manifestations of sarcoidosis occurring in approximately 5% of patients, recent studies have revealed cardiac involvement to be at 25% in patients with the disease, highlighting the fact that cardiac involvement in sarcoidosis is much more common than was once thought to be. Purpose With cardiac involvement in sarcoidosis being increasingly recognized due to the availability of advanced cardiac imaging, large scale data regarding in-hospital mortality and clinical outcomes of patients admitted with cardiac sarcoidosis (CS) is lacking. Our study aimed to fill this knowledge gap by analyzing demographics and in-hospital outcomes of a large cohort of patients admitted with CS across the United States (US). Methods We analyzed data from the national inpatient sample (NIS) database between October 2015 to December 2018 to identify patients who had been admitted with primary and secondary diagnoses of CS. The NIS is an administrative database sponsored by the Agency for Healthcare Research and Quality consisting of data from 46 participating states, representing more than 95% of the US population and providing nationwide estimates of over 35 million hospitalizations annually. The NIS uses de-identified hospital discharges as samples and hence no additional ethical committee approval was required. International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) code D86.85 was used to identify hospitalizations with CS in patients aged 18 years or older. SAS 9.4 (SAS Institute, Inc, Cary, NC) was used for statistical analyses. Results A total of 4275 patients were included in the analysis. A higher proportion of patients with CS were females (62.43% vs. 37.57%). Hypertension was the most common comorbidity (43.99%), followed by hyperlipidemia (39.21%) and chronic kidney disease (26.95%). All-cause in-hospital mortality was 2.57%. Atrial fibrillation (AF) was the most common arrhythmia (28.12%), followed by ventricular tachycardia (VT) (22.52%). About 16% of CS patients underwent implantable cardioverter-defibrillator (ICD) implantation during hospital stay. About 42% of patients had concurrent heart failure, out of whom 33.84% had heart failure with reduced ejection fraction (HFrEF). Mean length of hospital stay was 5 days (3–8 days), and the mean cost of hospitalization was $14,177 ($7,121–35,993). Conclusion Given the low prevalence of CS, most of the available studies have been retrospective in nature, based on small sample sizes. Despite being retrospective and cross-sectional, our study has the advantage of being based on a nationally representative sample population, providing key formation on the demographics and in-hospital outcomes of patients with CS. Funding Acknowledgement Type of funding sources: None.

Cardiac sarcoidosis is a component of an often multiorgan granulomatous disease of still uncertain cause. It is being recognized with increasing frequency, mainly as the result of heightened awareness and new diagnostic tests, specifically cardiac magnetic resonance imaging and 18 F-fluorodeoxyglucose positron emission tomography scans. The purpose of this case-based review is to highlight the potentially life-saving importance of making the early diagnosis of cardiac sarcoidosis using these new tools and to provide a framework for the optimal care of patients with this disease. We will review disease mechanisms as currently understood, associated arrhythmias including conduction abnormalities, and atrial and ventricular tachyarrhythmias, guideline-directed diagnostic criteria, screening of patients with extracardiac sarcoidosis, and the use of pacemakers and defibrillators in this setting. Treatment options, including those related to heart failure, and those which may help clarify disease mechanisms are included.

Abstract This joint position paper illustrates the role and the correct use of echocardiography, radionuclide imaging with 18F-fluorodeoxyglucose positron emission tomography, radionuclide myocardial perfusion imaging and cardiovascular magnetic resonance imaging for the evaluation and management of patients with known or suspected cardiac sarcoidosis. This position paper will aid in standardizing imaging for cardiac sarcoidosis and may facilitate clinical trials and pooling of multi-centre data on cardiac sarcoidosis. Proposed flow charts for the work up and management of cardiac sarcoidosis are included.