COMPARATIVE EFFECTIVENESS OF PET AND SPECT MPI FOR PREDICTING RISK IN PATIENTS WITH CARDIOMETABOLIC DISEASE.

BACKGROUND: The epidemiology of coronary artery disease (CAD) has shifted, with increasing prevalence of cardiometabolic disease and decreasing findings of obstructive CAD on myocardial perfusion imaging (MPI). Coronary microvascular dysfunction (CMD), defined as impaired myocardial flow reserve (MFR) by positron emission tomography (PET), has emerged as a key mediator of risk. We aimed to assess whether PET MFR provides additive value for risk stratification of cardiometabolic disease patients compared with single-photon emission computed tomography (SPECT) MPI. METHODS: We retrospectively followed patients referred for PET, exercise SPECT, or pharmacologic SPECT MPI with cardiometabolic disease (obesity, diabetes, or chronic kidney disease) and without known CAD. We compared rates and hazards of composite MACE (annualized cardiac mortality or acute myocardial infarction) among propensity-matched PET and SPECT patients using Poisson and Cox regression. Normal SPECT was defined as a total perfusion deficit (TPD) <5% reflecting the absence of obstructive CAD. Normal PET was defined as TPD <5% plus MFR ≥2.0. RESULTS: Among 21,544 patients referred from 2006-2020, cardiometabolic disease was highly prevalent (PET: 2308 [67%], SPECT: 9984 [55%]) and higher among patients referred to PET (p <0.001). Obstructive CAD findings (TPD >5%) were uncommon (PET: 21% and SPECT 11%). Conversely, impaired MFR on PET (<2.0) was common (62%). In propensity-matched analysis over a median 6.4-year follow-up, normal PET identified low-risk (0.9%/year MACE) patients, and abnormal PET identified high-risk (4.2%/year MACE) patients with cardiometabolic disease; conversely, those with normal pharmacologic SPECT remained moderate-risk (1.6%/year, p<0.001 compared to normal PET). CONCLUSIONS: Cardiometabolic disease is common among patients referred for MPI and is associated with heterogenous level of risk. Compared with pharmacologic SPECT, PET with MFR can detect nonobstructive CAD including CMD and can more accurately discriminate low-risk from higher-risk individuals.

Lipoprotein(a) as a cardiovascular risk factor among patients with and without diabetes Mellitus: the Mass General Brigham Lp(a) Registry.

BACKGROUND: Diabetes mellitus (DM) and Lp(a) are well-established predictors of coronary artery disease (CAD) outcomes. However, their combined association remains poorly understood. OBJECTIVE: To investigate the relationship between elevated Lp(a) and DM with CAD outcomes. METHODS: Retrospective analysis of the MGB Lp(a) Registry involving patients ≥ 18 years who underwent Lp(a) measurements between 2000 and 2019. Exclusion criteria were severe kidney dysfunction, malignant neoplasms, and prior atherosclerotic cardiovascular disease (ASCVD). The primary outcome was a combination of cardiovascular death or myocardial infarction (MI). Elevated Lp(a) was defined as > 90th percentile (≥ 216 nmol/L). RESULTS: Among 6,238 patients who met the eligibility criteria, the median age was 54, 45% were women, and 12% had DM. Patients with DM were older, more frequently male, and had a higher prevalence of additional cardiovascular risk factors. Over a median follow-up of 12.9 years, patients with either DM or elevated Lp(a) experienced higher rates of the primary outcome. Notably, those with elevated Lp(a) had a higher incidence of the primary outcome regardless of their DM status. The annual event rates were as follows: No-DM and Lp(a) < 90th% - 0.6%; No-DM and Lp(a) > 90th% - 1.3%; DM and Lp(a) < 90th% - 1.9%; DM and Lp(a) > 90th% - 4.7% (p < 0.001). After adjusting for confounders, elevated Lp(a) remained independently associated with the primary outcome among both patients with DM (HR = 2.66 [95%CI: 1.55-4.58], p < 0.001) and those without DM (HR = 2.01 [95%CI: 1.48-2.74], p < 0.001). CONCLUSIONS: Elevated Lp(a) constitutes an independent and incremental risk factor for CAD outcomes in patients with and without DM.

Septal late enhancement by cardiac CT is associated with repeat ablation in nonischemic cardiomyopathy patients.

INTRODUCTION: Scar substrate in nonischemic cardiomyopathy (NICM) patients is often difficult to identify. Advances in cardiac imaging, especially using late iodine-enhanced computed tomography (LIE-CT), allow better characterization of scars giving rise to ventricular tachycardia (VT). Currently, there are limited data on clinical correlates of CT-derived scar substrates in NICM. We sought assess the relationship between scar location on LIE-CT and outcomes after radiofrequency catheter ablation (RFCA) in NICM patients with VT. METHODS: From 2020 to 2022, consecutive patients with NICM undergoing VT RFCA with integration of cardiac CT scar modeling (inHeart, Pessac, France) were included at two US tertiary care centers. The CT protocol included both arterial-enhanced imaging for anatomical modeling and LIE-CT for scar assessment. The distribution of substrate on CT was analyzed in relation to patient outcomes, with primary endpoints being VT recurrence and the need for repeat ablation procedure. RESULTS: Sixty patients were included (age 64 ± 12 years, 90% men). Over a median follow-up of 120 days (interquartile range [IQR]: 41-365), repeat ablation procedures were required in 32 (53%). VT recurrence occurred in 46 (77%), with a median time to recurrence of 40 days (IQR: 8-65). CT-derived total scar volume positively correlated with intrinsic QRS duration (r = .34, p = 0.008). Septal scar was found on CT in 34 (57%), and lateral scar in 40 (7%). On univariate logistic regression, septal scar was associated with increased odds of repeat ablation (odds ratio [OR]: 2.9 [1.0-8.4]; p = 0.046), while lateral scar was not (OR: 0.9 [0.3-2.7]; p = 0.855). Septal scar better predicted VT recurrence when compared to lateral scar, but neither were statistically significant (septal scar OR: 3.0 [0.9-10.7]; p = 0.078; lateral scar OR: 1.7 [0.5-5.9]; p = 0.391). CONCLUSION: In this tertiary care referral population, patients with NICM undergoing VT catheter ablation with septal LIE-CT have nearly threefold increased risk of need for repeat ablation.

Association of Lipoprotein (a) and Standard Modifiable Cardiovascular Risk Factors With Incident Myocardial Infarction: The Mass General Brigham Lp(a) Registry.

BACKGROUND: Lipoprotein (a) [Lp(a)] is a robust predictor of coronary heart disease outcomes, with targeted therapies currently under investigation. We aimed to evaluate the association of high Lp(a) with standard modifiable risk factors (SMuRFs) for incident first acute myocardial infarction (AMI). METHODS AND RESULTS: This retrospective study used the Mass General Brigham Lp(a) Registry, which included patients aged ≥18 years with an Lp(a) measurement between 2000 and 2019. Exclusion criteria were severe kidney dysfunction, malignant neoplasm, and prior known atherosclerotic cardiovascular disease. Diabetes, dyslipidemia, hypertension, and smoking were considered SMuRFs. High Lp(a) was defined as >90th percentile, and low Lp(a) was defined as <50th percentile. The primary outcome was fatal or nonfatal AMI. A combination of natural language processing algorithms, International Classification of Diseases (ICD) codes, and laboratory data was used to identify the outcome and covariates. A total of 6238 patients met the eligibility criteria. The median age was 54 (interquartile range, 43-65) years, and 45% were women. Overall, 23.7% had no SMuRFs, and 17.8% had ≥3 SMuRFs. Over a median follow-up of 8.8 (interquartile range, 4.2-12.8) years, the incidence of AMI increased gradually, with higher number of SMuRFs among patients with high (log-rank P=0.031) and low Lp(a) (log-rank P<0.001). Across all SMuRF subgroups, the incidence of AMI was significantly higher for patients with high Lp(a) versus low Lp(a). The risk of high Lp(a) was similar to having 2 SMuRFs. Following adjustment for confounders and number of SMuRFs, high Lp(a) remained significantly associated with the primary outcome (hazard ratio, 2.9 [95% CI, 2.0-4.3]; P<0.001). CONCLUSIONS: Among patients with no prior atherosclerotic cardiovascular disease, high Lp(a) is associated with significantly higher risk for first AMI regardless of the number of SMuRFs.

Prognostic value of myocardial flow reserve vs corrected myocardial flow reserve in patients without obstructive coronary artery disease.

BACKGROUND: Myocardial flow reserve (MFR) by positron emission tomography (PET) is a validated measure of cardiovascular risk. Elevated resting rate pressure product (RPP = heart rate x systolic blood pressure) can cause high resting myocardial blood flow (MBF), resulting in reduced MFR despite normal/near-normal peak stress MBF. When resting MBF is high, it is not known if RPP-corrected MFR (MFRcorrected) helps reclassify CV risk. We aimed to study this question in patients without obstructive coronary artery disease (CAD). METHODS: We retrospectively studied patients referred for rest/stress cardiac PET at our center from 2006 to 2020. Patients with abnormal perfusion (summed stress score >3) or prior coronary artery bypass grafting (CABG) were excluded. MFRcorrected was defined as stress MBF/corrected rest MBF where corrected rest MBF = rest MBF x 10,000/RPP. The primary outcome was major cardiovascular events (MACE): cardiovascular death or myocardial infarction. Associations of MFR and MFRcorrected with MACE were assessed using unadjusted and adjusted Cox regression. RESULTS: 3276 patients were followed for a median of 7 (IQR 3-12) years. 1685 patients (51%) had MFR <2.0, and of those 366 (22%) had an MFR ≥2.0 after RPP correction. MFR <2.0 was associated with an increased absolute risk of MACE (HR 2.24 [1.79-2.81], P < 0.0001). Among patients with MFR <2.0, the risk of MACE was not statistically different between patients with an MFRcorrected ≥2.0 compared with those with MFRcorrected <2.0 (1.9% vs 2.3% MACE/year, HR 0.84 [0.63-1.13], P = 0.26) even after adjustment for confounders (P = 0.66). CONCLUSIONS: In patients without overt obstructive CAD and MFR< 2.0, there was no significant difference in cardiovascular risk between patients with discordant (≥2.0) and concordant (<2) MFR following RPP correction. This suggests that RPP-corrected MFR may not consistently provide accurate risk stratification in patients with normal perfusion and MFR <2.0. Stress MBF and uncorrected MFR should be reported to more reliably convey cardiovascular risk beyond perfusion results.

Coronary Microvascular Function Following Severe Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. METHODS: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging. RESULTS: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (ß, -0.67 [95% CI, -1.21 to -0.13]; P=0.016), lower stress myocardial blood flow (ß, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; P=0.001), and higher stress coronary vascular resistance (ß, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P=0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow (r=0.71; P<0.001), independent of hemodynamics. CONCLUSIONS: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.

Coronary Microvascular Function Following Severe Preeclampsia.

Background: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating pro- and anti-angiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. Methods: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography (PET) within 4 weeks of delivery. A control group of pre-menopausal, non-postpartum women was also included. Myocardial flow reserve (MFR), myocardial blood flow (MBF), and coronary vascular resistance (CVR) were compared across groups. Soluble fms-like tyrosine kinase receptor-1 (sFlt-1) and placental growth factor (PlGF) were measured at imaging. Results: The primary cohort included 19 women with severe preeclampsia (imaged at a mean 16.0 days postpartum), 5 with normotensive pregnancy (mean 14.4 days postpartum), and 13 non-postpartum female controls. Preeclampsia was associated with lower MFR (ß=-0.67 [95% CI -1.21 to -0.13]; P=0.016), lower stress MBF (ß=-0.68 [95% CI, -1.07 to -0.29] mL/min/g; P=0.001), and higher stress CVR (ß=+12.4 [95% CI 6.0 to 18.7] mmHg/mL/min/g; P=0.001) vs. non-postpartum controls. MFR and CVR after normotensive pregnancy were intermediate between preeclamptic and non-postpartum groups. Following preeclampsia, MFR was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest MBF (r=0.71; P<0.001), independent of hemodynamics. Conclusions: In this exploratory study, we observed reduced coronary microvascular function in the early postpartum period following severe preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves the coronary microcirculation. Further research is needed to establish interventions to mitigate risk of preeclampsia-associated cardiovascular disease.

Lipoprotein(a) and Major Adverse Cardiovascular Events in Patients With or Without Baseline Atherosclerotic Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) [Lp(a)] is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). However, whether the optimal Lp(a) threshold for risk assessment should differ based on baseline ASCVD status is unknown. OBJECTIVES: The purpose of this study was to assess the association between Lp(a) and major adverse cardiovascular events (MACE) among patients with and without baseline ASCVD. METHODS: We studied a retrospective cohort of patients with Lp(a) measured at 2 medical centers in Boston, Massachusetts, from 2000 to 2019. To assess the association of Lp(a) with incident MACE (nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or cardiovascular mortality), Lp(a) percentile groups were generated with the reference group set at the first to 50th Lp(a) percentiles. Cox proportional hazards modeling was used to assess the association of Lp(a) percentile group with MACE. RESULTS: Overall, 16,419 individuals were analyzed with a median follow-up of 11.9 years. Among the 10,181 (62%) patients with baseline ASCVD, individuals in the 71st to 90th percentile group had a 21% increased hazard of MACE (adjusted HR: 1.21; P < 0.001), which was similar to that of individuals in the 91st to 100th group (adjusted HR: 1.26; P < 0.001). Among the 6,238 individuals without established ASCVD, there was a continuously higher hazard of MACE with increasing Lp(a), and individuals in the 91st to 100th Lp(a) percentile group had the highest relative risk with an adjusted HR of 1.93 (P < 0.001). CONCLUSIONS: In a large, contemporary U.S. cohort, elevated Lp(a) is independently associated with long-term MACE among individuals with and without baseline ASCVD. Our results suggest that the threshold for risk assessment may be different in primary vs secondary prevention cohorts.

Comparative Effectiveness of PET and SPECT MPI for Predicting Cardiovascular Events After Kidney Transplant.

BACKGROUND: Advanced chronic kidney disease is associated with high cardiovascular risk, even after kidney transplant. Pretransplant cardiac testing may identify patients who require additional assessment before transplant or would benefit from risk optimization. The objective of the current study was to determine the relative prognostic utility of pretransplant positron emission tomography (PET) and single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) for posttransplant major adverse cardiovascular events (MACEs). METHODS: We retrospectively followed patients who underwent MPI before kidney transplant for the occurrence of MACE after transplant including myocardial infarction, stroke, heart failure, and cardiac death. An abnormal MPI result was defined as a total perfusion deficit >5% of the myocardium. To determine associations of MPI results with MACE, we utilized Cox hazard regression with propensity weighting for PET versus SPECT with model factors, including demographics and cardiovascular risk factors. RESULTS: A total of 393 patients underwent MPI (208 PET and 185 SPECT) and were followed for a median of 5.9 years post-transplant. Most were male (58%), median age was 58 years, and there was a high burden of hypertension (88%) and diabetes (33%). A minority had abnormal MPI (n=58, 15%). In propensity-weighted hazard regression, abnormal PET result was associated with posttransplant MACE (hazard ratio, 3.02 [95% CI, 1.78-5.11]; P<0.001), while there was insufficient evidence of an association of abnormal SPECT result with MACE (1.39 [95% CI, 0.72-2.66]; P=0.33). The explained relative risk of the PET result was higher than the SPECT result (R2 0.086 versus 0.007). Normal PET was associated with the lowest risk of MACE (2.2%/year versus 3.6%/year for normal SPECT; P<0.001). CONCLUSIONS: Kidney transplant recipients are at high cardiovascular risk, despite a minority having obstructive coronary artery disease on MPI. PET MPI findings predict posttransplant MACE. Normal PET may better discriminate lower risk patients compared with normal SPECT, which should be confirmed in a larger prospective study.

Body Composition, Coronary Microvascular Dysfunction, and Future Risk of Cardiovascular Events Including Heart Failure.

BACKGROUND: Body mass index (BMI) is a controversial marker of cardiovascular prognosis, especially in women. Coronary microvascular dysfunction (CMD) is prevalent in obese patients and a better discriminator of risk than BMI, but its association with body composition is unknown. OBJECTIVES: The authors used a deep learning model for body composition analysis to investigate the relationship between CMD, skeletal muscle (SM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT), and their contribution to adverse outcomes in patients referred for evaluation of coronary artery disease. METHODS: Consecutive patients (n = 400) with normal perfusion and preserved left ventricular ejection fraction on cardiac stress positron emission tomography were followed (median, 6.0 years) for major adverse events, including death and hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was quantified as stress/rest myocardial blood flow from positron emission tomography. SM, SAT, and VAT cross-sectional areas were extracted from abdominal computed tomography at the third lumbar vertebra using a validated automated algorithm. RESULTS: Median age was 63, 71% were female, 50% non-White, and 50% obese. Compared with the nonobese, patients with obesity (BMI: 30.0-68.4 kg/m2) had higher SAT, VAT, and SM, and lower CFR (all P < 0.001). In adjusted analyses, decreased SM but not increased SAT or VAT was significantly associated with CMD (CFR <2; OR: 1.38; 95% CI: 1.08-1.75 per -10 cm2/m2 SM index; P < 0.01). Both lower CFR and SM, but not higher SAT or VAT, were independently associated with adverse events (HR: 1.83; 95% CI: 1.25-2.68 per -1 U CFR and HR: 1.53; 95% CI: 1.20-1.96 per -10 cm2/m2 SM index, respectively; P < 0.002 for both), especially heart failure hospitalization (HR: 2.36; 95% CI: 1.31-4.24 per -1 U CFR and HR: 1.87; 95% CI: 1.30-2.69 per -10 cm2/m2 SM index; P < 0.004 for both). There was a significant interaction between CFR and SM (adjusted P = 0.026), such that patients with CMD and sarcopenia demonstrated the highest rate of adverse events, especially among young, female, and obese patients (all P < 0.005). CONCLUSIONS: In a predominantly female cohort of patients without flow-limiting coronary artery disease, deficient muscularity, not excess adiposity, was independently associated with CMD and future adverse outcomes, especially heart failure. In patients with suspected ischemia and no obstructive coronary artery disease, characterization of lean body mass and coronary microvascular function may help to distinguish obese phenotypes at risk for cardiovascular events.

Coronary Microcirculatory Dysfunction in People With HIV and Its Association With Antiretroviral Therapy.

BACKGROUND: HIV infection and abacavir-containing antiretroviral regimens are associated with vascular endothelial dysfunction and increased cardiovascular risk. Positron emission tomography (PET)-derived myocardial blood flow reserve (MBFR), the ratio of vasodilator stress to rest myocardial blood flow, is a well-validated measure of coronary microvascular health and marker of cardiovascular risk. Our objective was to compare MBFR among people with HIV (PWH) with matched non-HIV controls and to assess whether switching from dolutegravir/lamivudine/abacavir to the non-abacavir regimen bictegravir/emtricitabine/tenofovir alafenamide (TAF) would improve MBFR. METHODS AND RESULTS: Thirty-seven PWH were 1:2 matched on cardiovascular risk factors to 75 people without HIV, and MBFR corrected for differences in resting hemodynamics was compared in a cross-sectional design. PWH were majority men (68%) with a mean age of 56 years. Mean stress myocardial blood flow (1.83 mL/min per g [95% CI, 1.68-1.98] versus 2.40 mL/min per g [95% CI, 2.25-2.54]; P<0.001) and MBFR (2.18 [95% CI, 1.96-2.40] versus 2.68 [95% CI, 2.47-2.89]; P=0.002) was significantly lower in PWH than in people without HIV. In a single-arm, multicenter trial, a subset of 25 PWH who were virologically suppressed on dolutegravir/lamivudine/abacavir underwent positron emission tomography myocardial perfusion imaging at baseline and after switching to bictegravir/emtricitabine/TAF. MBFR was unchanged after switching to bictegravir/emtricitabine/TAF for a mean of 27 weeks (MBFR, 2.34 to 2.29; P=0.61), except in PWH with impaired MBFR at baseline (<2.00; N=6) in whom MBFR increased from 1.58 to 2.02 (P=0.02). CONCLUSIONS: PWH had reduced coronary microvascular function compared with controls without HIV. Coronary microvascular function did not improve after switching from dolutegravir/lamivudine/abacavir to bictegravir/emtricitabine/TAF. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT03656783.

Sex and Racial Disparities in Peripheral Artery Disease.

Several studies have shown that women and racial and ethnic minority patients are at increased risk of developing lower extremity peripheral artery disease and suffering adverse outcomes from it, but a knowledge gap remains regarding the underlying causes of these increased risks. Both groups are more likely to be underdiagnosed, have poorly managed contributory comorbidities, and incur disparities in treatment and management postdiagnosis. Opportunities for improvement in the care of women and racial and ethnic minorities with peripheral artery disease include increased rates of screening, higher rates of clinical suspicion (particularly in the absence of typical symptoms of intermittent claudication), and more aggressive risk factor management before and after the diagnosis of peripheral artery disease.

Radionuclide Assessment of Sarcoidosis.

This review provides an overview of the techniques used in nuclear cardiology for the assessment of suspected or known cardiac sarcoidosis, how radionuclide imaging assists with regard to diagnosis, risk stratification, and monitoring response to therapy, and work that is on the horizon with novel tracers.

High-throughput approaches to uncover synergistic drug combinations in leukemia.

We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate a panel of cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicted a priori, and open source code for automation and analyses. We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community.