Leanne Barrett

BACKGROUND: Physiologic interaction between the cardiovascular and renal systems is pivotal in the understanding of disease and as a target for therapeutic interventions, as highlighted in the cardiovascular-kidney-metabolic syndrome. This study explores the association of renal blood flow, derived noninvasively from cardiac positron emission tomography–computed tomography, with cardiovascular and renal outcomes. METHODS: We evaluated the association between renal blood flow and outcomes in a retrospective cohort of 295 consecutive patients who underwent ¹³ N-ammonia positron emission tomography–computed tomography myocardial perfusion imaging between September 1, 2019, and March 1, 2020 (Brigham and Women’s Hospital, Boston). Global myocardial blood flow, myocardial flow reserve, semiquantitative coronary artery calcium, and previously validated resting renal blood flow were obtained, along with clinical and laboratory data. Patients were followed for 4.0 (interquartile range, 1.7–4.1) years for a composite cardiovascular outcome of all-cause mortality, heart failure hospitalization, or acute coronary syndrome, and a composite renal outcome of 25% reduction in estimated glomerular filtration rate or end-stage renal disease. Survival analyses were adjusted for demographic and clinical characteristics and additionally for estimated glomerular filtration rate and myocardial flow reserve. RESULTS: The population had a mean age of 65.6 years, a body mass index of 29.2 kg/m ² , and was 49% female. Overall, 36% had chronic kidney disease stage ≥3. Patients were stratified into 3 renal blood flow groups: ≥75%, 25 to 75th, and ≤25% percentile. Lower renal blood flow was significantly associated with a higher risk of cardiovascular events (adjusted hazard ratio, 5.21 [95% CI 1.53–17.75]; P =0.008; lowest versus highest quartile), and with an elevated risk of adverse renal outcomes ( P =0.026), independent of estimated glomerular filtration rate and myocardial flow reserve. CONCLUSIONS: Impaired renal blood flow is associated with cardiac and kidney events, independent of the highly prognostic estimated glomerular filtration rate and myocardial flow reserve. Simultaneous quantification of cardiac and renal perfusion by noninvasive ¹³ N-ammonia positron emission tomography–computed tomography may provide a valuable tool to interrogate pathophysiology and prognosis in the cardiovascular-kidney-metabolic syndrome.

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), 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.

BACKGROUND: Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic endothelial dysfunction. The pathophysiology of preeclampsia remains incompletely understood. This study used human venous endothelial cell (EC) transcriptional profiling to investigate potential novel mechanisms underlying EC dysfunction in preeclampsia. METHODS: Venous ECs were isolated from postpartum patients with severe preeclampsia and those with normotensive pregnancy using a J wire–based technique in the antecubital vein followed by CD144 (vascular endothelial cadherin) magnetic bead isolation. Venous EC transcriptomes were compared between preeclamptic and normotensive individuals. Differentially expressed genes were carried forward for genetic validation using expression quantitative trait loci from the Genotype-Tissue Expression project as exposures for vascular-specific Mendelian randomization. Functional validation of the top candidate was performed in human umbilical vein ECs using gain- and loss-of-function genetic approaches. RESULTS: Seventeen individuals with preeclampsia and 7 normotensive controls were included. Pairwise analysis yielded 14 protein-coding genes nominally differentially expressed in participants with preeclampsia. Mendelian randomization revealed a significant association between higher genetically predicted METAP1 (methionyl aminopeptidase 1) expression in aortic and tibial arterial tissues and greater risk of preeclampsia. METAP1 overexpression in human umbilical vein ECs decreased angiogenesis, with a 66% decrease in tube formation ( P =7.9×10 ⁻³ ) and 72% decrease in cell proliferation ( P =2.9×10 ⁻² ). Furthermore, METAP1 overexpression decreased VEGFA expression and increased expression of multiple preeclampsia-related genes, for example, FLT1 , INHBA , and IL1B . Conversely, METAP1 knockdown produced opposite effects on tube formation, cell proliferation, and inflammation-related gene expression. CONCLUSIONS: In a cohort of early postpartum individuals, we observed greater METAP1 expression in venous ECs of women with preeclampsia versus normotensive delivery. Mendelian randomization supported a causal relationship between greater vascular METAP1 expression and higher preeclampsia risk, and functional experiments demonstrated antiangiogenic and proinflammatory effects of METAP1 in human ECs consistent with alterations observed in preeclampsia. Ex vivo EC transcriptomics can identify novel mechanisms underlying preeclampsia pathophysiology, with implications for prevention and treatment.

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 (β, −0.67 [95% CI, −1.21 to −0.13]; P =0.016), lower stress myocardial blood flow (β, −0.68 [95% CI, −1.07 to −0.29] mL/min per g; P =0.001), and higher stress coronary vascular resistance (β, +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.

Background: Coronary microvascular dysfunction as measured by myocardial flow reserve (MFR) is associated with increased cardiovascular risk in rheumatoid arthritis (RA). The objective of this study was to determine the association between reducing inflammation with MFR and other measures of cardiovascular risk. Methods and Results: Patients with RA with active disease about to initiate a tumor necrosis factor inhibitor were enrolled (NCT02714881). All subjects underwent a cardiac perfusion positron emission tomography scan to quantify MFR at baseline before tumor necrosis factor inhibitor initiation, and after tumor necrosis factor inhibitor initiation at 24 weeks. MFR P =0.6) or hs‐cTnT. A correlation was observed between a reduction in hsCRP and interleukin‐1b with a reduction in hs‐cTnT. Conclusions: In this RA cohort with low prevalence of cardiovascular risk factors, nearly 50% of subjects had coronary microvascular dysfunction at baseline. A reduction in inflammation was not associated with improved MFR. However, a modest reduction in interleukin‐1b and no other inflammatory pathways was correlated with a reduction in subclinical myocardial injury. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02714881.

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 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 (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.

BACKGROUND: Given the central importance of cardiorenal interactions, mechanistic tools for evaluating cardiorenal physiology are needed. In the heart and kidneys, shared pathways of neurohormonal activation, hypertension, and vascular and interstitial fibrosis implicate the relevance of systemic vascular health. The availability of a long axial field of view positron emission tomography (PET)/computed tomography (CT) system enables simultaneous evaluation of cardiac and renal blood flow. METHODS: This study evaluated the feasibility of quantification of renal blood flow using data acquired during routine, clinically indicated ¹³ N-ammonia myocardial perfusion PET/CT. Dynamic PET image data were used to calculate renal blood flow. Reproducibility was assessed by the intraclass correlation coefficient among 3 independent readers. PET-derived renal blood flow was correlated with imaging and clinical parameters in the overall cohort and with histopathology in a small companion study of patients with a native kidney biopsy. RESULTS: Among 386 consecutive patients with myocardial perfusion PET/CT, 296 (76.7%) had evaluable images to quantify renal perfusion. PET quantification of renal blood flow was highly reproducible (intraclass correlation coefficient 0.98 [95% CI, 0.93–0.99]) and was correlated with the estimated glomerular filtration rate ( r =0.64; P r =−0.85; P 13 N-ammonia PET/CT and allows for simultaneous assessment of myocardial and renal perfusion, opening a potential novel avenue to interrogate the mechanisms of emerging therapies with overlapping cardiac and renal benefits.