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Background: Coronary microvascular dysfunction has been implicated in the development of hypertensive heart disease and heart failure, with subendocardial ischemia identified as a driver of sustained myocardial injury and fibrosis. We aimed to evaluate the relationships of subendocardial perfusion with cardiac injury, structure, and a composite of major adverse cardiac and cerebrovascular events consisting of death, heart failure hospitalization, myocardial infarction, and stroke., Methods: Layer-specific blood flow and myocardial flow reserve (MFR; stress/rest myocardial blood flow) were assessed by 13 N-ammonia perfusion positron emission tomography in consecutive patients with hypertension without flow-limiting coronary artery disease (summed stress score <3) imaged at Brigham and Women's Hospital (Boston, MA) from 2015 to 2021. In this post hoc observational study, biomarkers, echocardiographic parameters, and longitudinal clinical outcomes were compared by tertiles of subendocardial MFR (MFR subendo )., Results: Among 358 patients, the mean age was 70.6±12.0 years, and 53.4% were male. The median MFR subendo was 2.57 (interquartile range, 2.08-3.10), and lower MFR subendo was associated with older age, diabetes, lower renal function, greater coronary calcium burden, and higher systolic blood pressure ( P <0.05 for all). In cross-sectional multivariable regression analyses, the lowest tertile of MFR subendo was associated with myocardial injury and with greater left ventricular wall thickness and volumes compared with the highest tertile. Relative to the highest tertile, low MFR subendo was independently associated with an increased rate of major adverse cardiac and cerebrovascular events (adjusted hazard ratio, 2.99 [95% CI, 1.39-6.44]; P =0.005) and heart failure hospitalization (adjusted hazard ratio, 2.76 [95% CI, 1.04-7.32; P =0.042) over 1.1 (interquartile range, 0.6-2.8) years median follow-up., Conclusions: Among patients with hypertension without flow-limiting coronary artery disease, impaired MFR subendo was associated with cardiovascular risk factors, elevated cardiac biomarkers, cardiac structure, and clinical events., Competing Interests: B.W. reports consulting fees from Horizon Therapeutics, Kiniksa Pharmaceuticals, and Novo Nordisk. B.A. reports consulting fees from Spectrum Dynamics Medical. S. Dorbala reports grant support from Attralus, Pfizer, GE Healthcare, Phillips, and Siemens; S. Dorbala has consulted with Novo Nordisk and Alexion. R.B. reports research support from Amgen and Novartis and has consulted for Caristo Inc and Elucid Inc. P.J.S. reports consulting fees from Synektik, SA, research support from Siemens, and software royalties from Cedars-Sinai licensing. J.M.B. reports consulting fees from Bayer AG and AstraZeneca. M.F.D.C. reports grant support from Gilead Sciences, in-kind research support from Amgen, and consulting fees from MedTrace and Sanofi. The other authors report no conflicts.

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 major adverse cardiovascular events (MACEs) (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) of <5%, reflecting the absence of obstructive CAD. Normal PET was defined as a TPD of <5% plus an MFR of ≥2.0., Results: Among 21,544 patients referred from 2006 to 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 a 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 a 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., (Copyright © 2024 American Society of Nuclear Cardiology. Published by Elsevier Inc. All rights reserved.)

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 (MFR corrected ) 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. MFR corrected 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 MFR corrected 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 MFR corrected ≥2.0 compared with those with MFR corrected <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., (Copyright © 2024 American Society of Nuclear Cardiology. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Funding Support and Author Disclosures This study was funded, in part, by Amgen Inc. Dr Januzzi is a Trustee of the American College of Cardiology; has received grant support from Abbott, Applied Therapeutics, HeartFlow Inc, Innolife, and Roche Diagnostics; has received consulting income from Abbott, AstraZeneca, Bayer, Beckman, Boehringer Ingelheim, Janssen, Novartis, Merck, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Intercept, Pfizer, and Takeda. Drs Booth III, López, and Kent are employees and shareholders of Amgen Inc. Dr Bhatt has served on the Advisory Board of Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; has served on the Board of Directors of American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); has served as a consultant for Broadview Ventures, Hims, SFJ, and Youngene; has served on Data Monitoring Committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical; and for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (American Heart Association lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); served as Deputy Editor of Clinical Cardiology; is named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon (neither he nor Brigham and Women's Hospital receive any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a Trustee of the American College of Cardiology; and has performed unfunded research for FlowCo. Dr Blankstein has received research support and consulting fees from Amgen Inc and Novartis Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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/m 2 ) 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 cm 2 /m 2 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 cm 2 /m 2 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 cm 2 /m 2 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., Competing Interests: Funding Support and Author Disclosures This research was supported by a Lemann Cardiovascular Research Fellowship (Dr Souza); the National Institutes of Health (NIH) (U01CA320272, U01CA200468, and U10CA180821), the Lustgarten Foundation Dedicated Lab at Dana-Farber Cancer Institute, the Lustgarten Foundation and Stand Up To Cancer Pancreatic Cancer Collaborative, and the Hale Family Center for Pancreatic Cancer Research at Dana-Farber (Dr Rosenthal); a joint KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from Harvard Catalyst and the Boston Claude D. Pepper Older Americans Independence Center (5P30AG031679-10) (Dr Divakaran); NIH K23HL151909 (Dr Osborne); and the Gilead Sciences Research Scholars Program in Cardiovascular Disease and NIH K23HL135438 (Dr Taqueti). Dr Blankenstein has received research support from Amgen Inc and Novartis Inc. Dr Osborne has received consulting fees from WCG Intrinsic Imaging for unrelated work. Dr Dorbala has received research grants from Pfizer, Attralus, and GE Healthcare; and consulting fees from Janssen, Pfizer, and GE Healthcare. Dr Di Carli has received research grants from Gilead Sciences and Spectrum Dynamics, and consulting fees from Bayer and Janssen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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 (R 2 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., Competing Interests: Disclosures Dr Weber reports consulting/scientific advisory board fees from Novo Nordisk, Kiniksa Pharmaceuticals, and Horizon Therapeutics. Dr Brown received consulting fees from Bayer, unrelated to the current work. Dr Divakaran received consulting fees from Kinevant Sciences, unrelated to the current work. Dr Blankstein reports research support and consulting from Amgen, Novartis, and Beren Therapeutics. Dr Dorbala reports personal consulting fees from GE HealthCare. Dr Chandraker reports grants from Bristol Myers Squibb, ViroPharma, Inc, IQVIA RDS, Inc, CSL Behring, LLC, Natera, Inc, Amgen, Inc, Hansa Biopharma AB, Sanofi US Services, Inc, and AlloVir, Inc, and personal consulting fees from AlloVir, Inc, eGenesis, Immucor, Natera, Inc, and Shire. Dr Di Carli received institutional research funding from Gilead Sciences, in-kind support from Amgen, and consulting fees from MedTrace and Sanofi. The other authors report no conflicts.

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.

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 <0.001). Compared across vascular beds, resting renal blood flow was correlated with maximal stress myocardial blood flow and myocardial flow reserve (stress/rest myocardial blood flow), an integrated marker of endothelial health. In patients with kidney biopsy (n=12), resting PET renal blood flow was strongly negatively correlated with histological interstitial fibrosis ( r =-0.85; P <0.001)., Conclusions: Renal blood flow can be reliably measured from cardiac 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., Competing Interests: Disclosures Dr Brown reports consulting fees from Bayer. Dr Weber reports consulting fees from Horizon Therapeutics and Kiniksa Pharmaceuticals. Dr Dorbala reports unrelated grant support from Attralus, Pfizer, GE healthcare, and Phillips. Dr Blankstein reports research support from Amgen and Novartis and has consulted for Caristo Inc and Elucid Inc. Dr Di Carli reports grant support from Gilead Sciences, in-kind research support from Amgen, and consulting fees from MedTrace. The other authors report no conflicts.

Control of locomotion involves the interplay of sensory signals and motor commands. Sensory information is essential for adjusting locomotion in response to environmental changes. A previous study using mathematical modelling of lamprey swimming has shown that, in the absence of sensory feedback, increasing fluid viscosity constrains swimming kinematics, limiting tail amplitude and body wavelength, resulting in decreased swimming speed. In contrast, previous experiments with Polypterus senegalus reported increased magnitude swimming kinematics (increased body curvature, body wave speed and frequency, and pectoral fin frequency) in high viscosity water suggesting that sensory information is used to adjust swimming form. It is not known what sensory systems are providing the necessary information to respond to these environmental changes. We tested the hypothesis that lateral line and visual input are responsible for the sensory-driven increase in swimming kinematics in response to experimentally increased fluid viscosity. The kinematics of five P. senegalus were recorded in two different viscosities of water while removing lateral line and visual sensory feedback. Unlike the mathematical model devoid of sensory feedback, P. senegalus with lateral line and/or visual senses removed did not reduce the magnitude of swimming kinematic variables, suggesting that additional sensory feedback mechanisms are present in these fish to help overcome increased fluid viscosity. Increases in swimming speed when both lateral line and visual sensory feedback were removed suggest that lateral line and visual information may be used to regulate swimming speed in P. senegalus, possibly using an internal model of predictions to adjust swimming form., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Background: Consensus guidelines recommend periodic screening for coronary artery disease (CAD) in Hodgkin lymphoma (HL) survivors treated with radiation therapy (RT) to the chest. However, the prognostic utility of screening strategies in this population remains unclear. We evaluated the association between functional testing, coronary artery calcifications (CAC), and guideline-based risk assessment and major adverse cardiovascular events (MACE) in HL survivors treated with RT., Methods: We retrospectively studied HL survivors treated with RT who underwent functional testing between 2003 and 2020 and chest computed tomography (CT) within 12 months of each other at our center. CAC was assessed semi-quantitatively from CT images. Cardiovascular risk was estimated using the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Diagnostic test characteristics were calculated using major adverse cardiac events (MACE) during follow-up as the gold standard., Results: The study included 159 patients (median age at functional testing 48 years, median age at HL diagnosis 27 years, 62.9% female). Abnormal functional testing had the highest specificity (94.2% (95% CI 88.4%-97.6%)) and positive likelihood ratio (4.55 (95% CI 1.86-11.13)) while CAC had the highest sensitivity (63.2% (95% CI 46.0%-78.2%)) and lowest negative likelihood ratio (0.52 (95% CI 0.34-0.80)). Specificity for ACC/AHA risk assessment was also high (88.5% (95% CI 81.1%-93.7%)). Over 3.3 years of follow-up, abnormal functional testing (adjusted subdistribution hazard ratio (SHR) 5.10, 95% CI 2.41 - 10.78, p < 0.001) and CAC (adjusted SHR 3.58, 95% CI 1.35 - 9.47, p = 0.010) were both significantly associated with MACE., Conclusions: In HL survivors treated with RT, both abnormal functional testing and ACC/AHA risk assessment had high specificity for subsequent MACE, but CAC had higher sensitivity. Further research is needed to inform CAD screening and primary prevention strategies in this population., (© 2023. The Author(s).)

Inflammation is a key determinant of cardiovascular outcomes, but its role in heart failure is uncertain. In patients with cardiometabolic disease enrolled in the prospective, multicenter ancillary study of CIRT (Cardiovascular Inflammation Reduction Trial), CIRT-CFR (Coronary Flow Reserve to Assess Cardiovascular Inflammation), impaired coronary flow reserve was independently associated with increased inflammation and myocardial strain despite well-controlled lipid, glycemic, and hemodynamic profiles. Inflammation modified the relationship between CFR and myocardial strain, disrupting the association between cardiac blood flow and function. Future studies are needed to investigate whether an early inflammation-mediated reduction in CFR capturing microvascular ischemia may lead to heart failure in patients with cardiometabolic disease. (Cardiovascular Inflammation Reduction Trial [CIRT]; NCT01594333; Coronary Flow Reserve to Assess Cardiovascular Inflammation [CIRT-CFR]; NCT02786134)., Competing Interests: This research was supported by National Institutes of Health (NIH) R01HL132021 (to Drs Di Carli and Taqueti) and K23HL135438 (to Dr Taqueti). Dr Shah was supported by NIH R01HL135008, R01HL143224, R01HL150342, R01HL14818, and K24HL152008. Dr Libby was supported by R01HL134892. Dr Shah has received research support from Novartis; and consulting fees from Philips Ultrasound and Edwards Lifesciences. Dr Dorbala has received research support from Pfizer, GE Healthcare, and Attralus; and consulting honoraria from Pfizer and GE Healthcare. Dr Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research; has received research support from TD Bank, AusculSciences, Siemens Healthineers, and Artrya; and has equity interest in General Electric. Dr Hage has received grant support from GE Healthcare, Novartis, and Idorsia Pharmaceuticals. Dr Beanlands holds the Chair in Cardiology at the University of Ottawa Heart Institute; is a University of Ottawa Distinguished Research Chair in Cardiovascular Imaging; and is a consultant for and has received grant funding from GE Healthcare, Lantheus Medical Imaging, and Jubilant DraxImage. Dr Libby is an unpaid consultant to or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Novartis, Pfizer, Sanofi-Regeneron; is on the Scientific Advisory Board for Amgen, Caristo, Cartesian, Corvidia Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, and XBiotech, Inc; is on the Board of Directors and has a financial interest in XBiotech, Inc; and has received research funding from Novartis, the American Heart Association, the RRM Charitable Fund, and the Simard Fund. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 Published by Elsevier on behalf of the American College of Cardiology Foundation.)

Background: Impaired MFR in the absence of flow-limiting CAD is associated with adverse events. Cardiovascular disease is an important cause of morbidity and mortality in patients with breast cancer. We sought to test the utility of MFR to predict outcomes in a cohort of patients with breast cancer., Methods: We retrospectively studied consecutive patients with breast cancer or breast cancer survivors who underwent cardiac stress PET imaging from 2006 to 2017 at Brigham and Women's Hospital. Patients with a history of clinically overt CAD, LVEF < 45%, or abnormal myocardial perfusion were excluded. Subjects were followed from time of PET to the occurrence of a first major adverse cardiovascular event (MACE) and all-cause death., Results: The final cohort included 87 patients (median age 69.0 years, 98.9% female, mean MFR 2.05). Over a median follow-up of 7.6 years after PET, the lowest MFR tertile was associated with higher cumulative incidence of MACE (adjusted subdistribution hazard ratio 4.91; 95% CI 1.68-14.38; p = 0.004) when compared with the highest MFR tertile., Conclusions: In patients with breast cancer, coronary vasomotor dysfunction was associated with incident cardiovascular events. MFR may have potential as a risk stratification biomarker among patients with/survivors of breast cancer., (© 2021. American Society of Nuclear Cardiology.)

Background Cardiovascular complications from COVID-19 contribute to its high morbidity and mortality. The effect of COVID-19 infection on the coronary vasculature is not known. The objective of this study was to investigate the prevalence of coronary vasomotor dysfunction identified by coronary flow reserve from cardiac positron emission tomography in patients with previous COVID-19 infection. Methods and Results All patients who had polymerase chain reaction-confirmed SARS-CoV-2 infection referred for myocardial stress perfusion positron emission tomography imaging at Brigham and Women's Hospital from April 2020 to July 2021 were compared with a matched control group without prior SARS-CoV-2 infection imaged in the same period. The main outcome was the prevalence of coronary vasomotor dysfunction. Myocardial perfusion and myocardial blood flow reserve were quantified using N13-ammonia positron emission tomography imaging. Thirty-four patients with prior COVID-19 were identified and compared with 103 matched controls. The median time from polymerase chain reaction-confirmed SARS-CoV-2 to cardiac positron emission tomography was 4.6 months (interquartile range,1.2-5.6 months). There were 16 out of 34 (47%) patients previously hospitalized for COVID-19 infection. Baseline cardiac risk factors were common, and 18 (53%) patients in the COVID-19 group had abnormal myocardial perfusion. Myocardial blood flow reserve was abnormal (<2) in 44.0% of the patients with COVID-19 compared with 11.7% of matched controls ( P <0.001). The mean myocardial blood flow reserve was 19.4% lower in patients with COVID-19 compared with control patients (2.00±0.45 versus 2.48±0.47, P <0.001). Conclusions Myocardial blood flow reserve was impaired in patients with prior COVID-19 infection compared with cardiovascular risk factor-matched controls, suggesting a relationship between SARS-CoV-2 infection and coronary vascular health. These data highlight the need to assess long-term consequences of COVID-19 on vascular health in future prospective studies.