Publications by authors named "Daniel Berman"

846 Publications

Intramyocardial Hemorrhage and the "Wave Front" of Reperfusion Injury Compromising Myocardial Salvage.

J Am Coll Cardiol 2022 Jan;79(1):35-48

Cedars-Sinai Medical Center, Los Angeles, California, USA; Krannert Cardiovascular Research Center, Indiana University School of Medicine/IU Health Cardiovascular Institute, Indianapolis, Indiana, USA. Electronic address:

Background: Reperfusion therapy for acute myocardial infarction (MI) is lifesaving. However, the benefit of reperfusion therapy can be paradoxically diminished by reperfusion injury, which can increase MI size.

Objectives: Hemorrhage is known to occur in reperfused MIs, but whether hemorrhage plays a role in reperfusion-mediated MI expansion is not known.

Methods: We studied cardiac troponin kinetics (cTn) of ST-segment elevation MI patients (n = 70) classified by cardiovascular magnetic resonance to be hemorrhagic (70%) or nonhemorrhagic following primary percutaneous coronary intervention. To isolate the effects of hemorrhage from ischemic burden, we performed controlled canine studies (n = 25), and serially followed both cTn and MI size with time-lapse imaging.

Results: CTn was not different before reperfusion; however, an increase in cTn following primary percutaneous coronary intervention peaked earlier (12 hours vs 24 hours; P < 0.05) and was significantly higher in patients with hemorrhage (P < 0.01). In hemorrhagic animals, reperfusion led to rapid expansion of myocardial necrosis culminating in epicardial involvement, which was not present in nonhemorrhagic cases (P < 0.001). MI size and salvage were not different at 1 hour postreperfusion in animals with and without hemorrhage (P = 0.65). However, within 72 hours of reperfusion, a 4-fold greater loss in salvageable myocardium was evident in hemorrhagic MIs (P < 0.001). This paralleled observations in patients with larger MIs occurring in hemorrhagic cases (P < 0.01).

Conclusions: Myocardial hemorrhage is a determinant of MI size. It drives MI expansion after reperfusion and compromises myocardial salvage. This introduces a clinical role of hemorrhage in acute care management, risk assessment, and future therapeutics.
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http://dx.doi.org/10.1016/j.jacc.2021.10.034DOI Listing
January 2022

Improved myocardial blood flow estimation with residual activity correction and motion correction in F-flurpiridaz PET myocardial perfusion imaging.

Eur J Nucl Med Mol Imaging 2021 Dec 30. Epub 2021 Dec 30.

Department of Medicine (Division of Artificial Intelligence)- Imaging- and Biomedical Sciences- Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Ste. Metro 203, Los Angeles, CA, 90048, USA.

Purpose: We sought to evaluate the diagnostic performance for coronary artery disease (CAD) of myocardial blood flow (MBF) quantification with F-flurpiridaz PET using motion correction (MC) and residual activity correction (RAC).

Methods: In total, 231 patients undergoing same-day pharmacologic rest and stress F-flurpiridaz PET from Phase III Flurpiridaz trial (NCT01347710) were studied. Frame-by-frame MC was performed and RAC was accomplished by subtracting the rest residual counts from the dynamic stress polar maps. MBF and myocardial flow reserve (MFR) were derived with a two-compartment early kinetic model for the entire left ventricle (global), each coronary territory, and 17-segment. Global and minimal values of three territorial (minimal vessel) and segmental estimation (minimal segment) of stress MBF and MFR were evaluated in the prediction of CAD. MBF and MFR were evaluated with and without MC and RAC (1: no MC/no RAC, 2: no MC/RAC, 3: MC/RAC).

Results: The area-under the receiver operating characteristics curve (AUC [95% confidence interval]) of stress MBF with MC/RAC was higher for minimal segment (0.89 [0.85-0.94]) than for minimal vessel (0.86 [0.81-0.92], p = 0.03) or global estimation (0.81 [0.75-0.87], p < 0.0001). The AUC of MFR with MC/RAC was higher for minimal segment (0.87 [0.81-0.93]) than for minimal vessel (0.83 [0.76-0.90], p = 0.014) or global estimation (0.77 [0.69-0.84], p < 0.0001). The AUCs of minimal segment stress MBF and MFR with MC/RAC were higher compared to those with no MC/RAC (p < 0.001 for both) or no MC/no RAC (p < 0.0001 for both).

Conclusions: Minimal segment MBF or MFR estimation with MC and RAC improves the diagnostic performance for obstructive CAD compared to global assessment.
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http://dx.doi.org/10.1007/s00259-021-05643-2DOI Listing
December 2021

Imaging Coronary Inflammatory Risk.

JACC Cardiovasc Imaging 2021 Dec 9. Epub 2021 Dec 9.

Department of Interventional Cardiology and Angiology, Institute of Cardiology, Warsaw, Poland.

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http://dx.doi.org/10.1016/j.jcmg.2021.11.007DOI Listing
December 2021

Global access to existing and future antimicrobials and diagnostics: antimicrobial subscription and pooled procurement.

Lancet Glob Health 2022 Feb 13;10(2):e293-e297. Epub 2021 Dec 13.

Antimicrobial Research Unit, University of KwaZulu-Natal, Durban, South Africa.

The COVID-19 pandemic has underlined the importance of an efficient and equitable supply of and access to essential health products. These factors are equally pertinent to the antimicrobial resistance pandemic, in which access to a portfolio of existing and pipeline antimicrobials plus complementary diagnostics is crucial. This Viewpoint focuses on market shaping in low-income and middle-income countries (LMICs), where the need for effective antimicrobials and complementary diagnostics is most acute. We propose the creation of a subscription and pooled procurement model that consolidates the growing demand for a portfolio of antimicrobials and diagnostics in LMICs. Anchored by regional market leaders, these pooling mechanisms would guarantee consistent private-sector and public-sector access in participating countries, while creating conditions for long-term best practice in stewardship. Supported by data from South Africa and India, this proposal sets out an innovative approach to tackle the antimicrobial resistance crisis in LMICs.
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http://dx.doi.org/10.1016/S2214-109X(21)00463-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8765761PMC
February 2022

Latest advances in multimodality imaging of aortic stenosis.

J Nucl Med 2021 Dec 9. Epub 2021 Dec 9.

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, United Kingdom.

Aortic stenosis is a common condition associated with major morbidity, mortality and healthcare costs. Despite this, we currently lack any effective medical therapies that can treat or prevent disease development or progression. Modern advances in echocardiography and computed tomography (CT) have helped improve the assessment of aortic stenosis severity and monitoring of disease progression, whilst cardiac magnetic resonance (CMR) imaging informs on myocardial health and the development of fibrosis. In a series of recent studies, F- sodium fluoride positron emission tomography and computed tomography has been shown to assess valvular disease activity and progression, providing mechanistic insights that can inform potential novel therapeutic approaches. This review will examine the latest advances in the imaging of aortic stenosis and bioprosthetic valve degeneration and explore how these techniques can assist patient management and potentially accelerate novel therapeutic developments.
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http://dx.doi.org/10.2967/jnumed.121.262304DOI Listing
December 2021

Mean Versus Peak Coronary Calcium Density on Non-Contrast CT: Calcium Scoring and ASCVD Risk Prediction.

JACC Cardiovasc Imaging 2021 Nov 6. Epub 2021 Nov 6.

Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objectives: This study sought to assess the relationship between mean vs peak calcified plaque density and their impact on calculating coronary artery calcium (CAC) scores and to compare the corresponding differential prediction of atherosclerotic cardiovascular disease (ASCVD) and coronary heart disease (CHD) mortality.

Background: The Agatston CAC score is quantified per lesion as the product of plaque area and a 4-level categorical peak calcium density factor. However, mean calcium density may more accurately measure the heterogenous mixture of lipid-rich, fibrous, and calcified plaque reflective of ASCVD risk.

Methods: We included 10,373 individuals from the CAC Consortium who had CAC >0 and per-vessel measurements of peak calcium density factor and mean calcium density. Area under the curve and continuous net reclassification improvement analyses were performed for CHD and ASCVD mortality to compare the predictive abilities of mean calcium density vs peak calcium density factor when calculating the Agatston CAC score.

Results: Participants were on average 53.4 years of age, 24.4% were women, and the median CAC score was 68 Agatston units. The average values for mean calcium density and peak calcium density factor were 210 ± 50 Hounsfield units and 3.1 ± 0.5, respectively. Individuals younger than 50 years of age and/or those with a total plaque area <100 mm had the largest differences between the peak and mean density measures. Among persons with CAC 1-99, the use of mean calcium density resulted in a larger improvement in ASCVD mortality net reclassification improvement (NRI) (NRI = 0.49; P < 0.001 vs. NRI = 0.18; P = 0.08) and CHD mortality discrimination (Δ area under the curve (AUC) = +0.169 vs +0.036; P < 0.001) compared with peak calcium density factor. Neither peak nor mean calcium density improved mortality prediction at CAC scores >100.

Conclusion: Mean and peak calcium density may differentially describe plaque composition early in the atherosclerotic process. Mean calcium density performs better than peak calcium density factor when combined with plaque area for ASCVD mortality prediction among persons with Agatston CAC 1-99.
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http://dx.doi.org/10.1016/j.jcmg.2021.09.018DOI Listing
November 2021

BSAC Vanguard Series: AMR diagnostics in light of evolving technologies and access in low- and middle-income countries.

J Antimicrob Chemother 2021 Dec;77(1):3-4

Nesta, 58 Victoria Embankment, Temple, London EC4Y 0DS, UK.

Rapid point-of-care tests are needed to control antimicrobial consumption, as recognized by the Longitude Prize. However, in addition to bacterial pathogen identification, clinicians need more information, such as which antimicrobial will be effective and how severe the infection really is. This technology is beginning to emerge, but both economic and technological challenges remain before it can be delivered, especially in low- and middle-income countries. This article outlines these challenges and how we might overcome them.
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http://dx.doi.org/10.1093/jac/dkab420DOI Listing
December 2021

Prognostic significance of plaque location in non-obstructive coronary artery disease: from the CONFIRM registry.

Eur Heart J Cardiovasc Imaging 2021 Nov 15. Epub 2021 Nov 15.

Department of Imaging, Cedars Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 USA.

Aim: Obstructive coronary artery disease (CAD) in proximal coronary segments is associated with a poor prognosis. However, the relative importance of plaque location regarding the risk for major adverse cardiovascular events (MACE) in patients with non-obstructive CAD has not been well defined.

Methods And Results: From the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry, 4644 patients without obstructive CAD were included in this study. The degree of stenosis was classified as 0 (no) and 1-49% (non-obstructive). Proximal involvement was defined as any plaque present in the left main or the proximal segment of the left anterior descending artery, left circumflex artery, and right coronary artery. Extensive CAD was defined as segment involvement score of >4. During a median follow-up of 5.2 years (interquartile range 4.1-6.0), 340 (7.3%) MACE occurred. Within the non-obstructive CAD group (n = 2065), proximal involvement was observed in 1767 (85.6%) cases. When compared to non-obstructive CAD patients without proximal involvement, those with proximal involvement had an increased MACE risk (log-rank P = 0.033). Multivariate Cox analysis showed when compared to patients with no CAD, proximal non-obstructive CAD was associated with increased MACE risk [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.47-2.45, P < 0.001] after adjusting for extensive CAD and conventional cardiovascular risk factors; however, non-proximal non-obstructive CAD did not increase MACE risk (HR 1.26, 95% CI 0.79-2.01, P = 0.339).

Conclusions: Independent of plaque extent, proximal coronary involvement was associated with increased MACE risk in patients with non-obstructive CAD. The plaque location information by coronary computed tomography angiography may provide additional risk prediction over CAD extent in patients with non-obstructive CAD.
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http://dx.doi.org/10.1093/ehjci/jeab223DOI Listing
November 2021

Comparison of diabetes to other prognostic predictors among patients referred for cardiac stress testing: A contemporary analysis from the REFINE SPECT Registry.

J Nucl Cardiol 2021 Nov 10. Epub 2021 Nov 10.

Departments of Medicine (Division of Artificial Intelligence), Imaging, and Biomedical Sciences, Cedars-Sinai, Los Angeles, CA, USA.

Background: Diabetes mellitus (DM) is increasingly prevalent among contemporary populations referred for cardiac stress testing, but its potency as a predictor for major adverse cardiovascular events (MACE) vs other clinical variables is not well delineated.

Methods And Results: From 19,658 patients who underwent SPECT-MPI, we identified 3122 patients with DM without known coronary artery disease (CAD) (DM+/CAD-) and 3564 without DM with known CAD (DM-/CAD+). Propensity score matching was used to control for the differences in characteristics between DM+/CAD- and DM-/CAD+ groups. There was comparable MACE in the matched DM+/CAD- and DM-/CAD+ groups (HR 1.15, 95% CI 0.97-1.37). By Chi-square analysis, type of stress (exercise or pharmacologic), total perfusion deficit (TPD), and left ventricular function were the most potent predictors of MACE, followed by CAD and DM status. The combined consideration of mode of stress, TPD, and DM provided synergistic stratification, an 8.87-fold (HR 8.87, 95% CI 7.27-10.82) increase in MACE among pharmacologically stressed patients with DM and TPD > 10% (vs non-ischemic, exercised stressed patients without DM).

Conclusions: Propensity-matched patients with DM and no known CAD have similar MACE risk compared to patients with known CAD and no DM. DM is synergistic with mode of stress testing and TPD in predicting the risk of cardiac stress test patients.
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http://dx.doi.org/10.1007/s12350-021-02810-8DOI Listing
November 2021

Coronary artery calcium is associated with long-term mortality from lung cancer: Results from the Coronary Artery Calcium Consortium.

Atherosclerosis 2021 Dec 18;339:48-54. Epub 2021 Oct 18.

Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Background And Aims: Coronary artery calcium (CAC) scores have been shown to be associated with CVD and cancer mortality. The use of CAC scores for overall and lung cancer mortality risk prediction for patients in the Coronary Artery Calcium Consortium was analyzed.

Methods: We included 55,943 patients aged 44-84 years without known heart disease from the CAC Consortium. There were 1,088 cancer deaths, among which 231 were lung cancer, identified by death certificates with a mean follow-up of 12.2 ± 3.9 years. Fine-and-Gray competing-risk regression was used for overall and lung cancer-specific mortality, accounting for the competing risk of CVD death and after adjustment for CVD risk factors. Subdistribution hazard ratios (SHR) were reported.

Results: The mean age of all patients was 57.1 ± 8.6 years, 34.9% were women, and 89.6% were white. Overall, CAC was strongly associated with cancer mortality. Lung cancer mortality increased with increasing CAC scores, with rates per 1000-person years of 0.2 (95% CI: 0.1-0.3) for CAC = 0 and 0.8 (95% CI: 0.6-1.0) for CAC ≥400. Compared with CAC = 0, hazards were increased for those with CAC ≥400 for lung cancer mortality [SHR: 1.7 (95% CI: 1.2-2.6)], which was driven by women [SHR: 2.3 (95% CI: 1.1-4.8)], but not significantly increased for men. Risks were higher in those with positive smoking history [SHR: 2.2 (95% CI: 1.2-4.2)], with associations driven by women [SHR: 4.0 (95% CI: 1.4-11.5)].

Conclusions: CAC scores were associated with increased risks for lung cancer mortality, with strongest associations for current and former smokers, especially in women. Used in conjunction with other clinical variables, our data pinpoint a potential synergistic use of CAC scanning beyond CVD risk assessment for identification of high-risk lung cancer screening candidates.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8678296PMC
December 2021

Detection of small coronary calcifications in patients with Agatston coronary artery calcium score of zero.

J Cardiovasc Comput Tomogr 2021 Oct 19. Epub 2021 Oct 19.

Department of Imaging (Division of Nuclear Medicine), Medicine, and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address:

Background: A coronary artery calcium score (CACS) of 0 is associated with a very low risk of cardiac event. However, the Agatston CACS may fail to detect very small or less dense calcifications. We investigated if an alteration of the Agatston criteria would affect the ability to detect such plaques.

Methods: We evaluated 322 patients, 161 who had a baseline scan with CACS ​= ​0 and a follow-up scan with CACS>0 and 161 with two serial CACS ​= ​0 scans (control group), to identify subtle calcification not detected in the baseline scan because it was not meeting the Agatston size and HU thresholds (≥1 ​mm and ≥130HU). Size threshold was set to <1 ​mm and the HU threshold modified in a stepwise manner to 120, 110, 100 and 90. New lesions were classified as true positive or false positive(noise) using the follow-up scan.

Results: We identified 69 visually suspected subtle calcified lesions in 65/322 (20.2%) patients with CAC ​= ​0 by the Agatston criteria. When size threshold was set as <1 ​mm and HU ​≥ ​130, 36 lesions scored CACS>0, 34 (94.4%) true positive and 2 (5.6%) false positive. When decrease in HU (120HU, 110HU, 100HU, and 90HU) threshold was added to the reduced size threshold, the number of lesions scoring>0 increased (46, 55, 59, and 69, respectively) at a cost of increased false positive rate (8.7%, 20%, 22%, and 30.4% respectively). Eliminating size or both size and HU threshold to ≥120HU correctly reclassified 9.6% and 12.1% of patients respectively.

Conclusion: Eliminating size and reducing HU thresholds to ≥120HU improved the detection of subtle calcification when compared to the Agatston CACS method.
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http://dx.doi.org/10.1016/j.jcct.2021.10.004DOI Listing
October 2021

Comparison of coronary atherosclerotic plaque progression in East Asians and Caucasians by serial coronary computed tomographic angiography: A PARADIGM substudy.

J Cardiovasc Comput Tomogr 2021 Oct 14. Epub 2021 Oct 14.

Division of Cardiology, Severance Cardiovascular Hospital, Integrative Cardiovascular Imaging Center, Yonsei University College of Medicine, Seoul, South Korea.

Objectives: To investigate potential differences in plaque progression (PP) between in East Asians and Caucasians as well as to determine clinical predictors of PP in East Asians.

Background: Studies have demonstrated differences in cardiovascular risk factors as well as plaque burden and progression across different ethnic groups.

Methods: The study comprised 955 East Asians (age 60.4 ​± ​9.3 years, 50.9% males) and 279 Caucasians (age 60.4 ​± ​8.6 years, 74.5% males) who underwent two serial coronary computed tomography angiography (CCTA) studies over a period of at least 24 months. Patients were enrolled and analyzed from the PARADIGM (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging) registry. After propensity-score matching, plaque composition and progression were compared between East Asian and Caucasian patients. Within East Asians, the plaque progression group (defined as plaque volume at follow-up CCTA minus plaque volume at baseline CCTA> 0) was compared to the no PP group to determine clinical predictors for PP in East Asians.

Results: In the matched cohort, baseline volumes of total plaque as well as all plaque subtypes were comparable. There was a trend towards increased annualized plaque progression among East Asians compared to Caucasians (18.3 ​± ​24.7 ​mm/year vs 16.6 ​mm/year, p ​= ​0.054). Among East Asians, 736 (77%) had PP. East Asians with PP had more clinical risk factors and higher plaque burden at baseline (normalized total plaque volume of144.9 ​± ​233.3 ​mm vs 36.6 ​± ​84.2 ​mm for PP and no PP, respectively, p ​< ​0.001). Multivariate logistic regression analysis showed that baseline normalized plaque volume (OR: 1.10, CI: 1.10-1.30, p ​< ​0.001), age (OR: 1.02, CI: 1.00-1.04, p ​= ​0.023) and body mass index (OR: 2.24, CI: 1.01-1.13, p ​= ​0.024) were all predictors of PP in East Asians. Clinical events, driven mainly by percutaneous coronary intervention, were higher among the PP group with a total of 124 (16.8%) events compared to 22 (10.0%) in the no PP group (p ​= ​0.014).

Conclusion: East Asians and Caucasians had comparable plaque composition and progression. Among East Asians, the PP group had a higher baseline plaque burden which was associated with greater PP and increased clinical events.
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http://dx.doi.org/10.1016/j.jcct.2021.09.012DOI Listing
October 2021

Modeling the Recommended Age for Initiating Coronary Artery Calcium Testing Among At-Risk Young Adults.

J Am Coll Cardiol 2021 10;78(16):1573-1583

Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: There are currently no recommendations guiding when best to perform coronary artery calcium (CAC) scanning among young adults to identify those susceptible for developing premature atherosclerosis.

Objectives: The purpose of this study was to determine the ideal age at which a first CAC scan has the highest utility according to atherosclerotic cardiovascular disease (ASCVD) risk factor profile.

Methods: We included 22,346 CAC Consortium participants aged 30-50 years who underwent noncontrast computed tomography. Sex-specific equations were derived from multivariable logistic modeling to estimate the expected probability of CAC >0 according to age and the presence of ASCVD risk factors.

Results: Participants were on average 43.5 years of age, 25% were women, and 34% had CAC >0, in whom the median CAC score was 20. Compared with individuals without risk factors, those with diabetes developed CAC 6.4 years earlier on average, whereas smoking, hypertension, dyslipidemia, and a family history of coronary heart disease were individually associated with developing CAC 3.3-4.3 years earlier. Using a testing yield of 25% for detecting CAC >0, the optimal age for a potential first scan would be at 36.8 years (95% CI: 35.5-38.4 years) in men and 50.3 years (95% CI: 48.7-52.1 years) in women with diabetes, and 42.3 years (95% CI: 41.0-43.9 years) in men and 57.6 years (95% CI: 56.0-59.5 years) in women without risk factors.

Conclusions: Our derived risk equations among health-seeking young adults enriched in ASCVD risk factors inform the expected prevalence of CAC >0 and can be used to determine an appropriate age to initiate clinical CAC testing to identify individuals most susceptible for early/premature atherosclerosis.
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http://dx.doi.org/10.1016/j.jacc.2021.08.019DOI Listing
October 2021

Overcoming GNA/RNA base-pairing limitations using isonucleotides improves the pharmacodynamic activity of ESC+ GalNAc-siRNAs.

Nucleic Acids Res 2021 11;49(19):10851-10867

Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

We recently reported that RNAi-mediated off-target effects are important drivers of the hepatotoxicity observed for a subset of GalNAc-siRNA conjugates in rodents, and that these findings could be mitigated by seed-pairing destabilization using a single GNA nucleotide placed within the seed region of the guide strand. Here, we report further investigation of the unique and poorly understood GNA/RNA cross-pairing behavior to better inform GNA-containing siRNA design. A reexamination of published GNA homoduplex crystal structures, along with a novel structure containing a single (S)-GNA-A residue in duplex RNA, indicated that GNA nucleotides universally adopt a rotated nucleobase orientation within all duplex contexts. Such an orientation strongly affects GNA-C and GNA-G but not GNA-A or GNA-T pairing in GNA/RNA heteroduplexes. Transposition of the hydrogen-bond donor/acceptor pairs using the novel (S)-GNA-isocytidine and -isoguanosine nucleotides could rescue productive base-pairing with the complementary G or C ribonucleotides, respectively. GalNAc-siRNAs containing these GNA isonucleotides showed an improved in vitro activity, a similar improvement in off-target profile, and maintained in vivo activity and guide strand liver levels more consistent with the parent siRNAs than those modified with isomeric GNA-C or -G, thereby expanding our toolbox for the design of siRNAs with minimized off-target activity.
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http://dx.doi.org/10.1093/nar/gkab916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565336PMC
November 2021

The prevalence and predictors of inducible myocardial ischemia among patients referred for radionuclide stress testing.

J Nucl Cardiol 2021 Oct 4. Epub 2021 Oct 4.

Departments of Imaging and Medicine and Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: The frequency of inducible myocardial ischemia has declined in contemporary stress test cohorts, suggesting a need to re-evaluate its optimal use. To-date, however, a comprehensive analysis of the most potent predictors of myocardial ischemia among cardiac stress test patients has not been conducted.

Methods: We assessed 27,615 patients referred for stress-rest SPECT myocardial perfusion imaging between January 1, 2004 and December 31, 2017. Chi-square analysis was used to ascertain the most potent predictors of ischemia.

Results: Among our cohort, CAD status (presence/absence of known CAD), rest left ventricular ejection fraction (LVEF), and typical angina were the most potent predictors of ischemia. The frequency of ischemia was only 6.6% among patients with an LVEF > 55% but 38.1% for patients with LVEF < 45% (P < 0.001). The frequency of myocardial ischemia was fourfold higher among patients with known CAD vs no known CAD (28.0% vs 6.5%, P < 0.001) and approximately threefold higher among patients with typical angina vs patients with atypical symptoms (P < 0.001).

Conclusions: The frequency of myocardial ischemia varies markedly according to the common clinical parameters and is particularly high among patients with known CAD, low LVEF, and typical angina. These observations may be used to develop more cost-effective strategies for referring patients for cardiac stress testing.
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http://dx.doi.org/10.1007/s12350-021-02797-2DOI Listing
October 2021

Association of coronary artery calcium score with qualitatively and quantitatively assessed adverse plaque on coronary CT angiography in the SCOT-HEART trial.

Eur Heart J Cardiovasc Imaging 2021 Sep 16. Epub 2021 Sep 16.

BHF Centre for Cardiovascular Science, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH164SB, UK.

Aims: Coronary artery calcification is a marker of cardiovascular risk, but its association with qualitatively and quantitatively assessed plaque subtypes is unknown.

Methods And Results: In this post-hoc analysis, computed tomography (CT) images and 5-year clinical outcomes were assessed in SCOT-HEART trial participants. Agatston coronary artery calcium score (CACS) was measured on non-contrast CT and was stratified as zero (0 Agatston units, AU), minimal (1-9 AU), low (10-99 AU), moderate (100-399 AU), high (400-999 AU), and very high (≥1000 AU). Adverse plaques were investigated by qualitative (visual categorization of positive remodelling, low-attenuation plaque, spotty calcification, and napkin ring sign) and quantitative (calcified, non-calcified, low-attenuation, and total plaque burden; Autoplaque) assessments. Of 1769 patients, 36% had a zero, 9% minimal, 20% low, 17% moderate, 10% high, and 8% very high CACS. Amongst patients with a zero CACS, 14% had non-obstructive disease, 2% had obstructive disease, 2% had visually assessed adverse plaques, and 13% had low-attenuation plaque burden >4%. Non-calcified and low-attenuation plaque burden increased between patients with zero, minimal, and low CACS (P < 0.001), but there was no statistically significant difference between those with medium, high, and very high CACS. Myocardial infarction occurred in 41 patients, 10% of whom had zero CACS. CACS >1000 AU and low-attenuation plaque burden were the only predictors of myocardial infarction, independent of obstructive disease, and 10-year cardiovascular risk score.

Conclusion: In patients with stable chest pain, zero CACS is associated with a good but not perfect prognosis, and CACS cannot rule out obstructive coronary artery disease, non-obstructive plaque, or adverse plaque phenotypes, including low-attenuation plaque.
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http://dx.doi.org/10.1093/ehjci/jeab135DOI Listing
September 2021

Trans-lesional fractional flow reserve gradient as derived from coronary CT improves patient management: ADVANCE registry.

J Cardiovasc Comput Tomogr 2022 Jan-Feb;16(1):19-26. Epub 2021 Sep 2.

Department of Radiology, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada; Department of Cardiology, Fiona Stanley Hospital, Harry Perkins Institute of Medical Research, University of Western Australia, Perth, Australia.

Background: The role of change in fractional flow reserve derived from CT (FFR) across coronary stenoses (ΔFFR) in guiding downstream testing in patients with stable coronary artery disease (CAD) is unknown.

Objectives: To investigate the incremental value of ΔFFR in predicting early revascularization and improving efficiency of catheter laboratory utilization.

Materials: Patients with CAD on coronary CT angiography (CCTA) were enrolled in an international multicenter registry. Stenosis severity was assessed as per CAD-Reporting and Data System (CAD-RADS), and lesion-specific FFR was measured 2 ​cm distal to stenosis. ΔFFR was manually measured as the difference of FFR across visible stenosis.

Results: Of 4730 patients (66 ​± ​10 years; 34% female), 42.7% underwent ICA and 24.7% underwent early revascularization. ΔFFR remained an independent predictor for early revascularization (odds ratio per 0.05 increase [95% confidence interval], 1.31 [1.26-1.35]; p ​< ​0.001) after adjusting for risk factors, stenosis features, and lesion-specific FFR. Among the 3 models (model 1: risk factors ​+ ​stenosis type and location ​+ ​CAD-RADS; model 2: model 1 ​+ ​FFR; model 3: model 2 ​+ ​ΔFFR), model 3 improved discrimination compared to model 2 (area under the curve, 0.87 [0.86-0.88] vs 0.85 [0.84-0.86]; p ​< ​0.001), with the greatest incremental value for FFR 0.71-0.80. ΔFFR of 0.13 was the optimal cut-off as determined by the Youden index. In patients with CAD-RADS ≥3 and lesion-specific FFR ≤0.8, a diagnostic strategy incorporating ΔFFR >0.13, would potentially reduce ICA by 32.2% (1638-1110, p ​< ​0.001) and improve the revascularization to ICA ratio from 65.2% to 73.1%.

Conclusions: ΔFFR improves the discrimination of patients who underwent early revascularization compared to a standard diagnostic strategy of CCTA with FFR, particularly for those with FFR 0.71-0.80. ΔFFR has the potential to aid decision-making for ICA referral and improve efficiency of catheter laboratory utilization.
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http://dx.doi.org/10.1016/j.jcct.2021.08.003DOI Listing
January 2022

Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity.

Circulation 2021 09 9;144(13):1024-1038. Epub 2021 Sep 9.

New York Universty Grossman School of Medicine (H.R.R.., S.B., J.D.N., J.S.H.).

Background: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) postulated that patients with stable coronary artery disease (CAD) and moderate or severe ischemia would benefit from revascularization. We investigated the relationship between severity of CAD and ischemia and trial outcomes, overall and by management strategy.

Methods: In total, 5179 patients with moderate or severe ischemia were randomized to an initial invasive or conservative management strategy. Blinded, core laboratory-interpreted coronary computed tomographic angiography was used to assess anatomic eligibility for randomization. Extent and severity of CAD were classified with the modified Duke Prognostic Index (n=2475, 48%). Ischemia severity was interpreted by independent core laboratories (nuclear, echocardiography, magnetic resonance imaging, exercise tolerance testing, n=5105, 99%). We compared 4-year event rates across subgroups defined by severity of ischemia and CAD. The primary end point for this analysis was all-cause mortality. Secondary end points were myocardial infarction (MI), cardiovascular death or MI, and the trial primary end point (cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest).

Results: Relative to mild/no ischemia, neither moderate ischemia nor severe ischemia was associated with increased mortality (moderate ischemia hazard ratio [HR], 0.89 [95% CI, 0.61-1.30]; severe ischemia HR, 0.83 [95% CI, 0.57-1.21]; =0.33). Nonfatal MI rates increased with worsening ischemia severity (HR for moderate ischemia, 1.20 [95% CI, 0.86-1.69] versus mild/no ischemia; HR for severe ischemia, 1.37 [95% CI, 0.98-1.91]; =0.04 for trend, =NS after adjustment for CAD). Increasing CAD severity was associated with death (HR, 2.72 [95% CI, 1.06-6.98]) and MI (HR, 3.78 [95% CI, 1.63-8.78]) for the most versus least severe CAD subgroup. Ischemia severity did not identify a subgroup with treatment benefit on mortality, MI, the trial primary end point, or cardiovascular death or MI. In the most severe CAD subgroup (n=659), the 4-year rate of cardiovascular death or MI was lower in the invasive strategy group (difference, 6.3% [95% CI, 0.2%-12.4%]), but 4-year all-cause mortality was similar.

Conclusions: Ischemia severity was not associated with increased risk after adjustment for CAD severity. More severe CAD was associated with increased risk. Invasive management did not lower all-cause mortality at 4 years in any ischemia or CAD subgroup. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01471522.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478888PMC
September 2021

Measurement of compensatory arterial remodelling over time with serial coronary computed tomography angiography and 3D metrics.

Eur Heart J Cardiovasc Imaging 2021 Sep 1. Epub 2021 Sep 1.

Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Yonsei University Health System, Seoul, South Korea.

Aims: The magnitude of alterations in which coronary arteries remodel and narrow over time is not well understood. We aimed to examine changes in coronary arterial remodelling and luminal narrowing by three-dimensional (3D) metrics from serial coronary computed tomography angiography (CCTA).

Methods And Results: From a multicentre registry of patients with suspected coronary artery disease who underwent clinically indicated serial CCTA (median interscan interval = 3.3 years), we quantitatively measured coronary plaque, vessel, and lumen volumes on both scans. Primary outcome was the per-segment change in coronary vessel and lumen volume from a change in plaque volume, focusing on arterial remodelling. Multivariate generalized estimating equations including statins were calculated comparing associations between groups of baseline percent atheroma volume (PAV) and location within the coronary artery tree. From 1245 patients (mean age 61 ± 9 years, 39% women), a total of 5721 segments were analysed. For each 1.00 mm3 increase in plaque volume, the vessel volume increased by 0.71 mm3 [95% confidence interval (CI) 0.63 to 0.79 mm3, P < 0.001] with a corresponding reduction in lumen volume by 0.29 mm3 (95% CI -0.37 to -0.21 mm3, P < 0.001). Serial 3D arterial remodelling and luminal narrowing was similar in segments with low and high baseline PAV (P ≥ 0.496). No differences were observed between left main and non-left main segments, proximal and distal segments and side branch and non-side branch segments (P ≥ 0.281).

Conclusions: Over time, atherosclerotic coronary plaque reveals prominent outward arterial remodelling that co-occurs with modest luminal narrowing. These findings provide additional insight into the compensatory mechanisms involved in the progression of coronary atherosclerosis.
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http://dx.doi.org/10.1093/ehjci/jeab138DOI Listing
September 2021

Implication of thoracic aortic calcification over coronary calcium score regarding the 2018 ACC/AHA Multisociety cholesterol guideline: results from the CAC Consortium.

Am J Prev Cardiol 2021 Dec 8;8:100232. Epub 2021 Aug 8.

Department of Imaging and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, United States.

Objective: TAC is associated with an increased atherosclerotic cardiovascular disease (ASCVD) risk, but it is unclear how to interpret thoracic aortic calcification (TAC) findings in conjunction with ASCVD risk and coronary artery calcium (CAC) score according to 2018 ACC/AHA Multisociety cholesterol guidelines. We evaluate the incremental value of thoracic aortic calcification TAC over CAC for predicting and reclassifying ASCVD mortality risk.

Method: The study included 30,630 asymptomatic individuals (mean age: 55 ± 8 years, male: 64%) from the CAC Consortium. TAC was categorized as TAC 0, 1-300, and >300. Patients were categorized as low (<5%), borderline (5-7.5%), intermediate (7.5-20%), or high (≥20%) 10-year ASCVD risk according to the Pooled Cohorts Equation. In the intermediate risk group, the utility of TAC beyond CAC for statin eligibility was assessed according to the guideline. CAC was categorized as CAC=0 (no statin), CAC 1-100 (favors statin), or CAC>100 (initiate stain).

Results: During the median 11.2 years (IQR 9.2-12.4) follow-up, 345 (1.1%) CVD deaths occurred. TAC>300 was associated with increased CVD mortality after adjusting for ASCVD risk and CAC (HR:4.72, 95% CI: 3.39-6.57, p<0.001). In borderline and intermediate risk groups, TAC improved discrimination when added to a model included ASCVD risk and CAC (C-statistic: 0.77 vs. 0.68 in borderline group; 0.67 vs. 0.63 in intermediate group, both  < 0.05). The addition of TAC over CAC improved risk reclassification in borderline, intermediate and high-risk groups (categorical net reclassification index: 0.40, 0.29, and 0.49, respectively, all  < 0.001). Of intermediate risk participants for whom consideration of CAC was recommended based on the guideline, TAC >300 was associated with an increased CVD mortality risk across each statin eligibility group (all  < 0.001, compared to TAC 0).

Conclusion: TAC was independently associated with CVD death. Among individuals with borderline or intermediate ASCVD risk, a TAC threshold of 300 may provide added prognostic and reclassification value beyond the current guideline-based approach.
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http://dx.doi.org/10.1016/j.ajpc.2021.100232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385171PMC
December 2021

Native Aortic Valve Disease Progression and Bioprosthetic Valve Degeneration in Patients With Transcatheter Aortic Valve Implantation.

Circulation 2021 10 29;144(17):1396-1408. Epub 2021 Aug 29.

Centre for Cardiovascular Science (E.T., T.R.G.C., A.F., M.K.D., R.B., N.L.C., A.K.B., N.G.U., M.C.W., E.J.R.v.B., D.E.N., M.R.D.), University of Edinburgh, UK.

Background: Major uncertainties remain regarding disease activity within the retained native aortic valve, and regarding bioprosthetic valve durability, after transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison with subjects with bioprosthetic surgical aortic valve replacement (SAVR).

Methods: In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, computed tomography angiography, and F-sodium fluoride (F-NaF) positron emission tomography. Participants (n=47) were imaged once with F-NaF positron emission tomography/computed tomography either at 1 month (n=9, 19%), 2 years (n=22, 47%), or 5 years (16, 34%) after valve implantation. Patients subsequently underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made with matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol.

Results: In patients with TAVI, native aortic valves demonstrated F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI (=0.36, =0.023). F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio, 1.3 [1.2-1.7] versus 1.3 [1.2-1.5], respectively; =0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8%, respectively; =0.78), computed tomography (15% versus 14%, respectively; =0.87), and positron emission tomography (15% versus 29%, respectively; =0.09). Baseline F-NaF uptake was associated with a subsequent change in peak aortic velocity for both TAVI (=0.7, <0.001) and SAVR (=0.7, <0.001). On multivariable analysis, F-NaF uptake was the only predictor of peak velocity progression (<0.001).

Conclusions: In patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease. Across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR, suggesting comparable midterm durability. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02304276.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542078PMC
October 2021

Association of Tube Voltage With Plaque Composition on Coronary CT Angiography: Results From PARADIGM Registry.

JACC Cardiovasc Imaging 2021 Dec 18;14(12):2429-2440. Epub 2021 Aug 18.

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Objectives: This study sought to investigate the impact of low tube voltage scanning heterogeneity of coronary luminal attenuation on plaque quantification and characterization with coronary computed tomography angiography (CCTA).

Background: The impact of low tube voltage and coronary luminal attenuation on quantitative coronary plaque remains uncertain.

Methods: A total of 1,236 consecutive patients (age: 60 ± 9 years; 41% female) who underwent serial CCTA at an interval of ≥2 years were included from an international registry. Patients with prior revascularization or nonanalyzable coronary CTAs were excluded. Total coronary plaque volume was assessed and subclassified based on specific Hounsfield unit (HU) threshold: necrotic core, fibrofatty plaque, and fibrous plaque and dense calcium. Luminal attenuation was measured in the aorta.

Results: With increasing luminal HU (<350, 350-500, and >500 HU), percent calcified plaque was increased (16%, 27%, and 40% in the median; P < 0.001), and fibrofatty plaque (26%, 13%, and 4%; P < 0.001) and necrotic core (1.6%, 0.3%, and 0.0%; P < 0.001) were decreased. Higher tube voltage scanning (80, 100, and 120 kV) resulted in decreasing luminal attenuation (689 ± 135, 497 ± 89, and 391 ± 73 HU; P < 0.001) and calcified plaque volume (59%, 34%, and 23%; P < 0.001) and increased fibrofatty plaque (3%, 9%, and 18%; P < 0.001) and necrotic core (0.2%, 0.1%, and 0.6%; P < 0.001). Mediation analysis showed that the impact of 100 kV on plaque composition, compared with 120 kV, was primarily caused by an indirect effect through blood pool attenuation. Tube voltage scanning of 80 kV maintained a direct effect on fibrofatty plaque and necrotic core in addition to an indirect effect through the luminal attenuation.

Conclusions: Low tube voltage usage affected plaque morphology, mainly through an increase in luminal HU with a resultant increase in calcified plaque and a reduction in fibrofatty and necrotic core. These findings should be considered as CCTA-based plaque measures are being used to guide medical management and, in particular, when being used as a measure of treatment response. (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging [PARADIGM]; NCT02803411).
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http://dx.doi.org/10.1016/j.jcmg.2021.07.011DOI Listing
December 2021

Association of Statin Treatment With Progression of Coronary Atherosclerotic Plaque Composition.

JAMA Cardiol 2021 11;6(11):1257-1266

Department of Pathology, CVPath Institute, Gaithersburg, Maryland.

Importance: The density of atherosclerotic plaque forms the basis for categorizing calcified and noncalcified morphology of plaques.

Objective: To assess whether alterations in plaque across a range of density measurements provide a more detailed understanding of atherosclerotic disease progression.

Design, Setting, And Participants: This cohort study enrolled 857 patients who underwent serial coronary computed tomography angiography 2 or more years apart and had quantitative measurements of coronary plaques throughout the entire coronary artery tree. The study was conducted from 2013 to 2016 at 13 sites in 7 countries.

Main Outcomes And Measures: The main outcome was progression of plaque composition of individual coronary plaques. Six plaque composition types were defined on a voxel-level basis according to the plaque attenuation (expressed in Hounsfield units [HU]): low attenuation (-30 to 75 HU), fibro-fatty (76-130 HU), fibrous (131-350 HU), low-density calcium (351-700 HU), high-density calcium (701-1000 HU), and 1K (>1000 HU). The progression rates of these 6 compositional plaque types were evaluated according to the interaction between statin use and baseline plaque volume, adjusted for risk factors and time interval between scans. Plaque progression was also examined based on baseline calcium density. Analysis was performed among lesions matched at baseline and follow-up. Data analyses were conducted from August 2019 through March 2020.

Results: In total, 2458 coronary lesions in 857 patients (mean [SD] age, 62.1 [8.7] years; 540 [63.0%] men; 548 [63.9%] received statin therapy) were included. Untreated coronary lesions increased in volume over time for all 6 compositional types. Statin therapy was associated with volume decreases in low-attenuation plaque (β, -0.02; 95% CI, -0.03 to -0.01; P = .001) and fibro-fatty plaque (β, -0.03; 95% CI, -0.04 to -0.02; P < .001) and greater progression of high-density calcium plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001) and 1K plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001). When analyses were restricted to lesions without low-attenuation plaque or fibro-fatty plaque at baseline, statin therapy was not associated with a change in overall calcified plaque volume (β, -0.03; 95% CI, -0.08 to 0.02; P = .24) but was associated with a transformation toward more dense calcium. Interaction analysis between baseline plaque volume and calcium density showed that more dense coronary calcium was associated with less plaque progression.

Conclusions And Relevance: The results suggest an association of statin use with greater rates of transformation of coronary atherosclerosis toward high-density calcium. A pattern of slower overall plaque progression was observed with increasing density. All findings support the concept of reduced atherosclerotic risk with increased densification of calcium.
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http://dx.doi.org/10.1001/jamacardio.2021.3055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374741PMC
November 2021

Association between coronary artery calcium and cardiovascular disease as a supporting cause in cancer: The CAC consortium.

Am J Prev Cardiol 2020 Dec 12;4:100119. Epub 2020 Nov 12.

Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, MD, USA.

Background: Identifying cancer patients at high risk of CVD is important for targeting CVD prevention strategies and evaluating chemotherapy options in the context of cardiotoxicity. Coronary artery calcium (CAC), a strong marker of coronary atherosclerosis, is used clinically to enhance risk assessment, yet the value of CAC for assessing risk of CVD complications in cancer is poorly understood.

Objective: In cases of cancer mortality, to determine the value of CAC for predicting risk of CVD as a supporting cause of death.

Methods: The CAC Consortium is a multi-center cohort of 66,636 asymptomatic adults without CVD who underwent CAC scanning. During a follow-up of 12.5 years, 1129 patients died of cancer and were included in this analysis. The primary outcome was presence of CVD listed as a supporting cause of cancer mortality on official death certificates obtained from the National Death Index. Logistic regression models were used to assess the odds of CVD being listed as a supporting cause of death by CAC.

Results: CVD was listed as a supporting cause of death in 306 (27%) cancer mortality cases. Baseline CAC was significantly higher in individuals with CVD-supported mortality. Odds ratios of having CVD-supported death increased by ASCVD risk score category [1.15 (0.81, 1.65) for 5-20% 10-year risk and 1.97 (1.36, 2.89) for ≥20% risk, in reference to <5% 10-year ASCVD risk] and CAC category [1.07 (0.73, 1.57) for CAC 1-99, 1.29 (0.87, 1.93) for CAC 100-399, and 2.14 (1.48, 3.09) for CAC ≥400 relative to CAC 0]. In the CAC ≥400 group, these associations remained significantly elevated after adjustment for traditional CVD risk factors [1.66 (1.08, 2.55)]. A sensitivity analysis using a more specific ASCVD-supported mortality outcome, defined as coronary heart disease, stroke, and peripheral artery disease, demonstrated that adjusted odds of ASCVD-supported cancer mortality were significantly elevated in the CAC ≥400 group relative to CAC 0 [3.09 (1.39, 7.38)].

Conclusions: In cancer mortality cases, high antecedent CAC predicted risk of having CVD as a supporting cause of death on official death certificates, independently of ASCVD risk score and CVD risk factors. CAC may be useful for identifying cancer patients at high CVD risk who might benefit from more intense preventive cardiovascular therapies.
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http://dx.doi.org/10.1016/j.ajpc.2020.100119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315471PMC
December 2020

Risk Markers for Limited Coronary Artery Calcium in Persons With Significant Aortic Valve Calcium (From the Multi-ethnic Study of Atherosclerosis).

Am J Cardiol 2021 10 27;156:58-64. Epub 2021 Jul 27.

The Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

The early stages of aortic valve calcification (AVC) and coronary artery calcification (CAC) include shared ASCVD risk factors, yet there is considerable heterogeneity between the burden of AVC, and CAC. We sought to identify the markers associated with limited CAC among persons with significant AVC. There were 325 participants from the Multi-Ethnic Study of Atherosclerosis without clinical ASCVD and with AVC ≥100 Agatston units (AU) at Visit 1. Multivariable-adjusted prevalence ratios for limited CAC (0 to 99 AU) were calculated using modified Poisson regression. Participants had a mean age of 72.1 years, median AVC score of 209, and 34% were women. A total of 133 (41%) participants had CAC <100, of whom 46/133 had CAC = 0. Younger age (PR = 1.40, 95% CI: 1.22 to 1.62, per 10-years), female gender (PR = 1.68, 95% CI: 1.28 to 2.20), and low 10-year ASCVD risk (PR = 2.30, 95% CI: 1.85 to 2.85) were most strongly associated with limited CAC. Neither a normal lipoprotein(a) nor normal measures of inflammation were significantly associated with limited CAC. Lower serum phosphate (PR = 1.15, 95% CI: 1.01 to 1.31; per 0.5 mg/dl lower) and calcium-phosphate product (PR = 1.16, 95% CI: 1.02 to 1.34; per SD lower) were associated with an approximately 15% higher prevalence of limited CAC. In conclusion, more than 40% of persons with significant AVC had CAC. Beyond traditional risk factors, lower serum phosphate, and lower calcium-phosphate product were associated with a higher prevalence of limited CAC.
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http://dx.doi.org/10.1016/j.amjcard.2021.06.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429123PMC
October 2021

Synergistic Assessment of Mortality Risk According to Body Mass Index and Exercise Ability and Capacity in Patients Referred for Radionuclide Stress Testing.

Mayo Clin Proc 2021 12 24;96(12):3001-3011. Epub 2021 Jul 24.

Department of Imaging and Department of Medicine, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

Objective: To determine the interrelationship between body mass index (BMI), mode of stress testing (exercise or pharmacological), exercise capacity, and all-cause mortality in patients referred for stress-rest single photon emission computed tomography myocardial perfusion imaging.

Patients And Methods: We evaluated all-cause mortality in 21,638 patients undergoing stress-rest single photon emission computed tomography myocardial perfusion imaging between January 2, 1991, and December 31, 2012. Patients were divided into exercise and pharmacologically tested groups and 9 BMI categories. The median follow-up was 12.8 years (range, 5.0-26.8 years).

Results: In exercise patients, mortality was increased with both low and high BMI vs patients with a normal referent BMI of 22.5 to 24.9 kg/m. In pharmacologically tested patients, only low BMI, but not high BMI, was associated with increased mortality vs normal BMI. When exercise and pharmacologically tested groups were compared directly, pharmacologically tested patients manifested a marked increase in mortality risk vs exercise patients within each BMI category, ranging from an approximately 4-fold increase in mortality in those with normal or high BMI to a 12.3-fold increase in those with low BMI values. Similar findings were observed in a cohort of 4804 exercise and 4804 pharmacologically tested patients matched to have similar age and coronary artery disease risk factor profiles. In exercise patients, further risk stratification was achieved when considering both BMI and metabolic equivalent tasks of achieved exercise.

Conclusion: The combined assessment of BMI and exercise ability and capacity provides synergistic and marked risk stratification of future mortality risk in patients referred for radionuclide stress testing, providing considerable insights into the "obesity paradox" that is observed in populations referred for stress testing.
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http://dx.doi.org/10.1016/j.mayocp.2021.05.021DOI Listing
December 2021

Prognostic Value of Phase Analysis for Predicting Adverse Cardiac Events Beyond Conventional Single-Photon Emission Computed Tomography Variables: Results From the REFINE SPECT Registry.

Circ Cardiovasc Imaging 2021 07 20;14(7):e012386. Epub 2021 Jul 20.

Department of Imaging, Medicine, and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA (K.K., R.J.H.M., Y.O., S.D.V.K., M.A.D., L.-H.H., H.G., J.X.L., T.P., P.B.K. B.K.T., D.D., D.S.B., P.J.S.).

Background: Phase analysis of single-photon emission computed tomography myocardial perfusion imaging provides dyssynchrony information which correlates well with assessments by echocardiography, but the independent prognostic significance is not well defined. This study assessed the independent prognostic value of single-photon emission computed tomography-myocardial perfusion imaging phase analysis in the largest multinational registry to date across all modalities.

Methods: From the REFINE SPECT (Registry of Fast Myocardial Perfusion Imaging With Next Generation SPECT), a total of 19 210 patients were included (mean age 63.8±12.0 years and 56% males). Poststress total perfusion deficit, left ventricular ejection fraction, and phase variables (phase entropy, bandwidth, and SD) were obtained automatically. Cox proportional hazards analyses were performed to assess associations with major adverse cardiac events (MACE).

Results: During a follow-up of 4.5±1.7 years, 2673 (13.9%) patients experienced MACE. Annualized MACE rates increased with phase variables and were ≈4-fold higher between the second and highest decile group for entropy (1.7% versus 6.7%). Optimal phase variable cutoff values stratified MACE risk in patients with normal and abnormal total perfusion deficit and left ventricular ejection fraction. Only entropy was independently associated with MACE. The addition of phase entropy significantly improved the discriminatory power for MACE prediction when added to the model with total perfusion deficit and left ventricular ejection fraction (<0.0001).

Conclusions: In a largest to date imaging study, widely representative, international cohort, phase variables were independently associated with MACE and improved risk stratification for MACE beyond the prediction by perfusion and left ventricular ejection fraction assessment alone. Phase analysis can be obtained fully automatically, without additional radiation exposure or cost to improve MACE risk prediction and, therefore, should be routinely reported for single-photon emission computed tomography-myocardial perfusion imaging studies.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.012386DOI Listing
July 2021

Diagnostic Accuracy of Cardiovascular Magnetic Resonance for Cardiac Transplant Rejection: A Meta-Analysis.

JACC Cardiovasc Imaging 2021 Dec 14;14(12):2337-2349. Epub 2021 Jul 14.

Department of Imaging, Mark Taper Imaging Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. Electronic address:

Objectives: The aim of this meta-analysis was to assess the diagnostic performance of various CMR imaging parameters for evaluating acute cardiac transplant rejection.

Background: Endomyocardial biopsy is the current gold standard for detection of acute cardiac transplant rejection. Cardiac magnetic resonance (CMR) is uniquely capable of myocardial tissue characterization and may be useful as a noninvasive alternative for the diagnosis of graft rejection.

Methods: PubMed and Web of Science were searched for relevant publications reporting on the use of CMR myocardial tissue characterization for detection of acute cardiac transplant rejection with endomyocardial biopsy as the reference standard. Pooled sensitivity, specificity, and hierarchical modeling-based summary receiver-operating characteristic curves were calculated.

Results: Of 478 papers, 10 studies comprising 564 patients were included. The sensitivity and specificity for the detection of acute cardiac transplant rejection were 84.6 (95% CI: 65.6-94.0) and 70.1 (95% CI: 54.2-82.2) for T1, 86.5 (95% CI: 72.1-94.1) and 85.9 (95% CI: 65.2-94.6) for T2, 91.3 (95% CI: 63.9-98.4) and 67.6 (95% CI: 56.1-77.4) for extracellular volume fraction (ECV), and 50.1 (95% CI: 31.2-68.9) and 60.2 (95% CI: 36.7-79.7) for late gadolinium enhancement (LGE). The areas under the hierarchical modeling-based summary receiver-operating characteristic curve were 0.84 (95% CI: 0.81-0.87) for T1, 0.92 (95% CI: 0.89-94) for T2, 0.78 (95% CI: 0.74-0.81) for ECV, and 0.56 (95% CI: 0.51-0.60) for LGE. T2 values demonstrated the highest diagnostic accuracy, followed by native T1, ECV, and LGE (all P values <0.001 for T1, ECV, and LGE vs T2).

Conclusions: T2 mapping demonstrated higher diagnostic accuracy than other CMR techniques. Native T1 and ECV provide high diagnostic use but lower diagnostic accuracy compared with T2, which was related primarily to lower specificity. LGE showed poor diagnostic performance for detection of rejection.
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http://dx.doi.org/10.1016/j.jcmg.2021.05.008DOI Listing
December 2021

Clinical Deployment of Explainable Artificial Intelligence of SPECT for Diagnosis of Coronary Artery Disease.

JACC Cardiovasc Imaging 2021 Jul 7. Epub 2021 Jul 7.

Department of Imaging (Division of Nuclear Medicine) Medicine (Division of Artificial Intelligence in Medicine), and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA. Electronic address:

Objectives: This study sought to develop and evaluate a novel, general purpose, explainable deep learning model (coronary artery disease-deep learning [CAD-DL]) for the detection of obstructive CAD following single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI).

Background: Explainable artificial intelligence (AI) can be integrated within standard clinical software to facilitate the acceptance of the diagnostic findings during clinical interpretation.

Methods: A total of 3,578 patients with suspected CAD undergoing SPECT MPI and invasive coronary angiography within a 6 month interval from 9 centers were studied. CAD-DL computes the probability of obstructive CAD from stress myocardial perfusion, wall motion, and wall thickening maps, as well as left ventricular volumes, age, and sex. Myocardial regions contributing to the CAD-DL prediction are highlighted to explain the findings to the physician. A clinical prototype was integrated using a standard clinical workstation. Diagnostic performance by CAD-DL was compared to automated quantitative total perfusion deficit (TPD) and reader diagnosis.

Results: In total, 2,247 patients (63%) had obstructive CAD. In 10-fold repeated testing, the area under the receiver-operating characteristic curve (AUC) (95% CI) was higher according to CAD-DL (AUC: 0.83; 95% CI: 0.82-0.85]) than stress TPD (AUC: 0.78; 95% CI: 0.77-0.80]) or reader diagnosis (AUC: 0.71; 95% CI: 0.69-0.72]; P < 0.0001 for both). In external testing, the AUC in 555 patients was higher according to CAD-DL (AUC: 0.80; 95% CI: 0.76-0.84]) than stress TPD (AUC: 0.73; 95% CI: 0.69-0.77) or reader diagnosis (AUC: 0.65; 95% CI: 0.61-0.69; P < 0.001). The present model can be integrated within standard clinical software and generates results rapidly (<12 s on a standard clinical workstation) and therefore could readily be incorporated into a typical clinical workflow.

Conclusions: The deep-learning model significantly surpasses the diagnostic accuracy of standard quantitative analysis and clinical visual reading for MPI. Explainable artificial intelligence can be integrated within standard clinical software to facilitate acceptance of artificial intelligence diagnosis of CAD following MPI.
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http://dx.doi.org/10.1016/j.jcmg.2021.04.030DOI Listing
July 2021
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