Publications by authors named "Renu Virmani"

636 Publications

Plaque erosion masquerading as spontaneous coronary artery dissection: A case of sudden coronary death.

J Cardiovasc Comput Tomogr 2021 Oct 8. Epub 2021 Oct 8.

Dalio Institute of Cardiovascular Imaging, Department of Radiology, New York-Presbyterian Hospital and Weill Cornell Medicine, New York, NY, USA.

The three most common mechanisms of thrombosis in acute coronary syndrome (ACS) are plaque rupture, plaque erosion and calcified nodule. Plaque erosion occurs over an intact fibrous cap, commonly over pathological intimal thickening (PIT) rather than thin cap fibroatheroma (TCFA), and is more common among younger and female patients. A very rare mechanism of ACS is spontaneous coronary artery dissection (SCAD), resulting from the formation of an intramural hematoma and/or intimal disruption. We present a case of sudden coronary death with the appearance of SCAD on coronary computed tomography angiography (CCTA).
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http://dx.doi.org/10.1016/j.jcct.2021.10.001DOI Listing
October 2021

Early spontaneous reperfusion after acute myocardial infarction: true association with plaque phenotype or simple clinical observation?

EuroIntervention 2021 Oct 1;17(8):e613-e615. Epub 2021 Oct 1.

Deutsches Herzzentrum München, Technical University of Munich, Munich, Germany.

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http://dx.doi.org/10.4244/EIJV17I8A110DOI Listing
October 2021

Autopsy findings of left atrial appendage closure device.

Cardiovasc Pathol 2021 Sep 15;56:107384. Epub 2021 Sep 15.

Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan.

We report an autopsy case of an 80-year-old woman who underwent left atrial appendage closure with a WATCHMAN (Boston Scientific, St. Paul, MN, USA) device. This is the first report of histologic assessment following left atrial appendage closure with a WATCHMAN device at 3 months. Gross and histopathological examinations revealed neoendocardial coverage of the WATCHMAN device. Partial endothelialization was verified by CD34 staining; however, it remains unclear when complete endothelialization is likely to occur.
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http://dx.doi.org/10.1016/j.carpath.2021.107384DOI Listing
September 2021

COBRA PzF™ coronary stent in clinical and preclinical studies: setting the stage for new antithrombotic strategies?

Future Cardiol 2021 Sep 15. Epub 2021 Sep 15.

CVPath Institute, 19 Firstfield Road, Gaithersburg, MD 20878, USA.

Major advances have been made in coronary artery stent technology over the last decades. Drug-eluting stents reduced in-stent restenosis and have shown better outcomes compared with bare metal stents, yet some limitations still exist to their use. Because they delay healing of the vessel wall, longer dual antiplatelet therapy is mandatory to mitigate against stent thrombosis and this limitation is most concerning in subjects at high risk for bleeding. The COBRA PzF nanocoated coronary stent has been associated with accelerated endothelialization relative to drug-eluting stents, reduced inflammation and thromboresistance in preclinical studies, suggesting more flexible dual antiplatelet therapy requirement with potential benefits especially in those at high bleeding risk. Here, we discuss the significance of COBRA PzF in light of recent experimental and clinical studies.
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http://dx.doi.org/10.2217/fca-2021-0057DOI Listing
September 2021

Medial Arterial Calcification: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 Sep;78(11):1145-1165

Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Medial arterial calcification (MAC) is a chronic systemic vascular disorder distinct from atherosclerosis that is frequently but not always associated with diabetes mellitus, chronic kidney disease, and aging. MAC is also a part of more complex phenotypes in numerous less common diseases. The hallmarks of MAC include disseminated and progressive precipitation of calcium phosphate within the medial layer, a prolonged and clinically silent course, and compromise of hemodynamics associated with chronic limb-threatening ischemia. MAC increases the risk of complications during vascular interventions and mitigates their outcomes. With the exception of rare monogenetic defects affecting adenosine triphosphate metabolism, MAC pathogenesis remains unknown, and causal therapy is not available. Implementation of genetics and omics-based approaches in research recognizing the critical importance of calcium phosphate thermodynamics holds promise to unravel MAC molecular pathogenesis and to provide guidance for therapy. The current state of knowledge concerning MAC is reviewed, and future perspectives are outlined.
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http://dx.doi.org/10.1016/j.jacc.2021.06.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439554PMC
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

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

JACC Cardiovasc Imaging 2021 Aug 11. Epub 2021 Aug 11.

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
August 2021

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

JAMA Cardiol 2021 Aug 18. Epub 2021 Aug 18.

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
August 2021

Efficacy and safety of cerebral embolic protection systems during transcatheter aortic valve replacement: a review of current clinical findings.

Expert Rev Cardiovasc Ther 2021 Aug 21;19(8):725-737. Epub 2021 Jul 21.

CVPath Institute, Gaithersburg, MD, USA.

Introduction: Cerebrovascular events are one of the most serious consequences after transcatheter aortic valve replacement (TAVR). More than half of the cerebrovascular events following TAVR are due to procedure-related emboli. Embolic protection devices (EPDs) have the potential to decrease cerebrovascular events during TAVR procedure. However, randomized controlled trials (RCTs) have not conclusively determined if EPDs are effective, likely because of small number of patients enrolled. However, meta-analyses and propensity-matched analyses from large registries have shown efficacy and suggest the importance of EPDs in prevention of stroke during TAVR and perhaps other structural heart procedures.

Areas Covered: This review will focus on clinical and histopathologic studies examining the efficacy, safety, and histopathologic device capture findings in the presence and absence of EPDs during TAVR procedures.

Expert Opinion: Clinical studies have not conclusively determined the efficacy of EPDs. Current ongoing large-scale RCT (PROTECTED TAVR [NCT04149535]) has the potential to prove their efficacy. Histopathological evaluation of debris captured by EPDs contributes to our understanding of the mechanisms of TAVR procedure-related embolic events and suggests the importance of preventing cerebral embolization of debris released during this and other structural heart procedures.
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http://dx.doi.org/10.1080/14779072.2021.1955346DOI Listing
August 2021

Acute thrombogenicity of fluoropolymer coated stents versus competitive drug-eluting stents under single antiplatelet therapy.

Int J Cardiol 2021 09 23;338:42-49. Epub 2021 Jun 23.

CVPath Institute, Inc., Gaithersburg, MD, USA; University of Maryland, Baltimore, MD, USA. Electronic address:

Background: Recent clinical studies have suggested the feasibility of 1-month dual antiplatelet therapy (DAPT) for patients receiving drug-eluting stent (DES). Although our previous ex-vivo swine arteriovenous (AV) shunt studies under low dose heparin treatment suggested superior thromboresistance of fluoropolymer-coated everolimus-eluting stent (FP-EES) when compared to other polymer-based DESs, the relative thromboresistance of different DESs under single antiplatelet therapy (SAPT) has never been examined. This study aimed to evaluate platelet adhesion under SAPT in competitive DESs in the in vitro flow loop model and ex vivo swine AV shunt model.

Methods: The thrombogenicity of FP-EES, BioLinx polymer zotarolimus-eluting stent (BL-ZES), and biodegradable polymer everolimus-eluting stent (BP-EES) was assessed acutely using the swine AV shunt model under aspirin or clopidogrel SAPT. Stents were immunostained using antibodies against platelets and inflammatory markers and evaluated by confocal microscopy. Also, the adhesion of platelet and albumin on the three DESs was assessed by an in-vitro flow loop model using human platelets under aspirin SAPT and fluorescent albumin, respectively.

Results: In the shunt model, FP-EES showed significantly less platelet and inflammatory cell adhesion than BL-ZES and BP-EES. In the flow loop model, FP-EES showed significantly less platelet coverage and more albumin adsorption than BL-ZES and BP-EES.

Conclusions: These results suggest FP-EES may have particular advantage for short-term DAPT compared to other DESs.
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http://dx.doi.org/10.1016/j.ijcard.2021.06.034DOI Listing
September 2021

Principles of Intravascular Lithotripsy for Calcific Plaque Modification.

JACC Cardiovasc Interv 2021 Jun;14(12):1275-1292

Columbia University Medical Center, New York, New York, USA.

A significant proportion of lesions treated with transcatheter interventions in the coronary and peripheral vascular beds exhibit moderate to severe calcific plaques known to portend lower procedural success rates, increased peri-procedural adverse events, and unfavorable clinical outcomes compared with noncalcific plaques. Adapted from lithotripsy technology used for treatment of ureterorenal calculi, intravascular lithotripsy (IVL) is a novel technique for the treatment of severely calcific plaque lesions that uses acoustic shockwaves in a balloon-based delivery system. Shockwaves induce calcium fractures, which facilitate stent expansion and luminal gain. In this review, the authors summarize the physics, preclinical and clinical data on IVL use in the coronary and peripheral vasculature, and future directions of IVL in transcatheter cardiovascular therapies.
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http://dx.doi.org/10.1016/j.jcin.2021.03.036DOI Listing
June 2021

Endothelial Recovery in Bare Metal Stents and Drug-Eluting Stents on a Single-Cell Level.

Arterioscler Thromb Vasc Biol 2021 08 24;41(8):2277-2292. Epub 2021 Jun 24.

CVPath Institute, Gaithersburg, MD (A.C., L.G., R.F., C.J., S.K., A.S., H.J., Y.S., K.H.P., F.D.K., M.E.R., D.S., R.V., A.V.F.).

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.316472DOI Listing
August 2021

Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals.

JAMA Cardiol 2021 09;6(9):1013-1022

CVPath Institute, Gaithersburg, Maryland.

Importance: Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined.

Objective: To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes.

Design, Setting, And Participants: This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021.

Main Outcomes And Measures: The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD.

Results: The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants.

Conclusions And Relevance: In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.
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http://dx.doi.org/10.1001/jamacardio.2021.1573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173469PMC
September 2021

Initial Clinical Trial of a Novel Pulmonary Valved Conduit.

Semin Thorac Cardiovasc Surg 2021 May 11. Epub 2021 May 11.

Heart Center, University Hospital of Cologne, Cologne, Germany.

Valved allografts and xenografts for reconstruction of the right ventricular outflow tract (RVOT) lack durability and do not grow. We report the first clinical use of a completely bioabsorbable valved conduit (Xeltis pulmonary valve - XPV) in children. Twelve children (six male), median age five (two to twelve) years and median weight 17 (10 to 43) kg, underwent RVOT reconstruction with the XPV. Diagnoses were: pulmonary atresia with ventricular septal defect (VSD) (n = 4), tetralogy of Fallot (n = 4), common arterial trunk (n = 3), and transposition of the great arteries with VSD and pulmonary stenosis (n = 1). All had had previous surgery, including prior RVOT conduit implantation in six. Two diameters of conduit 16mm (n = 5) and 18mm (n = 7) were used. At 24 months none of the patients has required surgical re-intervention, 9 of the 12 are in NYHA functional class I and three patients in NYHA class II. None of the conduits has shown evidence of progressive stenosis, dilation or aneurysm formation. Residual peak gradient of >40 mm Hg was observed in three patients, caused by kinking of the conduit at implantation in 1 and distal stenosis in the peripheral pulmonary arteries in 2 patients. Five patients developed severe pulmonary valve insufficiency (PI); the most common mechanism was prolapse of at least one of the valve leaflets. The XPV conduit is a promising innovation for RVOT reconstruction. Progressive PI requires however an improved design (geometry, thickness) of the valve leaflets.
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http://dx.doi.org/10.1053/j.semtcvs.2021.03.036DOI Listing
May 2021

Association between Aortic Valve Calcification Progression and Coronary Atherosclerotic Plaque Volume Progression in the PARADIGM Registry.

Radiology 2021 07 11;300(1):79-86. Epub 2021 May 11.

From the Division of Cardiology, Department of Internal Medicine, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul, South Korea (S.E.L.); Yonsei-Cedars-Sinai Integrative Cardiovascular Imaging Research Center, Yonsei University College of Medicine, Yonsei University Health System, Seoul, South Korea (S.E.L., J.M.S., H.J.C.); Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Yonsei University Health System, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea (J.M.S., S.S., H.J.C.); Centro Cardiologico Monzino, IRCCS, Milan, Italy (D.A., E.C., G.P.); Houston Methodist DeBakey Heart and Vascular Center, Houston Methodist Hospital, Houston, Tex (M.H.A.); Department of Medicine, Los Angeles Biomedical Research Institute, Torrance, Calif (M.J.B.); Cardiovascular Imaging Unit, SDN IRCCS, Naples, Italy (F.C.); Department of Cardiology, William Beaumont Hospital, Royal Oak, Mich (K.C.); Pusan University Hospital, Busan, South Korea (J.H.C.); Seoul National University Bundang Hospital, Seongnam, South Korea (E.J.C.); Department of Radiology, Casa de Saude São Jose, Rio de Janeiro, Brazil (I.G.); Department of Radiology and Nuclear Medicine, German Heart Center Munich, Munich, Germany (M.H.); Department of Internal Medicine, Seoul National University College of Medicine, Cardiovascular Center, Seoul National University Hospital, Seoul, South Korea (Y.J.K.); Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea (B.K.L.); Department of Medicine and Radiology, University of British Columbia, Vancouver, Canada (J.A.L.); Department of Radiology, Area Vasta 1/ASUR Marche, Urbino, Italy (E.M.); UNICA, Unit of Cardiovascular Imaging, Hospital da Luz, Lisbon, Portugal (H.M., P.d.A.G.); Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Mass (P.H.S.); Division of Cardiology, Emory University School of Medicine, Atlanta, Ga (H.S.); Department of Pathology, CVPath Institute, Gaithersburg, Md (R.V.); Icahn School of Medicine at Mount Sinai, New York, NY (J.N.); Department of Imaging and Medicine, Cedars-Sinai Medical Center, Los Angeles, Calif (D.S.B.); Department of Radiology, New York-Presbyterian Hospital and Weill Cornell Medicine, New York, NY (L.J.S., F.Y.L., J.K.M.); Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands (J.J.B.).

Background Aortic valve calcification (AVC) is a key feature of aortic stenosis, and patients with aortic stenosis often have coronary -artery disease. Therefore, proving the association between the progression of AVC and coronary atherosclerosis could improve follow-up and treatment strategies. Purpose To explore the association between the progression of AVC and the progression of total and plaque volume composition from a large multicenter registry of serial coronary CT angiographic examinations. Materials and Methods A prospective multinational registry (PARADIGM) of consecutive participants who underwent serial coronary CT angiography at intervals of every 2 years or more was performed (January 2003-December 2015). AVC and the total and plaque volume composition at baseline and follow-up angiography were quantitatively analyzed. Plaque volumes were normalized by using the mean total analyzed vessel length of the study population. Multivariable linear mixed-effects models were constructed. Results Overall, 594 participants (mean age ± standard deviation, 62 years ± 10; 330 men) were included (mean interval between baseline and follow-up angiography, 3.9 years ± 1.5). At baseline, the AVC score was 31 Agatston units ± 117, and the normalized total plaque volume at baseline was 122 mm ± 219. After adjustment for age, sex, clinical risk factors, and medication use, AVC was independently associated with total plaque volume (standardized β = 0.24; 95% CI: 0.16, 0.32; < .001) and both calcified (β = 0.26; 95% CI: 0.18, 0.34; < .001) and noncalcified (β = 0.17; 95% CI: 0.08, 0.25; < .001) plaque volumes at baseline. The progression of AVC was associated with the progression of total plaque volume (β = 0.13; 95% CI: 0.03, 0.22; = .01), driven solely by calcified plaque volume (β = 0.24; 95% CI: 0.14, 0.34; < .001) but not noncalcified plaque volumes (β = -0.06; 95% CI: -0.14, 0.03; = .17). Conclusion The overall burden of coronary atherosclerosis was associated with aortic valve calcification at baseline. However, the progression of aortic valve calcification was associated with only the progression of calcified plaque volume but not with the -progression of noncalcified plaque volume. Clinical trial registration no. NCT02803411 © RSNA, 2021 See also the editorial by Sinitsyn in this issue.
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http://dx.doi.org/10.1148/radiol.2021202630DOI Listing
July 2021

Intravascular imaging and histological correlates of medial and intimal calcification in peripheral artery disease.

EuroIntervention 2021 Oct 1;17(8):e688-e698. Epub 2021 Oct 1.

CVPath Institute, Gaithersburg, MD, USA.

Background: In peripheral artery disease, two different types of calcification are frequently observed, i.e., medial and intimal calcification.

Aims: The aim of this study was to determine the ability of intravascular ultrasound (IVUS) imaging and optical frequency domain imaging (OFDI) to detect medial and intimal calcification in human peripheral arteries.

Methods: We performed ex vivo intravascular imaging of cadaveric human peripheral arteries with calcifications. IVUS and OFDI images were co-registered with histology. A total of 12 legs from nine patients were examined, and 438 cross-sectional images were co-registered with histology.

Results: OFDI could detect 183 of 231 intimal calcifications by histology, whereas IVUS could detect 194 (OFDI: sensitivity 79%, specificity 86%, area under the curve [AUC] 0.83; IVUS: sensitivity 84%, specificity 85%, AUC 0.85). Of 245 medial calcifications by histology, 160 and 164 were detected by OFDI and IVUS, respectively (OFDI: sensitivity 65%, specificity 85%, AUC 0.75; IVUS: sensitivity 67%, specificity 80%, AUC 0.74). Medial calcification with overlying intimal calcification (overlapped calcification) and an unclear border between intima and media were the main reasons for misdiagnosis. Without those 89 overlapped calcifications, sensitivity in both OFDI and IVUS was improved (OFDI: sensitivity 81%, specificity 85%, AUC 0.83; IVUS: sensitivity 88%, specificity 80%, AUC 0.84).

Conclusions: There are limitations in detecting medial calcification in overlapped intimal calcification and with an unclear border between intima and media by both IVUS and OFDI. It is important to distinguish medial calcification from intimal calcification before proceeding with endovascular therapy since different approaches will be required.
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http://dx.doi.org/10.4244/EIJ-D-20-01336DOI Listing
October 2021

Paradise™ Ultrasound Renal Denervation System for the treatment of hypertension.

Future Cardiol 2021 Sep 20;17(6):931-944. Epub 2021 Apr 20.

CVPath Institute, Inc., Gaithersburg, MD, USA.

Catheter-based renal denervation is a novel treatment approach for patients with hypertension and initial unblinded trials have shown promising results. The Paradise™ Ultrasound Renal Denervation System (ReCor Medical, CA, USA) is an ultrasound-based catheter with a distal balloon that acts as a coolant to protect the renal arterial wall. This device received CE-mark in 2012. Randomized, sham-controlled trials and postmarket studies have shown promising efficacy and safety results. Currently, three additional ongoing randomized, sham-controlled trials are underway in the USA, Europe, Japan and Korea, and the results will be pivotal in device approval in some of these countries. These studies with larger numbers of patients and longer duration of follow-up are needed to further confirm the safety and efficacy of this device.
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http://dx.doi.org/10.2217/fca-2020-0228DOI Listing
September 2021

Effects of simulated COVID-19 cytokine storm on stent thrombogenicity.

Cardiovasc Revasc Med 2021 Apr 8. Epub 2021 Apr 8.

CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD 20878, United States of America. Electronic address:

Background: Cytokine storm-related hypercoagulation may be important in the pathogenesis of stent thrombosis in patients with SARS-CoV-2. Whether stent polymers behave differently under such conditions has never been explored.

Methods: Fluorinated polymer-nanocoated and uncoated COBRA stents (CeloNova), BioLinx-polymer-coated Resolute Onyx stents (Medtronic), and Synergy stents (Boston Scientific), which are abluminally coated with a bioabsorbable polymer, were exposed to human blood from healthy donors which was supplemented with 400 pg/mL IL-6 and 100 pg/mL TNF-α, similar to what is seen in cytokine storm caused by SARS-CoV-2. Platelet adhesion and neutrophil activation, assessed by immunofluorescence, were compared under cytokine storm and control conditions (untreated blood) (n = 4 experimental runs).

Results: Platelet adhesion values, defined as %platelet-covered area x staining intensity, were significantly lower in coated and uncoated COBRA and in Resolute Onyx than in Synergy under control conditions (1.28 × 10 ± 0.43 × 10 vs. 2.92 × 10 ± 0.49 × 10 vs. 3.57 × 10 ± 0.73 × 10 vs. 9.94 × 10 ± 0.99 × 10; p ≤0.0001). In cytokine storm, platelet adhesion values remained low in coated COBRA-PzF (1.78 × 10 ± 0.38 × 10) compared to all other devices (uncoated COBRA: 5.92 × 10 ± 0.96 × 10; Resolute Onyx: 7.27 × 10 ± 1.82 × 10; Synergy: 11.28 × 10 ± 1.08 × 10; p ≤ 0.0001). Although cytokine storm conditions significantly increased neutrophil activation in all stents, it was significantly less in coated and uncoated COBRA, and in Resolute Onyx than in Synergy.

Conclusions: Blood-biomaterials interactions may determine the thrombogenic potential of stents. Under simulated cytokine storm conditions, fluoropolymer-coated stents showed the most favorable anti-thrombogenic and anti-inflammatory properties.
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http://dx.doi.org/10.1016/j.carrev.2021.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026249PMC
April 2021

Radiation-Induced Vascular Disease-A State-of-the-Art Review.

Front Cardiovasc Med 2021 30;8:652761. Epub 2021 Mar 30.

Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Since the 1990s, there has been a steady increase in the number of cancer survivors to an estimated 17 million in 2019 in the US alone. Radiation therapy today is applied to a variety of malignancies and over 50% of cancer patients. The effects of ionizing radiation on cardiac structure and function, so-called radiation-induced heart disease (RIHD), have been extensively studied. We review the available published data on the mechanisms and manifestations of RIHD, with a focus on vascular disease, as well as proposed strategies for its prevention, screening, diagnosis, and management.
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http://dx.doi.org/10.3389/fcvm.2021.652761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042773PMC
March 2021

Atherogenic index of plasma and the risk of rapid progression of coronary atherosclerosis beyond traditional risk factors.

Atherosclerosis 2021 05 13;324:46-51. Epub 2021 Mar 13.

Department of Radiology, New York-Presbyterian Hospital and Weill Cornell Medicine, New York, NY, USA.

Background And Aims: The atherogenic index of plasma (AIP) has been suggested as a marker of plasma atherogenicity. This study aimed to assess the association between AIP and the rapid progression of coronary atherosclerosis using serial coronary computed tomography angiography (CCTA).

Methods: A total of 1488 adults (60.9 ± 9.2 years, 58.9% male) who underwent serial CCTA with a median inter-scan period of 3.4 years were included. AIP was defined as the base 10 logarithm of the ratio of the concentrations of triglyceride to high-density lipoprotein cholesterol. Rapid plaque progression (RPP) was defined as the change of percentage atheroma volume (PAV) ≥1.0%/year. All participants were divided into three groups based on AIP tertiles.

Results: Baseline total PAV (median [interquartile range (IQR)]) (%) (group I [lowest]: 1.91 [0.00, 6.21] vs. group II: 2.82 [0.27, 8.83] vs. group III [highest]: 2.70 [0.41, 7.50]), the annual change of total PAV (median [IQR]) (%/year) (group I: 0.27 [0.00, 0.81] vs. group II: 0.37 [0.04, 1.11] vs. group III: 0.45 [0.06, 1.25]), and the incidence of RPP (group I: 19.7% vs. group II: 27.3% vs. group III: 31.4%) were significantly different among AIP tertiles (all p < 0.05). In multiple logistic regression analysis, the risk of RPP was increased in group III (odds ratio: 1.52, 95% confidence interval: 1.02-2.26; p = 0.042) compared to group I after adjusting for clinical factors and baseline total PAV.

Conclusions: Based on serial CCTA findings, AIP is an independent predictive marker for RPP beyond traditional risk factors.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.009DOI Listing
May 2021

Eruptive Calcified Nodules as a Potential Mechanism of Acute Coronary Thrombosis and Sudden Death.

J Am Coll Cardiol 2021 04;77(13):1599-1611

CVPath Institute, Gaithersburg, Maryland, USA. Electronic address:

Background: Calcified nodule (CN) has a unique plaque morphology, in which an area of nodular calcification causes disruption of the fibrous cap with overlying luminal thrombus. CN is reported to be the least frequent cause of acute coronary thrombosis, and the pathogenesis of CN has not been well studied.

Objectives: The purpose of this study is to provide a comprehensive morphologic assessment of the CN in addition to providing an evolutionary perspective as to how CN causes acute coronary thrombosis in patients with acute coronary syndromes.

Methods: A total of 26 consecutive CN lesions from 25 subjects from our autopsy registry were evaluated. Detailed morphometric analysis was performed to understand the plaque characteristics of CN and nodular calcification.

Results: The mean age was 70 years, with a high prevalence of diabetes and chronic kidney disease. CNs were equally distributed between men and women, with 61.5% of CNs found in the right coronary artery (n = 16), mainly within its mid-portion (56%). All CNs demonstrated surface nonocclusive luminal thrombus, consisting of multiple nodular fragments of calcification, protruding and disrupting the overlying fibrous cap, with evidence of endothelial cell loss. The degree of circumferential sheet calcification was significantly less in the culprit section (89° [interquartile range: 54° to 177°]) than in the adjacent proximal (206° [interquartile range: 157° to 269°], p = 0.0034) and distal (240° [interquartile range: 178° to 333°], p = 0.0004) sections. Polarized picrosirius red staining showed the presence of necrotic core calcium at culprit sites of CNs, whereas collagen calcium was more prevalent at the proximal and distal regions of CNs.

Conclusions: Our study suggests that fibrous cap disruption in CN with overlying thrombosis is initiated through the fragmentation of necrotic core calcifications, which is flanked-proximally and distally-by hard, collagen-rich calcification in coronary arteries, which are susceptible to mechanical stress.
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http://dx.doi.org/10.1016/j.jacc.2021.02.016DOI Listing
April 2021

Novel device-based therapies to improve outcome in ST-segment elevation myocardial infarction.

Eur Heart J Acute Cardiovasc Care 2021 Aug;10(6):687-697

Oxford Heart Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Headley Way, Oxford OX3 9DU, UK.

Primary percutaneous coronary intervention (PPCI) has dramatically changed the outcome of patients with ST-elevation myocardial infarction (STEMI). However, despite improvements in interventional technology, registry data show little recent change in the prognosis of patients who survive STEMI, with a significant incidence of cardiogenic shock, heart failure, and cardiac death. Despite a technically successful PPCI procedure, a variable proportion of patients experience suboptimal myocardial reperfusion. Large infarct size and coronary microvascular injury, as the consequence of ischaemia-reperfusion injury and distal embolization of atherothrombotic debris, account for suboptimal long-term prognosis of STEMI patients. In order to address this unmet therapeutic need, a broad-range of device-based treatments has been developed. These device-based therapies can be categorized according to the pathophysiological pathways they target: (i) techniques to prevent distal atherothrombotic embolization, (ii) techniques to prevent or mitigate ischaemia/reperfusion injury, and (iii) techniques to enhance coronary microvascular function/integrity. This review is an overview of these novel technologies with a focus on their pathophysiological background, procedural details, available evidence, and with a critical perspective about their potential future implementation in the clinical care of STEMI patients.
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http://dx.doi.org/10.1093/ehjacc/zuab012DOI Listing
August 2021

Effects of chronic kidney disease and declining renal function on coronary atherosclerotic plaque progression: a PARADIGM substudy.

Eur Heart J Cardiovasc Imaging 2021 08;22(9):1072-1082

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

Aims: To investigate the change in atherosclerotic plaque volume in patients with chronic kidney disease (CKD) and declining renal function, using coronary computed tomography angiography (CCTA).

Methods And Results: In total, 891 participants with analysable serial CCTA and available glomerular filtration rate (GFR, derived using Cockcroft-Gault formulae) at baseline (CCTA 1) and follow-up (CCTA 2) were included. CKD was defined as GFR <60 mL/min/1.73 m2. Declining renal function was defined as ≥10% drop in GFR from the baseline. Quantitative assessment of plaque volume and composition were performed on both scans. There were 203 participants with CKD and 688 without CKD. CKD was associated with higher baseline total plaque volume, but similar plaque progression, measured by crude (57.5 ± 3.4 vs. 65.9 ± 7.7 mm3/year, P = 0.28) or annualized (17.3 ± 1.0 vs. 19.9 ± 2.0 mm3/year, P = 0.25) change in total plaque volume. There were 709 participants with stable GFR and 182 with declining GFR. Declining renal function was independently associated with plaque progression, with higher crude (54.1 ± 3.2 vs. 80.2 ± 9.0 mm3/year, P < 0.01) or annualized (16.4 ± 0.9 vs. 23.9 ± 2.6 mm3/year, P < 0.01) increase in total plaque volume. In CKD, plaque progression was driven by calcified plaques whereas in patients with declining renal function, it was driven by non-calcified plaques.

Conclusion: Decline in renal function was associated with more rapid plaque progression, whereas the presence of CKD was not.
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http://dx.doi.org/10.1093/ehjci/jeab029DOI Listing
August 2021

Vascular Response of a Polymer-Free Paclitaxel-Coated Stent (Zilver PTX) versus a Polymer-Coated Paclitaxel-Eluting Stent (Eluvia) in Healthy Swine Femoropopliteal Arteries.

J Vasc Interv Radiol 2021 06 4;32(6):792-801.e5. Epub 2021 Mar 4.

CVPath Institute, Gaithersburg, Maryland; Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland. Electronic address:

Purpose: To compare the long-term vascular healing responses of healthy swine iliofemoral arteries treated with a polymer-free paclitaxel-eluting stent (Z-PES, Zilver PTX) or a fluoropolymer-based paclitaxel-eluting stent (FP-PES, Eluvia).

Materials And Methods: Bilateral iliofemoral arteries in 20 swine were treated with a Z-PES (n = 16) or a FP-PES (n = 24) and were examined histologically at 1, 3, 6, and 12 months.

Results: Morphometric analysis revealed larger external and internal elastic lamina, stent expansion, and lumen area in the FP-PES than in the Z-PES at all timepoints. Luminal narrowing was similar in the 2 groups at 1 month; however, greater stenosis was observed in the Z-PES group at 3 months, with significant regression thereafter, resulting in equivalent stenosis at 6 and 12 months. Greater drug effect and less complete vessel healing were found in the FP-PES group at all timepoints, including greater numbers of malapposed struts with excessive fibrin deposition at 1 and 3 months, than in the Z-PES group. Three of 12 FP-PESs from the 6- and 12-month cohorts also showed circumferential medial disruption with peri-strut inflammation, whereas no abnormal findings were observed in contralateral Z-PESs.

Conclusions: Prolonged paclitaxel release with the presence of a permanent polymer may contribute to the differential vascular responses seen for the Z-PES and FP-PES groups, including medial layer disruption and aneurysmal vessel degeneration that was sometimes observed in the FP-PES group. These distinct features should be confirmed by pathology and in vivo imaging of human superficial femoral arteries to determine their clinical significance.
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http://dx.doi.org/10.1016/j.jvir.2021.02.014DOI Listing
June 2021

Single-cell analysis shows that adipose tissue of persons with both HIV and diabetes is enriched for clonal, cytotoxic, and CMV-specific CD4+ T cells.

Cell Rep Med 2021 Feb 16;2(2):100205. Epub 2021 Feb 16.

Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Persons with HIV are at increased risk for diabetes mellitus compared with individuals without HIV. Adipose tissue is an important regulator of glucose and lipid metabolism, and adipose tissue T cells modulate local inflammatory responses and, by extension, adipocyte function. Persons with HIV and diabetes have a high proportion of CX3CR1 GPR56 CD57 (C-G-C) CD4 T cells in adipose tissue, a subset of which are cytomegalovirus specific, whereas individuals with diabetes but without HIV have predominantly CD69 CD4 T cells. Adipose tissue CD69 and C-G-C CD4 T cell subsets demonstrate higher receptor clonality compared with the same cells in blood, potentially reflecting antigen-driven expansion, but C-G-C CD4 T cells have a more inflammatory and cytotoxic RNA transcriptome. Future studies will explore whether viral antigens have a role in recruitment and proliferation of pro-inflammatory C-G-C CD4 T cells in adipose tissue of persons with HIV.
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http://dx.doi.org/10.1016/j.xcrm.2021.100205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897802PMC
February 2021

Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRβ and bioenergetic mechanisms.

Nat Metab 2021 02 22;3(2):166-181. Epub 2021 Feb 22.

Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA.

Stable atherosclerotic plaques are characterized by a thick, extracellular matrix-rich fibrous cap populated by protective ACTA2 myofibroblast (MF)-like cells, assumed to be almost exclusively derived from smooth muscle cells (SMCs). Herein, we show that in murine and human lesions, 20% to 40% of ACTA2 fibrous cap cells, respectively, are derived from non-SMC sources, including endothelial cells (ECs) or macrophages that have undergone an endothelial-to-mesenchymal transition (EndoMT) or a macrophage-to-mesenchymal transition (MMT). In addition, we show that SMC-specific knockout of the Pdgfrb gene, which encodes platelet-derived growth factor receptor beta (PDGFRβ), in Apoe mice fed a Western diet for 18 weeks resulted in brachiocephalic artery lesions nearly devoid of SMCs but with no changes in lesion size, remodelling or indices of stability, including the percentage of ACTA2 fibrous cap cells. However, prolonged Western diet feeding of SMC Pdgfrb-knockout mice resulted in reduced indices of stability, indicating that EndoMT- and MMT-derived MFs cannot compensate indefinitely for loss of SMC-derived MFs. Using single-cell and bulk RNA-sequencing analyses of the brachiocephalic artery region and in vitro models, we provide evidence that SMC-to-MF transitions are induced by PDGF and transforming growth factor-β and dependent on aerobic glycolysis, while EndoMT is induced by interleukin-1β and transforming growth factor-β. Together, we provide evidence that the ACTA2 fibrous cap originates from a tapestry of cell types, which transition to an MF-like state through distinct signalling pathways that are either dependent on or associated with extensive metabolic reprogramming.
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http://dx.doi.org/10.1038/s42255-020-00338-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905710PMC
February 2021

Automated Histological Segmentation on Micro Computed Tomography Images of Atherosclerotic Arteries.

Eur J Vasc Endovasc Surg 2021 Apr 13;61(4):714-715. Epub 2021 Feb 13.

Groupe Européen de Recherche sur les Prothèses Appliquées à la Chirurgie Vasculaire, Strasbourg, France; Department of Vascular Surgery and Kidney Transplantation, University of Strasbourg, Strasbourg, France.

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http://dx.doi.org/10.1016/j.ejvs.2021.01.012DOI Listing
April 2021

Comprehensive Assessment of Human Accessory Renal Artery Periarterial Renal Sympathetic Nerve Distribution.

JACC Cardiovasc Interv 2021 02 25;14(3):304-315. Epub 2020 Nov 25.

CVPath Institute, Gaithersburg, Maryland, USA; University of Maryland, Baltimore, Maryland, USA. Electronic address:

Objectives: The aim of this study was to understand the anatomy of periarterial nerve distribution in human accessory renal arteries (ARAs).

Background: Renal denervation is a promising technique for blood pressure control. Despite the high prevalence of ARAs, the anatomic distribution of periarterial nerves around ARAs remains unknown.

Methods: Kidneys with surrounding tissues were collected from human autopsy subjects, and histological evaluation was performed using morphometric software. An ARA was defined as an artery arising from the aorta above or below the dominant renal artery (DRA) or an artery that bifurcated within 20 mm of the takeoff of the DRA from the aorta. The DRA was defined as an artery that perfused >50% of the kidney.

Results: A total of 7,287 nerves from 14 ARAs and 9 DRAs were evaluated. The number of nerves was smaller in the ARA than DRA (median: 30 [interquartile range: 17.5 to 48.5] vs. 49 [interquartile range: 36 to 76]; p < 0.0001). In both ARAs and DRAs, the distance from the arterial lumen to nerve was shortest in the distal, followed by the middle and proximal segments. On the basis of the post-mortem angiography, ARAs were divided into large (≥3 mm diameter) and small (<3 mm) groups. The number of nerves was greatest in the DRA, followed by the large and small ARA groups (53 [41 to 97], 38 [25 to 53], and 24.5 [10.5 to 36.3], respectively; p = 0.001).

Conclusions: ARAs showed a smaller number of nerves than DRAs, but these results were dependent on the size of the ARA. Ablation, especially in large ARAs, may allow more complete denervation with the potential to further reduce blood pressure.
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http://dx.doi.org/10.1016/j.jcin.2020.09.043DOI Listing
February 2021
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