Topic: Journal Club Selection

Abstract

Endovascular Therapy for Stroke Due to Basilar-Artery Occlusion.

Langezaal LCM, van der Hoeven EJRJ, Mont\'Alverne FJA, de Carvalho JJF, ... Schonewille WJ, BASICS Study Group
Background
The effectiveness of endovascular therapy in patients with stroke caused by basilar-artery occlusion has not been well studied.
Methods
We randomly assigned patients within 6 hours after the estimated time of onset of a stroke due to basilar-artery occlusion, in a 1:1 ratio, to receive endovascular therapy or standard medical care. The primary outcome was a favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 to 6, with 0 indicating no disability, 3 indicating moderate disability, and 6 indicating death) at 90 days. The primary safety outcomes were symptomatic intracranial hemorrhage within 3 days after the initiation of treatment and mortality at 90 days.
Results
A total of 300 patients were enrolled (154 in the endovascular therapy group and 146 in the medical care group). Intravenous thrombolysis was used in 78.6% of the patients in the endovascular group and in 79.5% of those in the medical group. Endovascular treatment was initiated at a median of 4.4 hours after stroke onset. A favorable functional outcome occurred in 68 of 154 patients (44.2%) in the endovascular group and 55 of 146 patients (37.7%) in the medical care group (risk ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.50). Symptomatic intracranial hemorrhage occurred in 4.5% of the patients after endovascular therapy and in 0.7% of those after medical therapy (risk ratio, 6.9; 95% CI, 0.9 to 53.0); mortality at 90 days was 38.3% and 43.2%, respectively (risk ratio, 0.87; 95% CI, 0.68 to 1.12).
Conclusions
Among patients with stroke from basilar-artery occlusion, endovascular therapy and medical therapy did not differ significantly with respect to a favorable functional outcome, but, as reflected by the wide confidence interval for the primary outcome, the results of this trial may not exclude a substantial benefit of endovascular therapy. Larger trials are needed to determine the efficacy and safety of endovascular therapy for basilar-artery occlusion. (Funded by the Dutch Heart Foundation and others; BASICS ClinicalTrials.gov number, NCT01717755; Netherlands Trial Register number, NL2500.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 19 May 2021; 384:1910-1920
Langezaal LCM, van der Hoeven EJRJ, Mont'Alverne FJA, de Carvalho JJF, ... Schonewille WJ, BASICS Study Group
N Engl J Med: 19 May 2021; 384:1910-1920 | PMID: 34010530
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Abstract

Final Report of a Trial of Intensive versus Standard Blood-Pressure Control.

SPRINT Research Group, Lewis CE, Fine LJ, Beddhu S, ... Wright JT, Ambrosius WT
Background
In a previously reported randomized trial of standard and intensive systolic blood-pressure control, data on some outcome events had yet to be adjudicated and post-trial follow-up data had not yet been collected.
Methods
We randomly assigned 9361 participants who were at increased risk for cardiovascular disease but did not have diabetes or previous stroke to adhere to an intensive treatment target (systolic blood pressure, <120 mm Hg) or a standard treatment target (systolic blood pressure, <140 mm Hg). The primary outcome was a composite of myocardial infarction, other acute coronary syndromes, stroke, acute decompensated heart failure, or death from cardiovascular causes. Additional primary outcome events occurring through the end of the intervention period (August 20, 2015) were adjudicated after data lock for the primary analysis. We also analyzed post-trial observational follow-up data through July 29, 2016.
Results
At a median of 3.33 years of follow-up, the rate of the primary outcome and all-cause mortality during the trial were significantly lower in the intensive-treatment group than in the standard-treatment group (rate of the primary outcome, 1.77% per year vs. 2.40% per year; hazard ratio, 0.73; 95% confidence interval [CI], 0.63 to 0.86; all-cause mortality, 1.06% per year vs. 1.41% per year; hazard ratio, 0.75; 95% CI, 0.61 to 0.92). Serious adverse events of hypotension, electrolyte abnormalities, acute kidney injury or failure, and syncope were significantly more frequent in the intensive-treatment group. When trial and post-trial follow-up data were combined (3.88 years in total), similar patterns were found for treatment benefit and adverse events; however, rates of heart failure no longer differed between the groups.
Conclusions
Among patients who were at increased cardiovascular risk, targeting a systolic blood pressure of less than 120 mm Hg resulted in lower rates of major adverse cardiovascular events and lower all-cause mortality than targeting a systolic blood pressure of less than 140 mm Hg, both during receipt of the randomly assigned therapy and after the trial. Rates of some adverse events were higher in the intensive-treatment group. (Funded by the National Institutes of Health; SPRINT ClinicalTrials.gov number, NCT01206062.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 19 May 2021; 384:1921-1930
SPRINT Research Group, Lewis CE, Fine LJ, Beddhu S, ... Wright JT, Ambrosius WT
N Engl J Med: 19 May 2021; 384:1921-1930 | PMID: 34010531
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Abstract

Genetic insight into sick sinus syndrome.

Thorolfsdottir RB, Sveinbjornsson G, Aegisdottir HM, Benonisdottir S, ... Stefansson K, DBDS Genomic Consortium
Aims
The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development.
Methods and results
We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05).
Conclusion
We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 20 May 2021; 42:1959-1971
Thorolfsdottir RB, Sveinbjornsson G, Aegisdottir HM, Benonisdottir S, ... Stefansson K, DBDS Genomic Consortium
Eur Heart J: 20 May 2021; 42:1959-1971 | PMID: 33580673
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Abstract

Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients With Cardiovascular Disease.

Akawi N, Checa A, Antonopoulos AS, Akoumianakis I, ... Wheelock CE, Antoniades C
Background
Obesity is associated with increased cardiovascular risk; however, the potential role of dysregulations in the adipose tissue (AT) metabolome is unknown.
Objectives
The aim of this study was to explore the role of dysregulation in the AT metabolome on vascular redox signaling and cardiovascular outcomes.
Methods
A screen was conducted for metabolites differentially secreted by thoracic AT (ThAT) and subcutaneous AT in obese patients with atherosclerosis (n = 48), and these metabolites were then linked with dysregulated vascular redox signaling in 633 patients undergoing coronary bypass surgery. The underlying mechanisms were explored in human aortic endothelial cells, and their clinical value was tested against hard clinical endpoints.
Results
Because ThAT volume was associated significantly with arterial oxidative stress, there were significant differences in sphingolipid secretion between ThAT and subcutaneous AT, with C16:0-ceramide and derivatives being the most abundant species released within adipocyte-derived extracellular vesicles. High ThAT sphingolipid secretion was significantly associated with reduced endothelial nitric oxide bioavailability and increased superoxide generated in human vessels. Circulating C16:0-ceramide correlated positively with ThAT ceramides, dysregulated vascular redox signaling, and increased systemic inflammation in 633 patients with atherosclerosis. Exogenous C16:0-ceramide directly increased superoxide via tetrahydrobiopterin-mediated endothelial nitric oxide synthase uncoupling and dysregulated protein phosphatase 2 in human aortic endothelial cells. High plasma C16:0-ceramide and its glycosylated derivative were independently related with increased risk for cardiac mortality (adjusted hazard ratios: 1.394; 95% confidence interval: 1.030 to 1.886; p = 0.031 for C16:0-ceramide and 1.595; 95% confidence interval: 1.042 to 2.442; p = 0.032 for C16:0-glycosylceramide per 1 SD). In a randomized controlled clinical trial, 1-year treatment of obese patients with the glucagon-like peptide-1 analog liraglutide suppressed plasma C16:0-ceramide and C16:0-glycosylceramide changes compared with control subjects.
Conclusions
These results demonstrate for the first time in humans that AT-derived ceramides are modifiable regulators of vascular redox state in obesity, with a direct impact on cardiac mortality in advanced atherosclerosis. (The Interaction Between Appetite Hormones; NCT02094183).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 24 May 2021; 77:2494-2513
Akawi N, Checa A, Antonopoulos AS, Akoumianakis I, ... Wheelock CE, Antoniades C
J Am Coll Cardiol: 24 May 2021; 77:2494-2513 | PMID: 34016263
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Abstract

Risk Associated With Valvular Regurgitation During Pregnancy.

Pfaller B, Dave Javier A, Grewal J, Gabarin N, ... Siu SC, Silversides CK
Background
Pregnancies in women with regurgitant valve lesions are generally considered low risk, but this has not been well studied.
Objectives
This study determined the frequency of adverse cardiac events (CEs) in pregnant women with moderate or severe regurgitant valve lesions.
Methods
Maternal and fetal outcomes in women with moderate or severe chronic valve regurgitation enrolled in a prospective multicenter study on pregnancy outcomes were examined. Adverse CEs included heart failure, sustained arrhythmias, cardiac arrest, or death. A multivariate logistic regression model was used to identify determinants of CEs in women at the highest risk.
Results
Outcomes of 430 pregnancies in women with moderate or severe regurgitant lesions were examined: 145 with mitral regurgitation (MR), 101 with pulmonary regurgitation (PR), 71 with multivalve disease, 73 with tricuspid regurgitation (TR), and 40 with aortic regurgitation (AR). Most women had associated congenital or acquired heart disease. Adverse CEs occurred in 13% of pregnancies: 27% of pregnancies with multivalve disease; 15% with MR; 15% with TR; 5% with AR; and 3% with PR. Maternal mortality was rare. In women with MR, TR, or multivalve disease (n = 289), left ventricular systolic dysfunction (p = 0.001), pulmonary hypertension (p = 0.005), and cardiac events before pregnancy (p < 0.001) were important determinants of CEs during pregnancy.
Conclusions
Women with AR and PR are at low risk for cardiac complications during pregnancy. While many women with MR, TR, and multivalve regurgitation do well during pregnancy, additional clinical variables help stratify those at highest risk. This new information will enhance the quality and precision of preconception counseling and pregnancy planning.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 31 May 2021; 77:2656-2664
Pfaller B, Dave Javier A, Grewal J, Gabarin N, ... Siu SC, Silversides CK
J Am Coll Cardiol: 31 May 2021; 77:2656-2664 | PMID: 34045022
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Abstract

Lipoproteins in chronic kidney disease: from bench to bedside.

Speer T, Ridker PM, von Eckardstein A, Schunk SJ, Fliser D
Chronic kidney disease (CKD) is associated with high cardiovascular risk. CKD patients exhibit a specific lipoprotein pattern termed \'uraemic dyslipidaemia\', which is characterized by rather normal low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, and high triglyceride plasma levels. All three lipoprotein classes are involved in the pathogenesis of CKD-associated cardiovascular diseases (CVDs). Uraemia leads to several modifications of the structure of lipoproteins such as changes of the proteome and the lipidome, post-translational protein modifications (e.g. carbamylation) and accumulation of small-molecular substances within the lipoprotein moieties, which affect their functionality. Lipoproteins from CKD patients interfere with lipid transport and promote inflammation, oxidative stress, endothelial dysfunction as well as other features of atherogenesis, thus contributing to the development of CKD-associated CVD. While, lipid-modifying therapies play an important role in the management of CKD patients, their efficacy is modulated by kidney function. Novel therapeutic agents to prevent the adverse remodelling of lipoproteins in CKD and to improve their functional properties are highly desirable and partially under development.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 06 Jun 2021; 42:2170-2185
Speer T, Ridker PM, von Eckardstein A, Schunk SJ, Fliser D
Eur Heart J: 06 Jun 2021; 42:2170-2185 | PMID: 33393990
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Abstract

Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm.

Oller J, Gabandé-Rodríguez E, Ruiz-Rodríguez MJ, Desdín-Micó G, ... Miguel Redondo J, Mittelbrunn M
Background
Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms.
Methods
Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (Fbn1 c1039g/+ ) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; Myh11-Cre ERT2 Tfam flox/flox mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration.
Results
The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1 c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young Fbn1 c1039g/+ mice. In vitro experiments in Fbn1-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in Fbn1 c1039g/+ mice.
Conclusions
Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.



Circulation: 24 May 2021; 143:2091-2109
Oller J, Gabandé-Rodríguez E, Ruiz-Rodríguez MJ, Desdín-Micó G, ... Miguel Redondo J, Mittelbrunn M
Circulation: 24 May 2021; 143:2091-2109 | PMID: 33709773
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Abstract

ALDH1A3 Coordinates Metabolism With Gene Regulation in Pulmonary Arterial Hypertension.

Li D, Shao NY, Moonen JR, Zhao Z, ... Snyder MP, Rabinovitch M
Background
Metabolic alterations provide substrates that influence chromatin structure to regulate gene expression that determines cell function in health and disease. Heightened proliferation of smooth muscle cells (SMC) leading to the formation of a neointima is a feature of pulmonary arterial hypertension (PAH) and systemic vascular disease. Increased glycolysis is linked to the proliferative phenotype of these SMC.
Methods
RNA sequencing was applied to pulmonary arterial SMC (PASMC) from PAH patients with and without a BMPR2 (bone morphogenetic receptor 2) mutation versus control PASMC to uncover genes required for their heightened proliferation and glycolytic metabolism. Assessment of differentially expressed genes established metabolism as a major pathway, and the most highly upregulated metabolic gene in PAH PASMC was aldehyde dehydrogenase family 1 member 3 (ALDH1A3), an enzyme previously linked to glycolysis and proliferation in cancer cells and systemic vascular SMC. We determined if these functions are ALDH1A3-dependent in PAH PASMC, and if ALDH1A3 is required for the development of pulmonary hypertension in a transgenic mouse. Nuclear localization of ALDH1A3 in PAH PASMC led us to determine whether and how this enzyme coordinately regulates gene expression and metabolism in PAH PASMC.
Results
ALDH1A3 mRNA and protein were increased in PAH versus control PASMC, and ALDH1A3 was required for their highly proliferative and glycolytic properties. Mice with Aldh1a3 deleted in SMC did not develop hypoxia-induced pulmonary arterial muscularization or pulmonary hypertension. Nuclear ALDH1A3 converted acetaldehyde to acetate to produce acetyl coenzyme A to acetylate H3K27, marking active enhancers. This allowed for chromatin modification at NFYA (nuclear transcription factor Y subunit α) binding sites via the acetyltransferase KAT2B (lysine acetyltransferase 2B) and permitted NFY-mediated transcription of cell cycle and metabolic genes that is required for ALDH1A3-dependent proliferation and glycolysis. Loss of BMPR2 in PAH SMC with or without a mutation upregulated ALDH1A3, and transcription of NFYA and ALDH1A3 in PAH PASMC was β-catenin dependent.
Conclusions
Our studies have uncovered a metabolic-transcriptional axis explaining how dividing cells use ALDH1A3 to coordinate their energy needs with the epigenetic and transcriptional regulation of genes required for SMC proliferation. They suggest that selectively disrupting the pivotal role of ALDH1A3 in PAH SMC, but not endothelial cells, is an important therapeutic consideration.



Circulation: 24 May 2021; 143:2074-2090
Li D, Shao NY, Moonen JR, Zhao Z, ... Snyder MP, Rabinovitch M
Circulation: 24 May 2021; 143:2074-2090 | PMID: 33764154
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Abstract

Integrated Single Cell Atlas of Endothelial Cells of the Human Lung.

Schupp JC, Adams TS, Cosme C, Raredon MSB, ... Rosas IO, Kaminski N
Background: The cellular diversity of the lung endothelium has not been systematically characterized in humans. Here, we provide a reference atlas of human lung endothelial cells (ECs) to facilitate a better understanding of the phenotypic diversity and composition of cells comprising the lung endothelium.
Methods:
We reprocessed human control single cell RNA sequencing (scRNAseq) data from six datasets. EC populations were characterized through iterative clustering with subsequent differential expression analysis. Marker genes were validated by fluorescent microscopy and in situ hybridization. scRNAseq of primary lung ECs cultured in-vitro was performed. The signaling network between different lung cell types was studied. For cross species analysis or disease relevance, we applied the same methods to scRNAseq data obtained from mouse lungs or from human lungs with pulmonary hypertension.
Results:
Six lung scRNAseq datasets were reanalyzed and annotated to identify over 15,000 vascular EC cells from 73 individuals. Differential expression analysis of EC revealed signatures corresponding to endothelial lineage, including pan-endothelial, pan-vascular and subpopulation-specific marker gene sets. Beyond the broad cellular categories of lymphatic, capillary, arterial and venous ECs, we found previously indistinguishable subpopulations: among venous EC, we identified two previously indistinguishable populations, pulmonary-venous ECs (COL15A1neg) localized to the lung parenchyma and systemic-venous ECs (COL15A1pos) localized to the airways and the visceral pleura; among capillary EC, we confirmed their subclassification into recently discovered aerocytes characterized by EDNRB, SOSTDC1 and TBX2 and general capillary EC. We confirmed that all six endothelial cell types, including the systemic-venous EC and aerocytes, are present in mice and identified endothelial marker genes conserved in humans and mice. Ligand-receptor connectome analysis revealed important homeostatic crosstalk of EC with other lung resident cell types. scRNAseq of commercially available primary lung ECs demonstrated a loss of their native lung phenotype in culture. scRNAseq revealed that the endothelial diversity is maintained in pulmonary hypertension. Our manuscript is accompanied by an online data mining tool (www.LungEndothelialCellAtlas.com). Conclusions: Our integrated analysis provides the comprehensive and well-crafted reference atlas of lung endothelial cells in the normal lung and confirms and describes in detail previously unrecognized endothelial populations across a large number of humans and mice.




Circulation: 24 May 2021; epub ahead of print
Schupp JC, Adams TS, Cosme C, Raredon MSB, ... Rosas IO, Kaminski N
Circulation: 24 May 2021; epub ahead of print | PMID: 34030460
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Abstract

Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Powell-Wiley TM, Poirier P, Burke LE, Després JP, ... St-Onge MP, American Heart Association Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; and Stroke Council
The global obesity epidemic is well established, with increases in obesity prevalence for most countries since the 1980s. Obesity contributes directly to incident cardiovascular risk factors, including dyslipidemia, type 2 diabetes, hypertension, and sleep disorders. Obesity also leads to the development of cardiovascular disease and cardiovascular disease mortality independently of other cardiovascular risk factors. More recent data highlight abdominal obesity, as determined by waist circumference, as a cardiovascular disease risk marker that is independent of body mass index. There have also been significant advances in imaging modalities for characterizing body composition, including visceral adiposity. Studies that quantify fat depots, including ectopic fat, support excess visceral adiposity as an independent indicator of poor cardiovascular outcomes. Lifestyle modification and subsequent weight loss improve both metabolic syndrome and associated systemic inflammation and endothelial dysfunction. However, clinical trials of medical weight loss have not demonstrated a reduction in coronary artery disease rates. In contrast, prospective studies comparing patients undergoing bariatric surgery with nonsurgical patients with obesity have shown reduced coronary artery disease risk with surgery. In this statement, we summarize the impact of obesity on the diagnosis, clinical management, and outcomes of atherosclerotic cardiovascular disease, heart failure, and arrhythmias, especially sudden cardiac death and atrial fibrillation. In particular, we examine the influence of obesity on noninvasive and invasive diagnostic procedures for coronary artery disease. Moreover, we review the impact of obesity on cardiac function and outcomes related to heart failure with reduced and preserved ejection fraction. Finally, we describe the effects of lifestyle and surgical weight loss interventions on outcomes related to coronary artery disease, heart failure, and atrial fibrillation.



Circulation: 24 May 2021; 143:e984-e1010
Powell-Wiley TM, Poirier P, Burke LE, Després JP, ... St-Onge MP, American Heart Association Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; and Stroke Council
Circulation: 24 May 2021; 143:e984-e1010 | PMID: 33882682
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Abstract

Natural History of Patients with Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study.

Reynolds HR, Picard MH, Spertus JA, Peteiro J, ... Maron DJ, Hochman JS
Background: Ischemia with no obstructive coronary artery disease (INOCA) is common and has an adverse prognosis. We set out to describe the natural history of symptoms and ischemia in INOCA.
Methods:
CIAO-ISCHEMIA (Changes in Ischemia and Angina over One year in ISCHEMIA trial screen failures with INOCA) was an international cohort study conducted from 2014-2019 involving angina assessments (Seattle Angina Questionnaire [SAQ]) and stress echocardiograms 1-year apart. This was an ancillary study that included patients with history of angina who were not randomized in the ISCHEMIA trial. Stress-induced wall motion abnormalities were determined by an echocardiographic core laboratory blinded to symptoms, coronary artery disease (CAD) status and test timing. Medical therapy was at the discretion of treating physicians. The primary outcome was the correlation between changes in SAQ Angina Frequency score and change in echocardiographic ischemia. We also analyzed predictors of 1-year changes in both angina and ischemia, and compared CIAO participants with ISCHEMIA participants with obstructive CAD who had stress echocardiography before enrollment, as CIAO participants did.
Results:
INOCA participants in CIAO were more often female (66% of 208 vs. 26% of 865 ISCHEMIA participants with obstructive CAD, p<0.001), but the magnitude of ischemia was similar (median 4 ischemic segments [IQR 3-5] both groups). Ischemia and angina were not significantly correlated at enrollment in CIAO (p=0.46) or ISCHEMIA stress echocardiography participants (p=0.35). At 1 year, the stress echocardiogram was normal in half of CIAO participants and 23% had moderate or severe ischemia (≥3 ischemic segments). Angina improved in 43% and worsened in 14%. Change in ischemia over one year was not significantly correlated with change in angina (rho=0.029). Conclusions:Improvement in ischemia and improvement in angina were common in INOCA, but not correlated. Our INOCA cohort had a similar degree of inducible wall motion abnormalities to concurrently enrolled ISCHEMIA participants with obstructive CAD. Our results highlight the complex nature of INOCA pathophysiology and the multifactorial nature of angina. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02347215.




Circulation: 31 May 2021; epub ahead of print
Reynolds HR, Picard MH, Spertus JA, Peteiro J, ... Maron DJ, Hochman JS
Circulation: 31 May 2021; epub ahead of print | PMID: 34058845
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Abstract

Comparison of one-month versus twelve-month dual antiplatelet therapy after implantation of drug-eluting stents guided by either intravascular ultrasound or angiography in patients with acute coronary syndrome: rationale and design of prospective, multicenter, randomized, controlled IVUS-ACS and ULTIMATE-DAPT trial.

Ge Z, Gao XF, Kan J, Kong XQ, ... Zhang JJ, Chen SL
Background
Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor.
Methods
The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population.
Conclusion
The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am Heart J: 30 May 2021; 236:49-58
Ge Z, Gao XF, Kan J, Kong XQ, ... Zhang JJ, Chen SL
Am Heart J: 30 May 2021; 236:49-58 | PMID: 33621541
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Abstract

Positron emission tomography in clinically suspected myocarditis - STREAM study design.

Ozierański K, Tymińska A, Kobylecka M, Caforio ALP, ... Opolski G, Grabowski M
Aim
Myocarditis is an inflammatory disease associated with increased glucose uptake. The hypothesis of this study assumes that 18F-2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) may improve specificity and sensitivity in the diagnosis of myocarditis and referral for endomyocardial biopsy (EMB), adding additional information for post-discharge risk stratification. The aim of the study is to assess the diagnostic and prognostic feasibility of FDG-PET/CT in comparison to cardiac magnetic resonance (CMR) (alone or in combination) in patients with clinically suspected myocarditis undergoing EMB.
Methods
Fifty hospitalized patients with clinically suspected myocarditis who meet the inclusion/exclusion criteria will be enrolled in a prospective, observational, multicentre, cohort study (NCT04085718). The primary endpoint is the sensitivity and specificity of FDG-PET/CT imaging in the diagnosis of myocarditis. The main secondary endpoints include correlation of FDG-PET/CT imaging with CMR, echocardiography, and EMB results. The patients will undergo the following evaluations: clinical examination, blood tests (including biomarkers of fibrosis and anti-heart autoantibodies (AHA)), ECG, 24 h Holter ECG, echocardiography, CMR, as well as resting single photon emission computed tomography (SPECT) to assess possible myocardial perfusion defects, cardiac FDG-PET/CT and right ventricular EMB. After 6-months a follow-up visit will be performed (including 24 h Holter ECG, echocardiography and CMR). Investigators evaluating individual studies (CMR, SPECT, FDG-PET/CT and EMB) are to be blinded to the other tests\' results.
Conclusion
We believe that FDG-PET/CT alone or in combination with CMR may be a useful tool for improving diagnostic accuracy in patients with clinically suspected myocarditis.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 May 2021; 332:113-118
Ozierański K, Tymińska A, Kobylecka M, Caforio ALP, ... Opolski G, Grabowski M
Int J Cardiol: 31 May 2021; 332:113-118 | PMID: 33657398
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Impact:
Abstract

Directional atherectomy before paclitaxel coated balloon angioplasty in complex femoropopliteal disease: The VIVA REALITY study.

Rocha-Singh KJ, Sachar R, DeRubertis BG, Nolte-Ernsting CCA, ... Zeller T, REALITY Investigators
Background
Drug coated balloon (DCB) angioplasty significantly reduces reintervention rates in patients with symptomatic femoropopliteal peripheral artery disease (PAD). However, stand-alone DCB use in long, severely calcified lesions is frequently associated with vessel recoil and/or high-grade dissections necessitating provisional stent implantation.
Objectives
Assess the safety and effectiveness of a vessel preparation strategy with directional atherectomy (DA) prior to DCB angioplasty in patients with symptomatic severely calcified femoropopliteal PAD.
Methods
REALITY (NCT02850107) prospectively enrolled subjects at 13 multinational centers with 8-36 cm femoropopliteal stenoses or occlusions with bilateral vessel wall calcification treated with DA prior to DCB angioplasty. The primary effectiveness endpoint was 12-month primary patency, and the primary safety endpoint was freedom from major adverse events through 30 days. Independent angiographic and duplex core laboratories assessed outcomes and a Clinical Events Committee adjudicated events.
Results
A total of 102 subjects were enrolled; one lesion was treated per subject. The mean lesion length was 17.9 ± 8.1 cm, 39.0% were chronic total occlusions (mean lesion length 22.6 ± 8.6 cm); 86.2% of lesions exhibited moderate to severe bilateral calcification. Provisional stents were implanted in 8.8% (9/102) of subjects. Twelve-month primary patency rate was 76.7% (66/86) and freedom from CD-TLR rate was 92.6% (87/94). No device or procedure related deaths and one index-limb major amputation were reported.
Conclusions
Plaque excision with DA in patients with symptomatic severely calcified femoropopliteal arterial disease prior to DCB angioplasty is a safe and effective treatment strategy with a low provisional stent rate.

© 2021 Wiley Periodicals LLC.

Catheter Cardiovasc Interv: 02 Jun 2021; epub ahead of print
Rocha-Singh KJ, Sachar R, DeRubertis BG, Nolte-Ernsting CCA, ... Zeller T, REALITY Investigators
Catheter Cardiovasc Interv: 02 Jun 2021; epub ahead of print | PMID: 34080792
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Impact:
Abstract

Deformation and stenosis of the sinus-SuperFlex-DS stent after ductal stenting for the hybrid stage 1 procedure.

Hribernik I, Thomson J, Bentham J
We present five cases of sinus-SuperFlex-DS stent stenosis during early follow up that resulted in inadequate ductal patency and required urgent re-stenting with a balloon-expandable stent. This causes concern that these stents lack sufficient radial force against ductal constriction and if used need to be kept under close scrutiny.

© 2021 Wiley Periodicals LLC.

Catheter Cardiovasc Interv: 01 Jun 2021; epub ahead of print
Hribernik I, Thomson J, Bentham J
Catheter Cardiovasc Interv: 01 Jun 2021; epub ahead of print | PMID: 34076321
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Impact:
Abstract

Scan-rescan measurement repeatability of F-FDG PET/MR imaging of vascular inflammation.

Robson PM, Kaufman A, Pruzan A, Dweck MR, ... Fayad ZA, Mani V
Non-invasive positron emission tomography (PET) of vascular inflammation and atherosclerotic plaque by identifying increased uptake of 18F-fluordeoxyglucose (18F-FDG) is a powerful tool for monitoring disease activity, progression, and its response to therapy. 18F-FDG PET/computed tomography (PET/CT) of the aorta and carotid arteries has become widely used to assess changes in inflammation in clinical trials. However, the recent advent of hybrid PET/magnetic resonance (PET/MR) scanners has advantages for vascular imaging due to the reduction in radiation exposure and improved soft tissue contrast of MR compared to CT. Important for research and clinical use is an understanding of the scan-rescan repeatability of the PET measurement. While this has been studied for PET/CT, no data is currently available for vascular PET/MR imaging. In this study, we determined the scan-rescan measurement repeatability of 18F-FDG PET/MR in the aorta and carotid arteries was less than 5%, comparable to similar findings for 18F-FDG PET/CT.



J Nucl Cardiol: 26 May 2021; epub ahead of print
Robson PM, Kaufman A, Pruzan A, Dweck MR, ... Fayad ZA, Mani V
J Nucl Cardiol: 26 May 2021; epub ahead of print | PMID: 34046803
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Impact:

This program is still in alpha version.