Topic: Journal Club Selection

Abstract

Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial.

Ye N, Jardine MJ, Oshima M, Hockham C, ... Perkovic V, Neuen BL
Background
People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown.
Methods
The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups.
Results
The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61-0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59-0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes.
Conclusions
In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.



Circulation: 03 May 2021; 143:1735-1749
Ye N, Jardine MJ, Oshima M, Hockham C, ... Perkovic V, Neuen BL
Circulation: 03 May 2021; 143:1735-1749 | PMID: 33554616
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Abstract

Effect of Sleep Disturbances on Blood Pressure.

Makarem N, Alcántara C, Williams N, Bello NA, Abdalla M
This review summarizes recent literature addressing the association of short sleep duration, shift work, and obstructive sleep apnea with hypertension risk, blood pressure (BP) levels, and 24-hour ambulatory BP. Observational studies demonstrate that subjectively assessed short sleep increases hypertension risk, though conflicting results are observed in studies of objectively assessed short sleep. Intervention studies demonstrate that mild and severe sleep restriction are associated with higher BP. Rotating and night shift work are associated with hypertension as shift work may exacerbate the detrimental impact of short sleep on BP. Further, studies demonstrate that shift work may increase nighttime BP and reduce BP control in patients with hypertension. Finally, moderate to severe obstructive sleep apnea is associated with hypertension, particularly resistant hypertension. Obstructive sleep apnea is also associated with abnormal 24-hour ambulatory BP profiles, including higher daytime and nighttime BP, nondipping BP, and a higher morning surge. Continuous positive airway pressure treatment may lower BP and improve BP dipping. In conclusion, efforts should be made to educate patients and health care providers about the importance of identifying and treating sleep disturbances for hypertension prevention and management. Empirically supported sleep health interventions represent a critical next step to advance this research area and establish causality.



Hypertension: 29 Apr 2021; 77:1036-1046
Makarem N, Alcántara C, Williams N, Bello NA, Abdalla M
Hypertension: 29 Apr 2021; 77:1036-1046 | PMID: 33611935
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Abstract

From Brain to Blood Vessel: Insights From Muscle Sympathetic Nerve Recordings: Arthur C. Corcoran Memorial Lecture 2020.

Floras JS
Multiunit recordings of postganglionic sympathetic outflow to muscle yield otherwise imperceptible insights into sympathetic neural modulation of human vascular resistance and blood pressure. This Corcoran Lecture will illustrate the utility of microneurography to investigate neurogenic cardiovascular regulation; review data concerning muscle sympathetic nerve activity of women and men with normal and high blood pressure; explore 2 concepts, central upregulation of muscle sympathetic outflow and cortical autonomic neuroplasticity; present sleep apnea as an imperfect model of neurogenic hypertension; and expose the paradox of sympathetic excitation without hypertension. In awake healthy normotensive individuals, resting muscle sympathetic nerve activity increases with age, sleep fragmentation, and obstructive apnea. Its magnitude is not signaled by heart rate. Age-related changes are nonlinear and differ by sex. In men, sympathetic nerve activity increases with age but without relation to their blood pressure, whereas in women, both rise concordantly after age 40. Mean values for muscle sympathetic nerve activity burst incidence are consistently higher in cohorts with hypertension than in matched normotensives, yet women\'s sympathetic nerve traffic can increase 3-fold between ages 30 and 70 without causing hypertension. Thus, increased sympathetic nerve activity may be necessary but is insufficient for primary hypertension. Moreover, its inhibition does not consistently decrease blood pressure. Despite a half-century of microneurographic research, large gaps remain in our understanding of the content of the sympathetic broadcast from brain to blood vessel and its specific individual consequences for circulatory regulation and cardiovascular, renal, and metabolic risk.



Hypertension: 04 May 2021; 77:1456-1468
Floras JS
Hypertension: 04 May 2021; 77:1456-1468 | PMID: 33775112
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Abstract

Cardiovascular magnetic resonance imaging: emerging techniques and applications.

Chowdhary A, Garg P, Das A, Nazir MS, Plein S
This review gives examples of emerging cardiovascular magnetic resonance (CMR) techniques and applications that have the potential to transition from research to clinical application in the near future. Four-dimensional flow CMR (4D-flow CMR) allows time-resolved three-directional, three-dimensional (3D) velocity-encoded phase-contrast imaging for 3D visualisation and quantification of valvular or intracavity flow. Acquisition times of under 10 min are achievable for a whole heart multidirectional data set and commercial software packages are now available for data analysis, making 4D-flow CMR feasible for inclusion in clinical imaging protocols. Diffusion tensor imaging (DTI) is based on the measurement of molecular water diffusion and uses contrasting behaviour in the presence and absence of boundaries to infer tissue structure. Cardiac DTI is capable of non-invasively phenotyping the 3D micro-architecture within a few minutes, facilitating transition of the method to clinical protocols. Hybrid positron emission tomography-magnetic resonance (PET-MR) provides quantitative PET measures of biological and pathological processes of the heart combined with anatomical, morphological and functional CMR imaging. Cardiac PET-MR offers opportunities in ischaemic, inflammatory and infiltrative heart disease.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Apr 2021; 107:697-704
Chowdhary A, Garg P, Das A, Nazir MS, Plein S
Heart: 29 Apr 2021; 107:697-704 | PMID: 33402364
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Abstract

Spontaneous Cervical Artery Dissection in Vascular Ehlers-Danlos Syndrome: A Cohort Study.

Adham S, Billon C, Legrand A, Domigo V, ... Jeunemaitre X, Frank M
Background:
and purpose
Vascular Ehlers-Danlos syndrome is a rare inherited connective tissue disorder because of pathogenic variants in the COL3A1 gene. Arterial complications can affect all anatomic areas and about 25% involve supra-aortic trunks (SATs) but no systematic assessment of cervical artery lesions has been made. The primary objective was to determine an accurate prevalence of spontaneous SAT lesions in a large series of patients with vascular Ehlers-Danlos syndrome at diagnosis and during follow-up. Secondary objectives were to study their neurological consequences (transient ischemic attack or stroke) and the possible relationships with sex, genotype, ascertainment status.
Methods
A retrospective review of a monocentric cohort of patients with molecularly proven vascular Ehlers-Danlos syndrome followed in a tertiary referral center from 2000 to 2017.
Results
One hundred forty-four patients were analyzed, 56.9% (n=82) had SAT lesions: 64.6% females, 74.4% index-case patients. Most lesions were identified in early arterial assessment (48% at first work-up, mean age of 35.7±13.0 years). Cumulative incidence of a first identification of a SAT lesion was 41.7% at 40 years old. On the complete period of survey, 183 SAT lesions (with 132 dissections and 33 aneurysms) were identified, mainly in internal carotid arteries (56.3%) and vertebral arteries (28.9%), more rarely in patients with COL3A1 null mutations (P=0.008). Transient ischemic attack or stroke were reported in n=16 (19.5%) of the 82 patients with SAT lesions without relation with age, sex, treatment, or hypertension.
Conclusions
Cervical artery lesions are frequent and mostly asymptomatic in patients with vascular Ehlers-Danlos syndrome. Local dissections and aneurysms are the most frequent type of lesions, but transient ischemic attack or stroke seem rare.



Stroke: 29 Apr 2021; 52:1628-1635
Adham S, Billon C, Legrand A, Domigo V, ... Jeunemaitre X, Frank M
Stroke: 29 Apr 2021; 52:1628-1635 | PMID: 33641388
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Abstract

Current Therapeutic Options in Aortic Stenosis.

Boskovski MT, Gleason TG
Aortic stenosis is the most common valvular disease requiring valve replacement. Valve replacement therapies have undergone progressive evolution since the 1960s. Over the last 20 years, transcatheter aortic valve replacement has radically transformed the care of aortic stenosis, such that it is now the treatment of choice for many, particularly elderly, patients. This review provides an overview of the pathophysiology, presentation, diagnosis, indications for intervention, and current therapeutic options for aortic stenosis.



Circ Res: 29 Apr 2021; 128:1398-1417
Boskovski MT, Gleason TG
Circ Res: 29 Apr 2021; 128:1398-1417 | PMID: 33914604
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Abstract

Premature permanent discontinuation of apixaban or warfarin in patients with atrial fibrillation.

Carnicelli AP, Al-Khatib SM, Xavier D, Dalgaard F, ... Wallentin L, Granger CB
Aims
The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought to describe patients from ARISTOTLE who prematurely permanently discontinued study drug.
Methods/results
We performed a posthoc analysis of patients from ARISTOTLE who prematurely permanently discontinued study drug during the study or follow-up period. Discontinuation rates and reasons for discontinuation were described. Death, thromboembolism (stroke, transient ischaemic attack, systemic embolism), myocardial infarction and major bleeding rates were stratified by ≤30 days or >30 days after discontinuation. A total of 4063/18 140 (22.4%) patients discontinued study drug at a median of 7.3 (2.2, 15.2) months after randomisation. Patients with discontinuation were more likely to be female and had a higher prevalence of cardiovascular disease, diabetes, renal impairment and anaemia. Premature permanent discontinuation was more common in those randomised to warfarin than apixaban (23.4% vs 21.4%; p=0.002). The most common reasons for discontinuation were patient request (46.1%) and adverse event (34.9%), with no significant difference between treatment groups. The cumulative incidence of clinical events ≤30 days after premature permanent discontinuation for all-cause death, thromboembolism, myocardial infarction, and major bleeding was 5.8%, 2.6%, 0.9%, and 3.0%, respectively. No significant difference was seen between treatment groups with respect to clinical outcomes after discontinuation.
Conclusion
Premature permanent discontinuation of study drug in ARISTOTLE was common, less frequent in patients receiving apixaban than warfarin and was followed by high 30-day rates of death, thromboembolism and major bleeding. Initiatives are needed to reduce discontinuation of oral anticoagulation.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Apr 2021; 107:713-720
Carnicelli AP, Al-Khatib SM, Xavier D, Dalgaard F, ... Wallentin L, Granger CB
Heart: 29 Apr 2021; 107:713-720 | PMID: 32938772
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Abstract

Device-induced platelet dysfunction in patients after left ventricular assist device implantation.

Klaeske K, Dieterlen MT, Eifert S, Scholz U, ... Borger MA, Meyer AL
Background
Non-surgical bleeding (NSB) is a major complication after left ventricular assist device (LVAD) implantation. It has been reported that non-physiological shear stress caused by LVADs could alter platelet receptor expression, which leads to bleeding disorders caused by coagulation dysfunctions.
Objectives
Because bleeding diathesis could be multifactorial, we focused on the combined characterization of platelet receptor expression patterns and oxidative stress to compare patients with NSB and patients without coagulation disorder in a monocentric, prospective study.
Methods
Blood samples were obtained from LVAD patients with NSB (bleeder group, n = 19) and without NSB (non-bleeder group, n = 20). The platelet receptors platelet endothelial cell adhesion molecule-1 (PECAM-1), glycoprotein (GP)Ibα, P-selectin, CD63, and GPIIb/IIIa, as well as the production of intraplatelet reactive oxygen species (ROS) were quantified by flow cytometry. Aggregation capacity was evaluated by aggregometry.
Results
The surface expression level of P-selectin and GPIbα on platelets was decreased in bleeders (P-selectin: 465 ± 72 U; GPIbα: 435 ± 41 U) compared to non-bleeders (P-selectin: 859 ± 115 U, P < .01; GPIbα: 570 ± 49 U, p = .04). Additionally, the mean fluorescence intensity of ADP-stimulated P-selectin and PECAM-1 expressing platelets were reduced in bleeders (P-selectin: 944 ± 84 U; PECAM-1: 6722 ± 419 U) compared to non-bleeders (P-selectin: 1269 ± 130 U, P = .04; PECAM-1: 8542 ± 665 U, P = .03). Bleeders showed a higher amount of ROS formation in platelets (88.0 ± 2.6%) than non-bleeders (81.5 ± 2.1%, P = .05).
Conclusions
These findings suggested that changes of three platelet receptors (GPIbα, P-selectin, and PECAM-1) and elevated oxidative stress may play a role in patients with bleeding complications following LVAD implantation. These results might help to explain the high incidence of spontaneous hemorrhage during LVAD support through an altered platelet function.

© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 29 Apr 2021; 19:1331-1341
Klaeske K, Dieterlen MT, Eifert S, Scholz U, ... Borger MA, Meyer AL
J Thromb Haemost: 29 Apr 2021; 19:1331-1341 | PMID: 33636040
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Abstract

Off-target effects of oral anticoagulants - vascular effects of vitamin K antagonist and non-vitamin K antagonist oral anticoagulant dabigatran etexilate.

van Gorp RH, Dijkgraaf I, Bröker V, Bauwens M, ... Reutelingsperger CP, Schurgers LJ
Introduction
Vitamin K antagonists (VKA) and non-vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off-target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup.
Material and methods
Female Apoe-/- mice (age 12 weeks) were fed Western-type diet as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [18 F]-NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin, and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed.
Results
Short-term treatment with warfarin promoted formation of atherosclerotic lesions with a pro-inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long-term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran.
Conclusion
Warfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.

© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 29 Apr 2021; 19:1348-1363
van Gorp RH, Dijkgraaf I, Bröker V, Bauwens M, ... Reutelingsperger CP, Schurgers LJ
J Thromb Haemost: 29 Apr 2021; 19:1348-1363 | PMID: 33687782
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Abstract

Transcriptional characterization of human megakaryocyte polyploidization and lineage commitment.

Choudry FA, Bagger FO, Macaulay IC, Farrow S, ... Teichmann SA, Frontini M
Background
Megakaryocytes (MKs) originate from cells immuno-phenotypically indistinguishable from hematopoietic stem cells (HSCs), bypassing intermediate progenitors. They mature within the adult bone marrow and release platelets into the circulation. Until now, there have been no transcriptional studies of primary human bone marrow MKs.
Objectives
To characterize MKs and HSCs from human bone marrow using single-cell RNA sequencing, to investigate MK lineage commitment, maturation steps, and thrombopoiesis.
Results
We show that MKs at different levels of polyploidization exhibit distinct transcriptional states. Although high levels of platelet-specific gene expression occur in the lower ploidy classes, as polyploidization increases, gene expression is redirected toward translation and posttranslational processing transcriptional programs, in preparation for thrombopoiesis. Our findings are in keeping with studies of MK ultrastructure and supersede evidence generated using in vitro cultured MKs. Additionally, by analyzing transcriptional signatures of a single HSC, we identify two MK-biased HSC subpopulations exhibiting unique differentiation kinetics. We show that human bone marrow MKs originate from these HSC subpopulations, supporting the notion that they display priming for MK differentiation. Finally, to investigate transcriptional changes in MKs associated with stress thrombopoiesis, we analyzed bone marrow MKs from individuals with recent myocardial infarction and found a specific gene expression signature. Our data support the modulation of MK differentiation in this thrombotic state.
Conclusions
Here, we use single-cell sequencing for the first time to characterize the human bone marrow MK transcriptome at different levels of polyploidization and investigate their differentiation from the HSC.

© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 29 Apr 2021; 19:1236-1249
Choudry FA, Bagger FO, Macaulay IC, Farrow S, ... Teichmann SA, Frontini M
J Thromb Haemost: 29 Apr 2021; 19:1236-1249 | PMID: 33587817
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Abstract

Transcatheter Closure of Atrial Septal Defect Associated With Pulmonary Artery Hypertension using Fenestrated Devices.

Wang JK, Chiu SN, Lin MT, Chen CA, Lu CW, Wu MH
In patients with pulmonary artery hypertension (PAH) associated with atrial septal defect (ASD), closure of ASD may carry significant risks. We aimed to evaluate the safety and efficacy of transcatheter closure of ASD in selected patients with PAH using a fenestrated device followed by pulmonary vasodilator therapy. During the 14.8-year period, 51 ASD patients (10 males, age 46 ± 18 years) with a mean pulmonary artery pressure (PAP) ≥ 35 mm Hg and/or systolic PAP ≥ 60 mm Hg, underwent closure with a fenestrated device. Of them, mean Qp/Qs ratio, systolic PAP and mean PAP were 2.6 ± 1.2, 73 ± 14 mm Hg, and 44 ± 8 mm Hg, respectively. A total of 35 patients received pulmonary vasodilator therapy. The New York Heart Association (NYHA) functional class improved at 3 to 6 months follow-up. (p < 0.001) Nineteen patients underwent repeated catheterization. A comparison of the hemodynamic parameters between baseline and repeated catheterization revealed significant decreases in both systolic and mean PAP (77 ± 11 vs 55 ± 14 mm Hg, p < 0.0001 & 48 ± 7 vs 37 ± 8 mm Hg, p = 0.001, respectively), pulmonary vascular resistance (PVR) (5.1 ± 2.3 vs 4.0 ± 1.7 WU, p = 0.011) and PVRi (7.7 ± 3.3 vs 6.2 ± 2.4 WU*m2, p = 0.024). After a follow-up period of 84 ± 45 months, 6 mortalities were noted in which 2 were due to cardiac causes. In conclusion, catheter closure of ASD in patients with PAH using a fenestrated device followed by vasodilator therapy is safe and effective.

Copyright © 2021. Published by Elsevier Inc.

Am J Cardiol: 14 May 2021; 147:122-128
Wang JK, Chiu SN, Lin MT, Chen CA, Lu CW, Wu MH
Am J Cardiol: 14 May 2021; 147:122-128 | PMID: 33667439
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Abstract

A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate.

D\'Souza A, Wang Y, Anderson C, Bucchi A, ... DiFrancesco D, Boyett MR
Background
Heart rate follows a diurnal variation, and slow heart rhythms occur primarily at night.
Objective
The lower heart rate during sleep is assumed to be neural in origin, but here we tested whether a day-night difference in intrinsic pacemaking is involved.
Methods
In vivo and in vitro electrocardiographic recordings, vagotomy, transgenics, quantitative polymerase chain reaction, Western blotting, immunohistochemistry, patch clamp, reporter bioluminescence recordings, and chromatin immunoprecipitation were used.
Results
The day-night difference in the average heart rate of mice was independent of fluctuations in average locomotor activity and persisted under pharmacological, surgical, and transgenic interruption of autonomic input to the heart. Spontaneous beating rate of isolated (ie, denervated) sinus node (SN) preparations exhibited a day-night rhythm concomitant with rhythmic messenger RNA expression of ion channels including hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4). In vitro studies demonstrated 24-hour rhythms in the human HCN4 promoter and the corresponding funny current. The day-night heart rate difference in mice was abolished by HCN block, both in vivo and in the isolated SN. Rhythmic expression of canonical circadian clock transcription factors, for example, Brain and muscle ARNT-Like 1 (BMAL1) and Cryptochrome (CRY) was identified in the SN and disruption of the local clock (by cardiomyocyte-specific knockout of Bmal1) abolished the day-night difference in Hcn4 and intrinsic heart rate. Chromatin immunoprecipitation revealed specific BMAL1 binding sites on Hcn4, linking the local clock with intrinsic rate control.
Conclusion
The circadian variation in heart rate involves SN local clock-dependent Hcn4 rhythmicity. Data reveal a novel regulator of heart rate and mechanistic insight into bradycardia during sleep.

Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Heart Rhythm: 29 Apr 2021; 18:801-810
D'Souza A, Wang Y, Anderson C, Bucchi A, ... DiFrancesco D, Boyett MR
Heart Rhythm: 29 Apr 2021; 18:801-810 | PMID: 33278629
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This program is still in alpha version.