Topic: Electrophysiology

Abstract

Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination.

Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S
Background
Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder.
Methods
We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay.
Results
Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4-heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation.
Conclusions
Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 08 Apr 2021; epub ahead of print
Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S
N Engl J Med: 08 Apr 2021; epub ahead of print | PMID: 33835769
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Myocardial Angiotensin Metabolism in End-Stage Heart Failure.

Pavo N, Prausmüller S, Spinka G, Goliasch G, ... Zuckermann A, Hülsmann M
Background
The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy.
Objectives
This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy.
Methods
Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients.
Results
AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity.
Conclusions
The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.

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

J Am Coll Cardiol: 12 Apr 2021; 77:1731-1743
Pavo N, Prausmüller S, Spinka G, Goliasch G, ... Zuckermann A, Hülsmann M
J Am Coll Cardiol: 12 Apr 2021; 77:1731-1743 | PMID: 33832600
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Incidence and Outcomes of Pneumonia in Patients With Heart Failure.

Shen L, Jhund PS, Anand IS, Bhatt AS, ... Solomon SD, McMurray JJV
Background
The incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).
Objectives
This study aimed to examine the rate and impact of pneumonia in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials.
Methods
The authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro-B-type natriuretic peptide).
Results
In PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58).
Conclusions
The incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711).

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

J Am Coll Cardiol: 26 Apr 2021; 77:1961-1973
Shen L, Jhund PS, Anand IS, Bhatt AS, ... Solomon SD, McMurray JJV
J Am Coll Cardiol: 26 Apr 2021; 77:1961-1973 | PMID: 33888245
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction.

Broch K, Anstensrud AK, Woxholt S, Sharma K, ... Aukrust P, Gullestad L
Background
Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response.
Objectives
This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI.
Methods
The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days.
Results
We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups.
Conclusions
Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703).

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

J Am Coll Cardiol: 19 Apr 2021; 77:1845-1855
Broch K, Anstensrud AK, Woxholt S, Sharma K, ... Aukrust P, Gullestad L
J Am Coll Cardiol: 19 Apr 2021; 77:1845-1855 | PMID: 33858620
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome.

Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Aims 
Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported.
Methods and results 
Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients.
Conclusion 
Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.

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

Eur Heart J: 20 Apr 2021; 42:1609-1617
Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Eur Heart J: 20 Apr 2021; 42:1609-1617 | PMID: 33355356
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome.

Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Aims 
Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported.
Methods and results 
Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients.
Conclusion 
Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.

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

Eur Heart J: 20 Apr 2021; 42:1609-1617
Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Eur Heart J: 20 Apr 2021; 42:1609-1617 | PMID: 33355356
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Therapeutic Manipulation of Myocardial Metabolism: JACC State-of-the-Art Review.

Honka H, Solis-Herrera C, Triplitt C, Norton L, Butler J, DeFronzo RA
The mechanisms responsible for the positive and unexpected cardiovascular effects of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes remain to be defined. It is likely that some of the beneficial cardiac effects of these antidiabetic drugs are mediated, in part, by altered myocardial metabolism. Common cardiometabolic disorders, including the metabolic (insulin resistance) syndrome and type 2 diabetes, are associated with altered substrate utilization and energy transduction by the myocardium, predisposing to the development of heart disease. Thus, the failing heart is characterized by a substrate shift toward glycolysis and ketone oxidation in an attempt to meet the high energetic demand of the constantly contracting heart. This review examines the metabolic pathways and clinical implications of myocardial substrate utilization in the normal heart and in cardiometabolic disorders, and discusses mechanisms by which antidiabetic drugs and metabolic interventions improve cardiac function in the failing heart.

Copyright © 2021. Published by Elsevier Inc.

J Am Coll Cardiol: 26 Apr 2021; 77:2022-2039
Honka H, Solis-Herrera C, Triplitt C, Norton L, Butler J, DeFronzo RA
J Am Coll Cardiol: 26 Apr 2021; 77:2022-2039 | PMID: 33888253
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prognostic Value of Nonischemic Ringlike Left Ventricular Scar in Patients With Apparently Idiopathic Nonsustained Ventricular Arrhythmias.

Muser D, Nucifora G, Muser D, Nucifora G, ... Marchlinski FE, Santangeli P
Background
Left ventricular (LV) scar on late gadolinium enhancement (LGE) cardiac magnetic resonance has been correlated with life-threatening arrhythmic events in patients with apparently idiopathic ventricular arrhythmias (VAs). We investigated the prognostic significance of a specific LV-LGE phenotype characterized by a ringlike pattern of fibrosis.
Methods
A total of 686 patients with apparently idiopathic nonsustained VA underwent contrast-enhanced cardiac magnetic resonance. A ringlike pattern of LV scar was defined as LV subepicardial/midmyocardial LGE involving at least 3 contiguous segments in the same short-axis slice. The end point of the study was time to the composite outcome of all-cause death, resuscitated cardiac arrest because of ventricular fibrillation or hemodynamically unstable ventricular tachycardia and appropriate implantable cardioverter defibrillator therapy.
Results
A total of 28 patients (4%) had a ringlike pattern of scar (group A), 78 (11%) had a non-ringlike pattern (group B), and 580 (85%) had normal cardiac magnetic resonance with no LGE (group C). Group A patients were younger compared with groups B and C (median age, 40 vs 52 vs 45 years; P<0.01), more frequently men (96% vs 82% vs 55%; P<0.01), with a higher prevalence of family history of sudden cardiac death or cardiomyopathy (39% vs 14% vs 6%; P<0.01) and more frequent history of unexplained syncope (18% vs 9% vs 3%; P<0.01). All patients in group A showed VA with a right bundle-branch block morphology versus 69% in group B and 21% in group C (P<0.01). Multifocal VAs were observed in 46% of group A patients compared with 26% of group B and 4% of group C (P<0.01). After a median follow-up of 61 months (range, 34-84 months), the composite outcome occurred in 14 patients (50.0%) in group A versus 15 (19.0%) in group B and 2 (0.3%) in group C (P<0.01). After multivariable adjustment, the presence of LGE with ringlike pattern remained independently associated with increased risk of the composite end point (hazard ratio, 68.98 [95% CI, 14.67-324.39], P<0.01).
Conclusions
In patients with apparently idiopathic nonsustained VA, nonischemic LV scar with a ringlike pattern is associated with malignant arrhythmic events.



Circulation: 05 Apr 2021; 143:1359-1373
Muser D, Nucifora G, Muser D, Nucifora G, ... Marchlinski FE, Santangeli P
Circulation: 05 Apr 2021; 143:1359-1373 | PMID: 33401956
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Perioperative Neurological Evaluation and Management to Lower the Risk of Acute Stroke in Patients Undergoing Noncardiac, Nonneurological Surgery: A Scientific Statement From the American Heart Association/American Stroke Association.

Benesch C, Glance LG, Derdeyn CP, Fleisher LA, ... American Heart Association Stroke Council; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Epidemiology and Prevention
Perioperative stroke is a potentially devastating complication in patients undergoing noncardiac, nonneurological surgery. This scientific statement summarizes established risk factors for perioperative stroke, preoperative and intraoperative strategies to mitigate the risk of stroke, suggestions for postoperative assessments, and treatment approaches for minimizing permanent neurological dysfunction in patients who experience a perioperative stroke. The first section focuses on preoperative optimization, including the role of preoperative carotid revascularization in patients with high-grade carotid stenosis and delaying surgery in patients with recent strokes. The second section reviews intraoperative strategies to reduce the risk of stroke, focusing on blood pressure control, perioperative goal-directed therapy, blood transfusion, and anesthetic technique. Finally, this statement presents strategies for the evaluation and treatment of patients with suspected postoperative strokes and, in particular, highlights the value of rapid recognition of strokes and the early use of intravenous thrombolysis and mechanical embolectomy in appropriate patients.



Circulation: 07 Apr 2021:CIR0000000000000968; epub ahead of print
Benesch C, Glance LG, Derdeyn CP, Fleisher LA, ... American Heart Association Stroke Council; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Epidemiology and Prevention
Circulation: 07 Apr 2021:CIR0000000000000968; epub ahead of print | PMID: 33827230
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Relationship of LVEF and Myocardial Scar to Long-Term Mortality Risk and Mode of Death in Patients With Nonischemic Cardiomyopathy.

Klem I, Klein M, Khan M, Yang EY, ... Heitner JF, Shah DJ
Background
Nonischemic cardiomyopathy is a leading cause of reduced left ventricular ejection fraction (LVEF) and is associated with high mortality risk from progressive heart failure and arrhythmias. Myocardial scar on cardiovascular magnetic resonance imaging is increasingly recognized as a risk marker for adverse outcomes; however, left ventricular dysfunction remains the basis for determining a patient\'s eligibility for primary prophylaxis with implantable cardioverter-defibrillator. We investigated the relationship of LVEF and scar with long-term mortality and mode of death in a large cohort of patients with nonischemic cardiomyopathy.
Methods
This study is a prospective, longitudinal outcomes registry of 1020 consecutive patients with nonischemic cardiomyopathy who underwent clinical cardiovascular magnetic resonance imaging for the assessment of LVEF and scar at 3 centers.
Results
During a median follow-up of 5.2 (interquartile range, 3.8, 6.6) years, 277 (27%) patients died. On survival analysis, LVEF ≤35% and scar were strongly associated with all-cause (log-rank test P=0.002 and P<0.001, respectively) and cardiac death (P=0.001 and P<0.001, respectively). Whereas scar was strongly related to sudden cardiac death (SCD; P=0.001), there was no significant association between LVEF ≤35% and SCD risk (P=0.57). On multivariable analysis including established clinical factors, LVEF and scar are independent risk markers of all-cause and cardiac death. The addition of LVEF provided incremental prognostic value but insignificant discrimination improvement by C-statistic for all-cause and cardiac death, but no incremental prognostic value for SCD. Conversely, scar extent demonstrated significant incremental prognostic value and discrimination improvement for all 3 end points. On net reclassification analysis, the addition of LVEF resulted in no significant improvement for all-cause death (11.0%; 95% CI, -6.2% to 25.9%), cardiac death (9.8%; 95% CI, -5.7% to 29.3%), or SCD (7.5%; 95% CI, -41.2% to 42.9%). Conversely, the addition of scar extent resulted in significant reclassification improvement of 25.5% (95% CI, 11.7% to 41.0%) for all-cause death, 27.0% (95% CI, 11.6% to 45.2%) for cardiac death, and 40.6% (95% CI, 10.5% to 71.8%) for SCD.
Conclusions
Myocardial scar and LVEF are both risk markers for all-cause and cardiac death in patients with nonischemic cardiomyopathy. However, whereas myocardial scar has strong and incremental prognostic value for SCD risk stratification, LVEF has no incremental prognostic value over clinical measures. Scar assessment should be incorporated into patient selection criteria for primary prevention implantable cardioverter-defibrillator placement.



Circulation: 05 Apr 2021; 143:1343-1358
Klem I, Klein M, Khan M, Yang EY, ... Heitner JF, Shah DJ
Circulation: 05 Apr 2021; 143:1343-1358 | PMID: 33478245
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ablation Versus Drug Therapy for Atrial Fibrillation in Heart Failure: Results From the CABANA Trial.

Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, ... Mark DB, CABANA Investigators
Background
In patients with heart failure and atrial fibrillation (AF), several clinical trials have reported improved outcomes, including freedom from AF recurrence, quality of life, and survival, with catheter ablation. This article describes the treatment-related outcomes of the AF patients with heart failure enrolled in the CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation).
Methods
The CABANA trial randomized 2204 patients with AF who were ≥65 years old or <65 years old with ≥1 risk factor for stroke at 126 sites to ablation with pulmonary vein isolation or drug therapy including rate or rhythm control drugs. Of these, 778 (35%) had New York Heart Association class >II at baseline and form the subject of this article. The CABANA trial\'s primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest.
Results
Of the 778 patients with heart failure enrolled in CABANA, 378 were assigned to ablation and 400 to drug therapy. Ejection fraction at baseline was available for 571 patients (73.0%), and 9.3% of these had an ejection fraction <40%, whereas 11.7% had ejection fractions between 40% and 50%. In the intention-to-treat analysis, the ablation arm had a 36% relative reduction in the primary composite end point (hazard ratio, 0.64 [95% CI, 0.41-0.99]) and a 43% relative reduction in all-cause mortality (hazard ratio, 0.57 [95% CI, 0.33-0.96]) compared with drug therapy alone over a median follow-up of 48.5 months. AF recurrence was decreased with ablation (hazard ratio, 0.56 [95% CI, 0.42-0.74]). The adjusted mean difference for the AFEQT (Atrial Fibrillation Effect on Quality of Life) summary score averaged over the entire 60-month follow-up was 5.0 points, favoring the ablation arm (95% CI, 2.5-7.4 points), and the MAFSI (Mayo Atrial Fibrillation-Specific Symptom Inventory) frequency score difference was -2.0 points, favoring ablation (95% CI, -2.9 to -1.2).
Conclusions
In patients with AF enrolled in the CABANA trial who had clinically diagnosed stable heart failure at trial entry, catheter ablation produced clinically important improvements in survival, freedom from AF recurrence, and quality of life relative to drug therapy. These results, obtained in a cohort most of whom had preserved left ventricular function, require independent trial verification. Registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT00911508; Unique identifier: NCT0091150.



Circulation: 05 Apr 2021; 143:1377-1390
Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, ... Mark DB, CABANA Investigators
Circulation: 05 Apr 2021; 143:1377-1390 | PMID: 33554614
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ablation Versus Drug Therapy for Atrial Fibrillation in Heart Failure: Results From the CABANA Trial.

Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, ... Mark DB, CABANA Investigators
Background
In patients with heart failure and atrial fibrillation (AF), several clinical trials have reported improved outcomes, including freedom from AF recurrence, quality of life, and survival, with catheter ablation. This article describes the treatment-related outcomes of the AF patients with heart failure enrolled in the CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation).
Methods
The CABANA trial randomized 2204 patients with AF who were ≥65 years old or <65 years old with ≥1 risk factor for stroke at 126 sites to ablation with pulmonary vein isolation or drug therapy including rate or rhythm control drugs. Of these, 778 (35%) had New York Heart Association class >II at baseline and form the subject of this article. The CABANA trial\'s primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest.
Results
Of the 778 patients with heart failure enrolled in CABANA, 378 were assigned to ablation and 400 to drug therapy. Ejection fraction at baseline was available for 571 patients (73.0%), and 9.3% of these had an ejection fraction <40%, whereas 11.7% had ejection fractions between 40% and 50%. In the intention-to-treat analysis, the ablation arm had a 36% relative reduction in the primary composite end point (hazard ratio, 0.64 [95% CI, 0.41-0.99]) and a 43% relative reduction in all-cause mortality (hazard ratio, 0.57 [95% CI, 0.33-0.96]) compared with drug therapy alone over a median follow-up of 48.5 months. AF recurrence was decreased with ablation (hazard ratio, 0.56 [95% CI, 0.42-0.74]). The adjusted mean difference for the AFEQT (Atrial Fibrillation Effect on Quality of Life) summary score averaged over the entire 60-month follow-up was 5.0 points, favoring the ablation arm (95% CI, 2.5-7.4 points), and the MAFSI (Mayo Atrial Fibrillation-Specific Symptom Inventory) frequency score difference was -2.0 points, favoring ablation (95% CI, -2.9 to -1.2).
Conclusions
In patients with AF enrolled in the CABANA trial who had clinically diagnosed stable heart failure at trial entry, catheter ablation produced clinically important improvements in survival, freedom from AF recurrence, and quality of life relative to drug therapy. These results, obtained in a cohort most of whom had preserved left ventricular function, require independent trial verification. Registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT00911508; Unique identifier: NCT0091150.



Circulation: 05 Apr 2021; 143:1377-1390
Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, ... Mark DB, CABANA Investigators
Circulation: 05 Apr 2021; 143:1377-1390 | PMID: 33554614
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

SARS-CoV-2 Cardiac Involvement in Young Competitive Athletes.

Moulson N, Petek BJ, Drezner JA, Harmon KG, ... Baggish AL, ORCCA Investigators
Background: Cardiac involvement among hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is common and associated with adverse outcomes. The objective of this study was to determine the prevalence and clinical implications of SARS-CoV-2 cardiac involvement in young competitive athletes.
Methods:
In this prospective multicenter observational cohort study with data from 42 colleges/universities, we assessed the prevalence, clinical characteristics, and outcomes of SARS-CoV-2 cardiac involvement among collegiate athletes in the United States. Data were collected from September 1, 2020 to December 31, 2020. The primary outcome was the prevalence of definite, probable, or possible SARS-CoV-2 cardiac involvement based on imaging definitions adapted from the Updated Lake Louise Criteria. Secondary outcomes included the diagnostic yield of cardiac testing, predictors for cardiac involvement, and adverse cardiovascular events or hospitalizations.
Results:
Among 19,378 athletes tested for SARS-CoV-2 infection, 3018 (mean age 20 years [SD,1 year]; 32% female) tested positive and underwent cardiac evaluation. A total of 2820 athletes underwent at least one element of cardiac \'triad\' testing [12-lead electrocardiography (ECG), troponin, and/or transthoracic echocardiography(TTE)] followed by cardiac magnetic resonance (CMR) if clinically indicated. In contrast, primary screening CMR was performed in 198 athletes. Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG (21/2999,0.7%), cardiac troponin (24/2719,0.9%), and TTE (24/2556,0.9%). Definite, probable, or possible SARS-COV-2 cardiac involvement was identified in 21/3018 (0.7%) athletes, including 15/2820 (0.5%) who underwent clinically indicated CMR (n=119) and 6/198 (3.0%) who underwent primary screening CMR. Accordingly, the diagnostic yield of CMR for SARS-COV-2 cardiac involvement was 4.2 times higher for a clinically indicated CMR (15/119,12.6%) versus a primary screening CMR (6/198,3.0%). After adjustment for race and sex, predictors of SARS-CoV-2 cardiac involvement included cardiopulmonary symptoms (OR:3.1,95% CI:1.2,7.7) or at least one abnormal triad test (OR:37.4,95% CI:13.3,105.3). Five (0.2%) athletes required hospitalization for non-cardiac complications of SARS-CoV-2. During clinical surveillance (median follow-up 113 days [IQR=90,146]), there was one (0.03%) adverse cardiac event likely unrelated to SARS-CoV-2 infection. Conclusions: SARS-CoV-2 infection among young competitive athletes is associated with a low prevalence of cardiac involvement and a low risk of clinical events in short term follow-up.




Circulation: 16 Apr 2021; epub ahead of print
Moulson N, Petek BJ, Drezner JA, Harmon KG, ... Baggish AL, ORCCA Investigators
Circulation: 16 Apr 2021; epub ahead of print | PMID: 33866822
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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: 21 Apr 2021:CIR0000000000000973; epub ahead of print
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: 21 Apr 2021:CIR0000000000000973; epub ahead of print | PMID: 33882682
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Invasive Management of Acute Myocardial Infarction Complicated by Cardiogenic Shock: A Scientific Statement From the American Heart Association.

Henry TD, Tomey MI, Tamis-Holland JE, Thiele H, ... American Heart Association Interventional Cardiovascular Care Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Cardiovascular and Stroke Nursing
Cardiogenic shock (CS) remains the most common cause of mortality in patients with acute myocardial infarction. The SHOCK trial (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) demonstrated a survival benefit with early revascularization in patients with CS complicating acute myocardial infarction (AMICS) 20 years ago. After an initial improvement in mortality related to revascularization, mortality rates have plateaued. A recent Society of Coronary Angiography and Interventions classification scheme was developed to address the wide range of CS presentations. In addition, a recent scientific statement from the American Heart Association recommended the development of CS centers using standardized protocols for diagnosis and management of CS, including mechanical circulatory support devices (MCS). A number of CS programs have implemented various protocols for treating patients with AMICS, including the use of MCS, and have published promising results using such protocols. Despite this, practice patterns in the cardiac catheterization laboratory vary across health systems, and there are inconsistencies in the use or timing of MCS for AMICS. Furthermore, mortality benefit from MCS devices in AMICS has yet to be established in randomized clinical trials. In this article, we outline the best practices for the contemporary interventional management of AMICS, including coronary revascularization, the use of MCS, and special considerations such as the treatment of patients with AMICS with cardiac arrest.



Circulation: 12 Apr 2021; 143:e815-e829
Henry TD, Tomey MI, Tamis-Holland JE, Thiele H, ... American Heart Association Interventional Cardiovascular Care Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Cardiovascular and Stroke Nursing
Circulation: 12 Apr 2021; 143:e815-e829 | PMID: 33657830
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Oxygen Pathway Limitations in Patients with Chronic Thromboembolic Pulmonary Hypertension.

Howden EJ, Ruiz-Carmona S, Claeys M, de Bosscher R, ... Delcroix M, Claessen G
Background: Exertional intolerance is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Traditionally the etiology has been attributed to central factors, including ventilation-perfusion mismatch, increased pulmonary vascular resistance and right heart dysfunction and uncoupling. Pulmonary endarterectomy and, balloon pulmonary angioplasty provide substantial improvement of functional status and hemodynamics. However, despite normalization of pulmonary hemodynamics, exercise capacity often does not return to age-predicted. By systematically evaluating the oxygen (O2) pathway we aimed to elucidate the cause/s of functional limitations in CTEPH patients before and after pulmonary vascular intervention.
Methods:
Using exercise cardiac magnetic resonance (CMR) imaging with simultaneous invasive hemodynamic monitoring, we sought to quantify the steps of the O2 transport cascade from the mouth to the mitochondria in patients with CTEPH (n=20) as compared to healthy subjects (n=10). Furthermore we evaluated the effect of pulmonary vascular intervention (pulmonary endarterectomy or balloon angioplasty) on the individual components of the cascade (n=10).
Results:
Peak VO2 was significantly reduced in CTEPH patients relative to controls (56±17 vs 112±20% of predicted, p<0.0001). The difference was due to impairments in multiple steps of the O2 cascade, including O2 delivery (product of cardiac output and arterial O2 content), skeletal muscle diffusion capacity, and pulmonary diffusion. The total O2 extracted in the periphery, i.e. ΔAVO2, was not different. Following pulmonary vascular intervention, peak VO2 increased significantly (12.5±4.0 to 17.8±7.5 ml/kg/min, p=0.036) but remained below age-predicted (70±11%). The O2 delivery was improved due to an increase in peak cardiac output and lung diffusion capacity. However, peak exercise ΔAVO2 was unchanged, as was skeletal muscle diffusion capacity. Conclusions: We demonstrated that CTEPH patients have significant impairment of all steps in the O2 utilisation cascade resulting in markedly impaired exercise capacity. Pulmonary vascular intervention increased peak VO2, by partly correcting O2 delivery but having no impact on abnormalities in peripheral O2 extraction. This suggests that current interventions only partially address patients\' limitations and that additional therapies may improve functional capacity.




Circulation: 14 Apr 2021; epub ahead of print
Howden EJ, Ruiz-Carmona S, Claeys M, de Bosscher R, ... Delcroix M, Claessen G
Circulation: 14 Apr 2021; epub ahead of print | PMID: 33853383
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Excessive -GlcNAcylation Causes Heart Failure and Sudden Death.

Umapathi P, Mesubi OO, Banerjee PS, Abrol N, ... Zachara NE, Anderson ME
Background
Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes. O-GlcNAcylation (the attachment of O-linked β-N-acetylglucosamine [O-GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels of O-GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Failing myocardium is marked by increased O-GlcNAcylation, but whether excessive O-GlcNAcylation contributes to cardiomyopathy and heart failure is unknown.
Methods
We developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to control O-GlcNAcylation independent of pathologic stress.
Results
We found that OGT transgenic hearts showed increased O-GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lower O-GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardial O-GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O-GlcNAc-mediated cardiac pathology.
Conclusions
Our data provide evidence that excessive O-GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O-GlcNAcylation is beneficial against pressure overload-induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.



Circulation: 26 Apr 2021; 143:1687-1703
Umapathi P, Mesubi OO, Banerjee PS, Abrol N, ... Zachara NE, Anderson ME
Circulation: 26 Apr 2021; 143:1687-1703 | PMID: 33593071
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial.

Pawade TA, Doris MK, Bing R, White AC, ... Newby DE, Dweck MR
Background: Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with pre-clinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis.
Methods:
In a single-centre parallel group double-blind randomized controlled trial, patients over 50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly) or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring and 18F-sodium fluoride positron emission tomography and computed tomography. The primary endpoint was the calculated 24-month change in aortic valve calcium score.
Results:
One-hundred and fifty patients (mean age 72±8 years; 21% female) with calcific aortic stenosis (peak aortic jet velocity 3.36 [2.93 to 3.82] m/s; aortic valve calcium score 1152 [655 to 2065] Agatston Units) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51) and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18 to 0.33] to 0.11 [0.08 to 0.17] µg/L) and alendronic acid (0.20 [0.14 to 0.28] to 0.09 [0.08 to 0.13] µg/L) but was unchanged with placebo (0.23 [0.17 to 0.30] to 0.26 [0.16 to 0.31] µg/L). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198 to 804] AU versus 354 [76 to 675] AU, p=0.41), or alendronic acid and placebo (326 [138 to 813] AU versus 354 [76 to 675] AU, p=0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18F-sodium fluoride aortic valve uptake. Conclusions: Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Clinical Trial Registration: https://www.clinicaltrials.gov Unique Identifier: NCT02132026.




Circulation: 28 Apr 2021; epub ahead of print
Pawade TA, Doris MK, Bing R, White AC, ... Newby DE, Dweck MR
Circulation: 28 Apr 2021; epub ahead of print | PMID: 33913339
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

MicroRNA Biophysically Modulates Cardiac Action Potential by Direct Binding to Ion Channel.

Yang D, Wan X, Dennis AT, Bektik E, ... Deschênes I, Fu JD
Background
MicroRNAs (miRs) play critical roles in regulation of numerous biological events, including cardiac electrophysiology and arrhythmia, through a canonical RNA interference mechanism. It remains unknown whether endogenous miRs modulate physiologic homeostasis of the heart through noncanonical mechanisms.
Methods
We focused on the predominant miR of the heart (miR1) and investigated whether miR1 could physically bind with ion channels in cardiomyocytes by electrophoretic mobility shift assay, in situ proximity ligation assay, RNA pull down, and RNA immunoprecipitation assays. The functional modulations of cellular electrophysiology were evaluated by inside-out and whole-cell patch clamp. Mutagenesis of miR1 and the ion channel was used to understand the underlying mechanism. The effect on the heart ex vivo was demonstrated through investigating arrhythmia-associated human single nucleotide polymorphisms with miR1-deficient mice.
Results
We found that endogenous miR1 could physically bind with cardiac membrane proteins, including an inward-rectifier potassium channel Kir2.1. The miR1-Kir2.1 physical interaction was observed in mouse, guinea pig, canine, and human cardiomyocytes. miR1 quickly and significantly suppressed IK1 at sub-pmol/L concentration, which is close to endogenous miR expression level. Acute presence of miR1 depolarized resting membrane potential and prolonged final repolarization of the action potential in cardiomyocytes. We identified 3 miR1-binding residues on the C-terminus of Kir2.1. Mechanistically, miR1 binds to the pore-facing G-loop of Kir2.1 through the core sequence AAGAAG, which is outside its RNA interference seed region. This biophysical modulation is involved in the dysregulation of gain-of-function Kir2.1-M301K mutation in short QT or atrial fibrillation. We found that an arrhythmia-associated human single nucleotide polymorphism of miR1 (hSNP14A/G) specifically disrupts the biophysical modulation while retaining the RNA interference function. It is remarkable that miR1 but not hSNP14A/G relieved the hyperpolarized resting membrane potential in miR1-deficient cardiomyocytes, improved the conduction velocity, and eliminated the high inducibility of arrhythmia in miR1-deficient hearts ex vivo.
Conclusions
Our study reveals a novel evolutionarily conserved biophysical action of endogenous miRs in modulating cardiac electrophysiology. Our discovery of miRs\' biophysical modulation provides a more comprehensive understanding of ion channel dysregulation and may provide new insights into the pathogenesis of cardiac arrhythmias.



Circulation: 19 Apr 2021; 143:1597-1613
Yang D, Wan X, Dennis AT, Bektik E, ... Deschênes I, Fu JD
Circulation: 19 Apr 2021; 143:1597-1613 | PMID: 33590773
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The Cardiac Late Sodium Channel Current is a Molecular Target for the Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin.

Philippaert K, Kalyaanamoorthy S, Fatehi M, Long W, ... Dyck JRB, Light PE
Background: Sodium/glucose co-transporter 2 (SGLT2) inhibitors exert robust cardioprotective effects against heart failure in diabetes patients and there is intense interest to identify the underlying molecular mechanisms that afford this protection. As the induction of the late component of the cardiac sodium channel current (late-INa) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-INa.
Methods:
Electrophysiological, in silico molecular docking, molecular, calcium imaging and whole heart perfusion techniques were employed to address this question.
Results:
The SGLT2 inhibitor empagliflozin reduced late-INa in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the LQT3 mutations R1623Q or ∆KPQ. Empagliflozin, dapagliflozin and canagliflozin are all potent and selective inhibitors of H2O2-induced late-INa (IC50s = 0.79, 0.58 and 1.26 µM respectively) with little effect on peak-INa. In mouse cardiomyocytes, empagliflozin reduced the incidence of spontaneous calcium transients induced by the late-INa activator veratridine in a similar manner to tetrodotoxin, ranolazine and lidocaine. The putative binding sites for empagliflozin within Nav1.5 were investigated by simulations of empagliflozin docking to a 3D homology model of human Nav1.5 and point mutagenic approaches. Our results indicate that empagliflozin binds to Nav1.5 in the same region as local anaesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 inflammasome and improved functional recovery after ischemia. Conclusions: Our results provide evidence that late-INa may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.




Circulation: 08 Apr 2021; epub ahead of print
Philippaert K, Kalyaanamoorthy S, Fatehi M, Long W, ... Dyck JRB, Light PE
Circulation: 08 Apr 2021; epub ahead of print | PMID: 33832341
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Variant Intronic Enhancer Controls Expression and Heart Conduction.

Man JCK, Bosada FM, Scholman KT, Offerhaus JA, ... Barnett P, Christoffels VM
Background: Genetic variants in SCN10A, encoding the neural voltage-gated sodium channel NaV1.8, are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities and heart rate. The cardiac function of SCN10A has not been resolved, however, and diverging mechanisms have been proposed. Here, we investigated the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, encoding the major essential cardiac sodium channel NaV1.5.
Methods:
The expression of SCN10A was investigated in mouse and human hearts. Using CRISPR/Cas9 genome editing, the mouse intronic enhancer was disrupted, and mutant mice were characterized by transcriptomic and electrophysiological analyses. The association of genetic variants at SCN5A-SCN10A enhancer regions and gene expression were evaluated by GWAS SNP mapping and expression QTL analysis.
Results:
We found that cardiomyocytes of the atria, sinoatrial node and ventricular conduction system express a short transcript comprising the last 7 exons of the gene (Scn10a-short). Transcription occurs from an intronic enhancer-promoter complex, while full length Scn10a transcript was undetectable in the human and mouse heart. Expression QTL analysis revealed that the genetic variants in linkage disequilibrium with genetic variant rs6801957 in the intronic enhancer associate with SCN10A transcript levels in the heart. Genetic modification of the enhancer in the mouse genome led to reduced cardiac Scn10a-short expression in atria and ventricles, reduced cardiac sodium current in atrial cardiomyocytes, atrial conduction slowing and arrhythmia, while expression of Scn5a, the presumed enhancer target gene, remained unaffected. In patch-clamp transfection experiments, expression of Scn10a-short-encoded NaV1.8-short increased NaV1.5-mediated sodium current. We propose that non-coding genetic variation modulates transcriptional regulation of Scn10a-short in cardiomyocytes that impacts on NaV1.5-mediated sodium current and heart rhythm. Conclusions: Genetic variants in and around SCN10A modulate enhancer function and expression of a cardiac-specific SCN10A-short transcript. We propose that non-coding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV1.8 in cardiomyocytes that impacts on NaV1.5 function, cardiac conduction velocities and arrhythmia susceptibility.




Circulation: 28 Apr 2021; epub ahead of print
Man JCK, Bosada FM, Scholman KT, Offerhaus JA, ... Barnett P, Christoffels VM
Circulation: 28 Apr 2021; epub ahead of print | PMID: 33910361
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Time-Dependent Risk of Atrial Fibrillation in Patients With Primary Aldosteronism After Medical or Surgical Treatment Initiation.

Kim KJ, Hong N, Yu MH, Lee H, ... Lim JS, Rhee Y
Increased risk of atrial fibrillation was reported in patients with primary aldosteronism. However, data are limited regarding the time-dependent risk of atrial fibrillation in surgically or medically treated primary aldosteronism. From the National Health Insurance Claim database in Korea (2003-2017), a total of 1418 patients with primary aldosteronism (adrenalectomy [ADX], n=755, mineralocorticoid receptor antagonist n=663) were age- and sex-matched at a 1:5 ratios to patients with essential hypertension (n=7090). Crude incidence of new onset atrial fibrillation was 2.96% in primary aldosteronism and 1.97% in essential hypertension. Because of nonproportional hazard observed in new onset atrial fibrillation, analysis time was split at 3 years. Compared with essential hypertension, risk of new onset atrial fibrillation peaked at 1 year gradually declined but remained elevated up to 3 years in overall treated primary aldosteronism (adjusted hazard ratio [aHR] 3.02; P<0.001) as well as in both ADX (aHR, 3.54; P<0.001) and mineralocorticoid receptor antagonist groups (aHR 2.27; P=0.031), which became comparable to essential hypertension afterward in both groups (ADX aHR, 0.38; P=0.102; mineralocorticoid receptor antagonist aHR, 0.60; P=0.214). Nonetheless, mineralocorticoid receptor antagonist group was associated with increased risk of nonfatal stroke (aHR, 1.21; P=0.031) compared with essential hypertension, whereas ADX was not (aHR, 1.26; P=0.288). Our results suggest the risk of new-onset atrial fibrillation remained elevated up to 3 years in treated primary aldosteronism compared with essential hypertension, which declined to comparable risk in essential hypertension thereafter. Monitoring for atrial fibrillation up to 3 years after treatment, particularly ADX, might be warranted.



Hypertension: 18 Apr 2021:HYPERTENSIONAHA12016909; epub ahead of print
Kim KJ, Hong N, Yu MH, Lee H, ... Lim JS, Rhee Y
Hypertension: 18 Apr 2021:HYPERTENSIONAHA12016909; epub ahead of print | PMID: 33866798
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Time-Dependent Risk of Atrial Fibrillation in Patients With Primary Aldosteronism After Medical or Surgical Treatment Initiation.

Kim KJ, Hong N, Yu MH, Lee H, ... Lim JS, Rhee Y
Increased risk of atrial fibrillation was reported in patients with primary aldosteronism. However, data are limited regarding the time-dependent risk of atrial fibrillation in surgically or medically treated primary aldosteronism. From the National Health Insurance Claim database in Korea (2003-2017), a total of 1418 patients with primary aldosteronism (adrenalectomy [ADX], n=755, mineralocorticoid receptor antagonist n=663) were age- and sex-matched at a 1:5 ratios to patients with essential hypertension (n=7090). Crude incidence of new onset atrial fibrillation was 2.96% in primary aldosteronism and 1.97% in essential hypertension. Because of nonproportional hazard observed in new onset atrial fibrillation, analysis time was split at 3 years. Compared with essential hypertension, risk of new onset atrial fibrillation peaked at 1 year gradually declined but remained elevated up to 3 years in overall treated primary aldosteronism (adjusted hazard ratio [aHR] 3.02; P<0.001) as well as in both ADX (aHR, 3.54; P<0.001) and mineralocorticoid receptor antagonist groups (aHR 2.27; P=0.031), which became comparable to essential hypertension afterward in both groups (ADX aHR, 0.38; P=0.102; mineralocorticoid receptor antagonist aHR, 0.60; P=0.214). Nonetheless, mineralocorticoid receptor antagonist group was associated with increased risk of nonfatal stroke (aHR, 1.21; P=0.031) compared with essential hypertension, whereas ADX was not (aHR, 1.26; P=0.288). Our results suggest the risk of new-onset atrial fibrillation remained elevated up to 3 years in treated primary aldosteronism compared with essential hypertension, which declined to comparable risk in essential hypertension thereafter. Monitoring for atrial fibrillation up to 3 years after treatment, particularly ADX, might be warranted.



Hypertension: 18 Apr 2021:HYPERTENSIONAHA12016909; epub ahead of print
Kim KJ, Hong N, Yu MH, Lee H, ... Lim JS, Rhee Y
Hypertension: 18 Apr 2021:HYPERTENSIONAHA12016909; epub ahead of print | PMID: 33866798
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Platelet Activation and Plasma Levels of Furin Are Associated With Prognosis of Patients With Coronary Artery Disease and COVID-19.

Langnau C, Rohlfing AK, Gekeler S, Günter M, ... Autenrieth SE, Mueller KAL
Objective
Patients with coronary artery disease (CAD) are at increased risk for cardiac death and respiratory failure following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Platelets are crucially involved in pathogenesis of CAD and might also contribute to pathophysiology of SARS-CoV-2 infection. Approach and
Results:
We enrolled a cohort of 122 participants from February 2020 to July 2020 including 55 patients with preexisting CAD and acute SARS-CoV-2 infection (CAD-SARS-CoV-2positive), 28 patients with CAD and without SARS-CoV-2 (CAD-SARS-CoV-2negative), and 39 healthy controls. Clinical and cardiac examination of the CAD-SARS-CoV-2positive group included blood sampling, echocardiography, and electrocardiography within 24 hours after hospital admission. Phenotyping of platelets was performed by flow cytometry; plasma levels of chemokines were analyzed by ELISA. Respiratory failure of patients was stratified by the Horovitz index as moderately/severely impaired when Horovitz index <200 mm Hg. The clinical end point was defined as Horovitz index <200 mm Hg with subsequent mechanical ventilation within a follow-up of 60 days. CAD-SARS-CoV-2positive patients display a significant enhanced platelet activation and hyper-inflammation early at time of hospital admission. Circulating platelet/leukocyte co-aggregates correlate with plasma levels of cytokines/chemokines like IL (interleukin)-6, CCL2, and CXCL10 as well as activation of platelets is associated with CCL5 and elevation of pulmonary artery pressure. Furthermore, furin is stored and released from activated platelets. High furin plasma levels are associated with poor clinical prognosis in CAD-SARS-CoV-2positive patients.
Conclusions
Patients with CAD and SARS-CoV-2 infection exhibit elevated systemic platelet activation and enhanced plasma levels of the subtilisin-like proprotein convertase furin, which may contribute to an unfavorable clinical prognosis.



Arterioscler Thromb Vasc Biol: 28 Apr 2021:ATVBAHA120315698; epub ahead of print
Langnau C, Rohlfing AK, Gekeler S, Günter M, ... Autenrieth SE, Mueller KAL
Arterioscler Thromb Vasc Biol: 28 Apr 2021:ATVBAHA120315698; epub ahead of print | PMID: 33910372
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Altered Responsiveness to TGFβ and BMP and Increased CD45+ Cell Presence in Mitral Valves Are Unique Features of Ischemic Mitral Regurgitation.

Castillero E, Howsmon DP, Rego BV, Keeney S, ... Levy RJ, Ferrari G
Objective
Ischemic mitral regurgitation (IMR) often develops after an ischemic event, which results in distortion of the valvulo-ventricular complex and incomplete mitral valve (MV) leaflet coaptation. After left ventricular ischemic events, only some patients develop IMR. The susceptibility of the MV to remodel may influence whether IMR develops. We hypothesized that impaired signaling response in MV cells may contribute to IMR development by inducing maladaptive tissue remodeling. Approach and
Results:
Sheep (n=14) were subjected to ligation of the circumflex coronary artery to induce myocardial infarction. IMR was reported by echocardiography. MV leaflets and MV interstitial cells (MVICs) were collected at baseline (control, n=10), 4 and 8 weeks post-myocardial infarction. RNA sequencing highlighted differences in TGFβ (transforming growth factor beta) signaling between MV with/without IMR. SMAD6/7 and ID2 (inhibitor of DNA binding 2) were the highest increased TGFβ-signaling genes associated with IMR. MVICs from myocardial infarction sheep were less responsive to BMP (bone morphogenic protein) 4 pro-osteogenic stimulation (ID2, OPN [osteopontin], and OC [osteocalcin] mRNA) than control. MVICs from IMR sheep had a diminished COL (collagen) 1A1 mRNA response to TGFβ1 and enhanced prochondrogenic RUNX2 (runt-related transcription factor 2) and SOX9 mRNA response to BMP4 versus non-IMR MVICs. Baseline CD45 expression was detectable only in IMR MVICs. Upon TGFβ1 stimulation, CD45 expression was detected in all groups. Immunostaining confirmed increased presence of CD45+ cells in IMR MV interstitium.
Conclusions
MVs from sheep with IMR had an altered TGFβ/BMP response, associated with increased CD45+ cell presence within the tissue interstitium. Pharmacological strategies aimed to modulate TGFβ/BMP signaling after myocardial infarction may protect from pathological MV remodeling leading to IMR.



Arterioscler Thromb Vasc Biol: 07 Apr 2021:ATVBAHA121316111; epub ahead of print
Castillero E, Howsmon DP, Rego BV, Keeney S, ... Levy RJ, Ferrari G
Arterioscler Thromb Vasc Biol: 07 Apr 2021:ATVBAHA121316111; epub ahead of print | PMID: 33827255
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling.

Nakagawa H, Kumazawa T, Onoue K, Nakada Y, ... Kawakami R, Saito Y
NEP (Neprilysin) degrades natriuretic peptides, and its inhibition is a clinically accepted target for heart failure treatment. NEP is widely expressed in various organs, including the heart. However, the pathophysiological significance of local cardiac NEP is not fully understood. To study the local function of NEP in the heart, we generated transgenic mice overexpressing NEP, specifically in cardiomyocytes (CM-NEP Tg). At baseline, CM-NEP Tg mice showed significantly lower levels of plasma ANP (atrial natriuretic peptide), plasma cGMP, and cardiac tissue cGMP versus wild-type (WT) mice. Blood pressure, heart weight, and cardiomyocyte diameter were greater in CM-NEP Tg than WT mice. There were no significant differences in interstitial fibrosis or ejection fraction. Transverse aortic constriction (TAC) surgery significantly increased left ventricular weight in WT and CM-NEP Tg mice 3 weeks post-op versus sham surgery; however, the cardiac hypertrophic response to TAC was higher in CM-NEP Tg than WT mice. Cardiac interstitial fibrosis was induced in TAC CM-NEP Tg mice, whereas TAC WT mice had none. TAC CM-NEP Tg, but not TAC WT, mice developed cardiac dysfunction secondary to TAC with echocardiography. Furthermore, administration of human ANP to raise plasma ANP levels comparable to those in WT mice neither improved the exacerbated cardiac hypertrophy and fibrosis nor recovered impaired cardiac function in CM-NEP Tg mice after TAC. In conclusion, overexpression of NEP in cardiomyocytes promoted degradation of natriuretic peptides in the heart and led to an exaggerated response of hypertrophy and fibrosis to pressure overload.



Hypertension: 11 Apr 2021:HYPERTENSIONAHA12016445; epub ahead of print
Nakagawa H, Kumazawa T, Onoue K, Nakada Y, ... Kawakami R, Saito Y
Hypertension: 11 Apr 2021:HYPERTENSIONAHA12016445; epub ahead of print | PMID: 33840200
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Loss of Transforming Growth Factor Beta Signaling in Aortic Smooth Muscle Cells Causes Endothelial Dysfunction and Aortic Hypercontractility.

Zhu J, Angelov S, Yildirim IA, Wei H, ... Kim F, Dichek DA
Objective
Humans and mice with loss-of-function variants of genes in the TGF-β (transforming growth factor beta) signaling pathway develop aortic aneurysms. These aneurysms could be caused by decreased aortic smooth muscle cell (SMC) contractile-protein levels and impaired aortic SMC contractile-unit function. Accordingly, we investigated whether loss of SMC TGF-β signaling in mice alters aortic contractile-protein levels and aortic contractility. Approach and
Results:
We used immunoblotting, wire myography, histological analyses, and measurements of aortic nitric oxide and superoxide levels to assess aortic contractile-protein levels and vasomotor function in mice with SMC-specific deletion of the type 2 TGF-β receptor (TBR2SMΔ mice). Aortic contractile-protein levels were not altered in TBR2SMΔ mice. Surprisingly, TBR2SMΔ mice had increased aortic contractility and severe endothelial dysfunction. Endothelial dysfunction was manifested as decreased relaxation to acetylcholine (Emax 37% versus 97%; P<0.0001), decreased aortic nitric oxide (50%; P=0.005), decreased endothelial nitric oxide synthase activation (31%; P=0.002), and lower aortic levels of phosphorylated vasodilator-stimulated phosphoprotein (an indicator of nitric oxide bioavailability: 65%; P<0.0001). Aortic hypercontractility was reduced by mechanical denudation of endothelium and was eliminated by pretreatment of TBR2SMΔ and control aortas with a nitric oxide synthase inhibitor, revealing a significant positive interaction between aortic hypercontractility and absence of endothelium-derived nitric oxide (P<0.05 for both denudation and nitric oxide inhibition).
Conclusions
Aortic aneurysms that develop in TBR2SMΔ mice are not caused by decreased SMC contractility. Loss of physiological SMC TGF-β signaling causes endothelial dysfunction leading to aortic hypercontractility. Endothelial dysfunction may contribute to vascular pathologies associated with abnormal TGF-β signaling.



Arterioscler Thromb Vasc Biol: 14 Apr 2021:ATVBAHA121315878; epub ahead of print
Zhu J, Angelov S, Yildirim IA, Wei H, ... Kim F, Dichek DA
Arterioscler Thromb Vasc Biol: 14 Apr 2021:ATVBAHA121315878; epub ahead of print | PMID: 33853348
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Hydrogel Strategy to Augment Tissue Adenosine to Improve Hindlimb Perfusion.

Sayegh MN, Cooney KA, Han WM, Wang L, ... García AJ, Levit RD
Objective
Adenosine is an important vasodilatory, anti-inflammatory, and antithrombotic agent; however, its delivery for the treatment of cardiovascular diseases is challenging due to the drug\'s short half-life and dose-limiting side effects. Peripheral artery disease, one of the most prevalent atherosclerotic diseases of the cardiovascular system, remains without adequate nonsurgical treatments, resulting in significant morbidity due to ischemia and inflammation. Here, we hypothesize that we can use an enzyme-loaded synthetic hydrogel for local adenosine production. Approach and
Results:
We engineer a protease-sensitive poly(ethylene glycol)-maleimide-based hydrogel and characterize its rheological parameters when modulating poly(ethylene glycol) density and tethering a peptide to the gel backbone, then test degradation in response to collagenase. We load the gel with an ecto-nucleotidase, CD73, which catalyzes adenosine production from phosphorylated substrates, and use the CD73-loaded gel to generate adenosine in vitro and inhibit neutrophils\' oxidative burst. When delivered in vivo, the CD73 hydrogel augments adenosine levels in hindlimb skeletal muscles 24 hours after induction of peripheral arterial ischemia and increases lower limb perfusion compared with control gel in healthy mice on laser Doppler imaging.
Conclusions
This enzyme-delivering hydrogel provides a strategy for local and sustained adenosine generation to improve perfusion, and future work will optimize its use for disease modulation.



Arterioscler Thromb Vasc Biol: 21 Apr 2021:ATVBAHA120315428; epub ahead of print
Sayegh MN, Cooney KA, Han WM, Wang L, ... García AJ, Levit RD
Arterioscler Thromb Vasc Biol: 21 Apr 2021:ATVBAHA120315428; epub ahead of print | PMID: 33882686
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Important Role of Concomitant Lymphangiogenesis for Reparative Angiogenesis in Hindlimb Ischemia.

Pu Z, Shimizu Y, Tsuzuki K, Suzuki J, ... Shibata R, Murohara T
Objective
Lymphatic vessels are distributed throughout the body and tightly collaborate with blood vessels to maintain tissue homeostasis. However, the functional roles of lymphangiogenesis in the process of reparative angiogenesis in ischemic tissues are largely unknown. Accordingly, we investigated potential roles of lymphangiogenesis using a mouse model of ischemia-induced angiogenesis. Approach and
Results:
Male C57BL/6J mice were subjected to unilateral hindlimb ischemia, in which not only angiogenesis but also lymphangiogenesis was induced. Next, the excessive and prolonged tissue edema model significantly deteriorated reparative angiogenesis and blood perfusion recovery in ischemic limbs. Finally, implantation of adipose-derived regenerative cells augmented ischemia-induced lymphangiogenesis, which was accompanied by reduced tissue edema and inflammation, resulting in improving reparative angiogenesis and blood perfusion recovery. In addition, inhibition of lymphangiogenesis by MAZ51, a specific VEGFR3 (vascular endothelial cell growth factor receptor 3) inhibitor, resulted in enhanced inflammatory cell infiltration, gene expression of TNF (tumor necrosis factor)-α, IL (interleukin)-1β, IL-6, TGF (transforming growth factor)-β, angiostatin, vasohibin, and endostatin, and tissue edema, resulting in reduced angiogenesis.
Conclusions
The lymphatic system may have a clearance role of tissue edema and inflammation, which contribute to functional reparative angiogenesis in response to tissue ischemia. Modulation of lymphangiogenesis would become a novel therapeutic strategy for severe ischemic disease in addition to ordinary vascular intervention and therapeutic angiogenesis.



Arterioscler Thromb Vasc Biol: 28 Apr 2021:ATVBAHA121316191; epub ahead of print
Pu Z, Shimizu Y, Tsuzuki K, Suzuki J, ... Shibata R, Murohara T
Arterioscler Thromb Vasc Biol: 28 Apr 2021:ATVBAHA121316191; epub ahead of print | PMID: 33910373
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prognostic implications of left atrial dilation in aortic regurgitation due to bicuspid aortic valve.

Butcher SC, Fortuni F, Kong W, Vollema EM, ... Bax JJ, Delgado V
Objective
To investigate the prognostic value of left atrial volume index (LAVI) in patients with moderate to severe aortic regurgitation (AR) and bicuspid aortic valve (BAV).
Methods
554 individuals (45 (IQR 33-57) years, 80% male) with BAV and moderate or severe AR were selected from an international, multicentre registry. The association between LAVI and the combined endpoint of all-cause mortality or aortic valve surgery was investigated with Cox proportional hazard regression analyses.
Results
Dilated LAVI was observed in 181 (32.7%) patients. The mean indexed aortic annulus, sinus of Valsalva, sinotubular junction and ascending aorta diameters were 13.0±2.0 mm/m2, 19.4±3.7 mm/m2, 16.5±3.8 mm/m2 and 20.4±4.5 mm/m2, respectively. After a median follow-up of 23 (4-82) months, 272 patients underwent aortic valve surgery (89%) or died (11%). When compared with patients with normal LAVI (<35 mL/m2), those with a dilated LAVI (≥35 mL/m2) had significantly higher rates of aortic valve surgery or mortality (43% and 60% vs 23% and 36%, at 1 and 5 years of follow-up, respectively, p<0.001). Dilated LAVI was independently associated with reduced event-free survival (HR=1.450, 95% CI 1.085 to 1.938, p=0.012) after adjustment for LV ejection fraction, aortic root diameter, LV end-diastolic diameter and LV end-systolic diameter.
Conclusions
In this large, multicentre registry of patients with BAV and moderate to severe AR, left atrial dilation was independently associated with reduced event-free survival. The role of this parameter for the risk stratification of individuals with significant AR merits further investigation.

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

Heart: 07 Apr 2021; epub ahead of print
Butcher SC, Fortuni F, Kong W, Vollema EM, ... Bax JJ, Delgado V
Heart: 07 Apr 2021; epub ahead of print | PMID: 33833069
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prognostic implications of left atrial dilation in aortic regurgitation due to bicuspid aortic valve.

Butcher SC, Fortuni F, Kong W, Vollema EM, ... Bax JJ, Delgado V
Objective
To investigate the prognostic value of left atrial volume index (LAVI) in patients with moderate to severe aortic regurgitation (AR) and bicuspid aortic valve (BAV).
Methods
554 individuals (45 (IQR 33-57) years, 80% male) with BAV and moderate or severe AR were selected from an international, multicentre registry. The association between LAVI and the combined endpoint of all-cause mortality or aortic valve surgery was investigated with Cox proportional hazard regression analyses.
Results
Dilated LAVI was observed in 181 (32.7%) patients. The mean indexed aortic annulus, sinus of Valsalva, sinotubular junction and ascending aorta diameters were 13.0±2.0 mm/m2, 19.4±3.7 mm/m2, 16.5±3.8 mm/m2 and 20.4±4.5 mm/m2, respectively. After a median follow-up of 23 (4-82) months, 272 patients underwent aortic valve surgery (89%) or died (11%). When compared with patients with normal LAVI (<35 mL/m2), those with a dilated LAVI (≥35 mL/m2) had significantly higher rates of aortic valve surgery or mortality (43% and 60% vs 23% and 36%, at 1 and 5 years of follow-up, respectively, p<0.001). Dilated LAVI was independently associated with reduced event-free survival (HR=1.450, 95% CI 1.085 to 1.938, p=0.012) after adjustment for LV ejection fraction, aortic root diameter, LV end-diastolic diameter and LV end-systolic diameter.
Conclusions
In this large, multicentre registry of patients with BAV and moderate to severe AR, left atrial dilation was independently associated with reduced event-free survival. The role of this parameter for the risk stratification of individuals with significant AR merits further investigation.

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

Heart: 07 Apr 2021; epub ahead of print
Butcher SC, Fortuni F, Kong W, Vollema EM, ... Bax JJ, Delgado V
Heart: 07 Apr 2021; epub ahead of print | PMID: 33833069
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The enigmatic immunoglobulin G4-related disease and its varied cardiovascular manifestations.

Shakir A, Wheeler Y, Krishnaswamy G
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disease characterised by multiorgan lymphoplasmacytic infiltration, obliterative phlebitis and storiform fibrosis. It can be associated with cardiovascular pathology. The objective of this narrative review is to summarise the published literature on cardiovascular manifestations of IgG4-RD and to provide a basis for diagnosis and management of the condition by the practising cardiologist.We propose the following categorisations of cardiovascular IgG4-RD: aortitis, medium-vessel arteritis, pulmonary vascular disease, phlebitis, valvulopathy, pericarditis, myocardial disease and antineutrophilic cytoplasmic antibody-associated vasculitis. We also review herein developments in radiological diagnosis and reported medical and surgical therapies. Cardiovascular lesions frequently require procedural and/or surgical interventions, such as aortic aneurysm repair and valve replacement. IgG4-RD of the cardiovascular system results in serious complications that can be missed if not evaluated aggressively. These are likely underdiagnosed, as clinical presentations frequently mimic cardiovascular disease due to more common aetiologies (myocardial infarction, abdominal aortic aneurysm and so on). While systemic corticosteroids are the mainstay of IgG4-RD treatment, biological and disease-modifying agents are becoming more widely used. Cardiologists should be aware of cardiovascular IgG4-RD as a differential diagnosis, and understand the roles of corticosteroids, disease-modifying agents and biologicals, as well as their integration with surgical approaches. There are several knowledge gaps, including diagnosis, risk factors, pathogenesis and appropriate management in Ig4-RD of the cardiovascular system. Areas lacking well-conducted randomized trials include safety of steroids in the setting of vascular aneurysms and the role of disease-modifying drugs and biological agents in patients with established cardiovascular complications of this multifaceted enigmatic disease.

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

Heart: 29 Apr 2021; 107:790-798
Shakir A, Wheeler Y, Krishnaswamy G
Heart: 29 Apr 2021; 107:790-798 | PMID: 33468575
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Oral Antiplatelet Therapy After Acute Coronary Syndrome: A Review.

Kamran H, Jneid H, Kayani WT, Virani SS, ... Nambi V, Khalid U
Importance
Acute coronary syndrome (ACS) is a major cause of morbidity and mortality in the United States with an annual incidence of approximately 1 million. Dual antiplatelet therapy (DAPT), consisting of aspirin and a P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) reduces cardiovascular event rates after ACS.
Observations
In 2016, the updated guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommended aspirin plus a P2Y12 inhibitor for at least 12 months for patients with ACS. Since these recommendations were published, new randomized clinical trials have studied different regimens and durations of antiplatelet therapy. Recommendations vary according to the risk of bleeding. If bleeding risk is low, prolonged DAPT may be considered, although the optimal duration of prolonged DAPT beyond 1 year is not well established. If bleeding risk is high, shorter duration (ie, 3-6 months) of DAPT may be reasonable. A high risk of bleeding traditionally is defined as a 1-year risk of serious bleeding (either fatal or associated with a ≥3-g/dL drop in hemoglobin) of at least 4% or a risk of an intracranial hemorrhage of at least 1%. Patients at higher risk are 65 years old or older; have low body weight (BMI <18.5), diabetes, or prior bleeding; or take oral anticoagulants. The newest P2Y12 inhibitors, prasugrel and ticagrelor, are more potent, with high on-treatment residual platelet reactivity of about 3% vs 30% to 40% with clopidogrel and act within 30 minutes compared with 2 hours for clopidogrel. Clinicians should avoid prescribing prasugrel to patients with a history of stroke or transient ischemic attack because of an increased risk of cerebrovascular events (6.5% vs 1.2% with clopidogrel, P = .002) and should avoid prescribing it to patients older than 75 years or who weigh less than 60 kg. The ISAR-REACT-5 trial found that prasugrel reduced rates of death, myocardial infarction, or stroke at 1 year compared with ticagrelor among patients with ACS undergoing percutaneous coronary intervention (9.3% vs 6.9%, P = .006) with no significant difference in bleeding. Recent trials suggested that discontinuing aspirin rather than the P2Y12 inhibitor may be associated with better outcomes.

Conclusions:
and relevance
Dual antiplatelet therapy reduces rates of cardiovascular events in patients with acute coronary syndrome. Specific combinations and duration of dual antiplatelet therapy should be based on patient characteristics-risk of bleeding myocardial ischemia.



JAMA: 19 Apr 2021; 325:1545-1555
Kamran H, Jneid H, Kayani WT, Virani SS, ... Nambi V, Khalid U
JAMA: 19 Apr 2021; 325:1545-1555 | PMID: 33877270
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Oral Antiplatelet Therapy After Acute Coronary Syndrome: A Review.

Kamran H, Jneid H, Kayani WT, Virani SS, ... Nambi V, Khalid U
Importance
Acute coronary syndrome (ACS) is a major cause of morbidity and mortality in the United States with an annual incidence of approximately 1 million. Dual antiplatelet therapy (DAPT), consisting of aspirin and a P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) reduces cardiovascular event rates after ACS.
Observations
In 2016, the updated guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommended aspirin plus a P2Y12 inhibitor for at least 12 months for patients with ACS. Since these recommendations were published, new randomized clinical trials have studied different regimens and durations of antiplatelet therapy. Recommendations vary according to the risk of bleeding. If bleeding risk is low, prolonged DAPT may be considered, although the optimal duration of prolonged DAPT beyond 1 year is not well established. If bleeding risk is high, shorter duration (ie, 3-6 months) of DAPT may be reasonable. A high risk of bleeding traditionally is defined as a 1-year risk of serious bleeding (either fatal or associated with a ≥3-g/dL drop in hemoglobin) of at least 4% or a risk of an intracranial hemorrhage of at least 1%. Patients at higher risk are 65 years old or older; have low body weight (BMI <18.5), diabetes, or prior bleeding; or take oral anticoagulants. The newest P2Y12 inhibitors, prasugrel and ticagrelor, are more potent, with high on-treatment residual platelet reactivity of about 3% vs 30% to 40% with clopidogrel and act within 30 minutes compared with 2 hours for clopidogrel. Clinicians should avoid prescribing prasugrel to patients with a history of stroke or transient ischemic attack because of an increased risk of cerebrovascular events (6.5% vs 1.2% with clopidogrel, P = .002) and should avoid prescribing it to patients older than 75 years or who weigh less than 60 kg. The ISAR-REACT-5 trial found that prasugrel reduced rates of death, myocardial infarction, or stroke at 1 year compared with ticagrelor among patients with ACS undergoing percutaneous coronary intervention (9.3% vs 6.9%, P = .006) with no significant difference in bleeding. Recent trials suggested that discontinuing aspirin rather than the P2Y12 inhibitor may be associated with better outcomes.

Conclusions:
and relevance
Dual antiplatelet therapy reduces rates of cardiovascular events in patients with acute coronary syndrome. Specific combinations and duration of dual antiplatelet therapy should be based on patient characteristics-risk of bleeding myocardial ischemia.



JAMA: 19 Apr 2021; 325:1545-1555
Kamran H, Jneid H, Kayani WT, Virani SS, ... Nambi V, Khalid U
JAMA: 19 Apr 2021; 325:1545-1555 | PMID: 33877270
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Improvement in left ventricular mechanics following medical treatment of constrictive pericarditis.

Sato K, Ayache A, Kumar A, Cremer PC, ... Johnston D, Klein AL
Objective
Patients with constrictive pericarditis (CP) with active inflammation may show resolution with anti-inflammatory therapy. We aimed to investigate the impact of anti-inflammatory medications on constrictive pathophysiology using echocardiography in patients with CP.
Methods
We identified 35 patients with CP who were treated with anti-inflammatory medications (colchicine, prednisone, non-steroidal anti-inflammatory drugs) after diagnosis of CP (mean age 58±13; 80% male). Clinical resolution of CP (transient CP) was defined as improvement in New York Heart Association class during follow-up. We assessed constrictive pathophysiology using regional myocardial mechanics by the ratio of peak early diastolic tissue velocity (e\') at the lateral and septal mitral annulus by tissue Doppler imaging (lateral/septal e\') or the ratio of the left ventricular lateral and septal wall longitudinal strain (LSlateral/LSseptal) by two-dimensional speckle-tracking echocardiography. Longitudinal data were analysed using a mixed effects model.
Results
During a median follow-up of 323 days, 20 patients had transient CP, whereas 15 patients had persistent CP. Transient CP had higher baseline erythrocyte sedimentation rates (ESR) (p=0.003) compared with persistent CP. There were no significant differences in LSlateral/LSseptal and lateral/septal e\'. During follow-up, only transient CP showed improvement in lateral/septal e\' (p<0.001) and LSlateral/LSseptal (p=0.003), and recovery of inflammatory markers was similar between the two groups. In the logistic model, higher baseline ESR and greater improvement in lateral/septal e\' and LSlateral/LSseptal were associated with clinical resolution of CP using anti-inflammatory therapy.
Conclusions
Improvement of constrictive physiology detected by lateral/septal e\' and LSlateral/LSseptal was associated with resolution of clinical symptoms after anti-inflammatory treatment. Serial monitoring of these markers could be used to identify transient CP.

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

Heart: 29 Apr 2021; 107:828-835
Sato K, Ayache A, Kumar A, Cremer PC, ... Johnston D, Klein AL
Heart: 29 Apr 2021; 107:828-835 | PMID: 33408090
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Randomized Trial of Etelcalcetide for Cardiac Hypertrophy in Hemodialysis.

Dörr K, Kammer M, Reindl-Schwaighofer R, Lorenz M, ... Erben RG, Oberbauer R
Rationale: Left ventricular hypertrophy (LVH) is highly prevalent in patients with chronic kidney disease and increases their risk of cardiac events and mortality. Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) levels, which are associated with the development of LVH, rise progressively with declining renal function. Objective: To determine whether FGF23 suppression by calcimimetic therapy may reduce LVH progression in comparison to FGF23 elevation under vitamin D analogs at equal PTH suppression under either therapy as well as tight volume control.
Methods and results:
We conducted a single-blinded trial with 1:1 block randomization to investigate the effect of the intravenous treatment with etelcalcetide (ETL) versus alfacalcidol (ALFA) on LVH progression in 62 maintenance hemodialysis patients with secondary hyperparathyroidism and LVH. In the intention-to-treat analysis of 59 patients, the mean difference in the change of left ventricular mass index (LVMI) determined by cardiac magnetic resonance imaging from baseline to 12 months of treatment was -6.9 g/m² (95% confidence interval [CI] -12.6 to -1.2, p=0.022) in the ETL compared to the ALFA group. The effect estimate was -8.2 g/m² (95% CI -14 to -2.4) in the per-protocol analysis on 52 patients. The trajectories of PTH, phosphate and Klotho were similar in both groups throughout follow-up. FGF23 levels, which showed a strong positive association with LVMI, were decreasing under ETL and increasing under ALFA at similar PTH suppression. Mild hypocalcemia was the most common adverse event under ETL. Blood pressure and the distribution of antihypertensive medications were similar between groups. Conclusions: In this trial we were able to show that FGF23 suppression by ETL inhibited the progression of LVH compared to ALFA in hemodialysis patients. A successful prevention of increasing hypertrophy may reduce the risk of sudden cardiac death in this population.




Circ Res: 06 Apr 2021; epub ahead of print
Dörr K, Kammer M, Reindl-Schwaighofer R, Lorenz M, ... Erben RG, Oberbauer R
Circ Res: 06 Apr 2021; epub ahead of print | PMID: 33825489
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Which Acute Ischemic Stroke Patients Are Fast Progressors?: Results From the ESCAPE Trial Control Arm.

Ospel JM, Hill MD, Kappelhof M, Demchuk AM, ... Baxter B, Goyal M
Background:
and purpose
Fast infarct progression in acute ischemic stroke has a severe impact on patient prognosis and benefit of endovascular thrombectomy. In this post hoc analysis of the ESCAPE trial (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke), we identified acute ischemic stroke patients with rapid infarct growth and investigated their baseline clinical and imaging characteristics.
Methods
Control arm patients were included if they had follow-up imaging at 2-8 hours without substantial recanalization, and if their baseline Alberta Stroke Program Early CT Score was ≥9. Fast infarct progression was defined as Alberta Stroke Program Early CT Score decay ≥3 points from baseline to 2- to 8-hour follow-up imaging. Clinical and imaging baseline characteristics were compared between fast progressors and other patients, and occlusion site and collateral flow patterns were assessed in detail.
Results
Fast infarct progression occurred in 15 of 43 included patients (34.9%). Fast progressors had worse collaterals (poor in 3/15 [20%] versus 0/28 patients, P=0.021) and more carotid-T or -L occlusions (8/15 [53.4%] versus 3/28[10.7%], P=0.021). In 8 out of 15 (53.3%), occlusion site and circle of Willis configuration prevented collateral flow via the anterior or posterior cerebral artery.
Conclusions
Most patients with fast infarct progression had terminal carotid occlusions and impaired collateral flow via the anterior or posterior cerebral artery, indicating that occlusion location and intracranial vascular anatomy are relevant for infarct progression.



Stroke: 29 Apr 2021; 52:1847-1850
Ospel JM, Hill MD, Kappelhof M, Demchuk AM, ... Baxter B, Goyal M
Stroke: 29 Apr 2021; 52:1847-1850 | PMID: 33813863
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Novel insights into the electrophysiology of murine cardiac macrophages: relevance of voltage-gated potassium channels.

Simon-Chica A, Fernández MC, Wülfers EM, Lother A, ... Kohl P, Schneider-Warme F
Aims
Macrophages (MΦ), known for immunological roles such as phagocytosis and antigen presentation, have been found to electrotonically couple to cardiomyocytes (CM) of the atrio-ventricular node via Cx43, affecting cardiac conduction in isolated mouse hearts. Here, we characterise passive and active electrophysiological properties of murine cardiac resident MΦ, and model their potential electrophysiological relevance for CM.
Methods and results
We combined classic electrophysiological approaches with 3 D florescence imaging, RNA-sequencing, pharmacological interventions and computer simulations. We used Cx3cr1eYFP/+ mice wherein cardiac MΦ were fluorescently labelled. FACS-purified fluorescent MΦ from mouse hearts were studied by whole-cell patch-clamp. MΦ electrophysiological properties include: membrane resistance 2.2 ± 0.1 GΩ (all data mean±SEM), capacitance 18.3 ± 0.1 pF, resting membrane potential -39.6 ± 0.3 mV, and several voltage-activated, outward or inwardly-rectifying potassium currents. Using ion channel blockers (barium, TEA, 4-AP, margatoxin, XEN-D0103, DIDS), flow cytometry, immuno-staining and RNA-sequencing, we identified Kv1.3, Kv1.5 and Kir2.1 as channels contributing to observed ion currents. MΦ displayed four patterns for outward and two for inward-rectifier potassium currents. Additionally, MΦ showed surface expression of Cx43, a prerequisite for homo- and/or heterotypic electrotonic coupling. Experimental results fed into development of an original computational model to describe cardiac MΦ electrophysiology. Computer simulations to quantitatively assess plausible effects of MΦ on electrotonically coupled CM showed that MΦ can depolarise resting CM, shorten early and prolong late action potential duration, with effects depending on coupling strength and individual MΦ electrophysiological properties, in particular resting membrane potential and presence/absence of Kir2.1.
Conclusions
Our results provide a first electrophysiological characterisation of cardiac resident MΦ, and a computational model to quantitatively explore their relevance in the heterocellular heart. Future work will be focussed at distinguishing electrophysiological effects of MΦ-CM coupling on both cell types during steady-state and in patho-physiological remodelling, when immune cells change their phenotype, proliferate, and/or invade from external sources.
Translational perspective
Cardiac tissue contains resident macrophages (MΦ) which, beyond immunological and housekeeping roles, have been found to electrotonically couple via connexins to cardiomyocytes (CM), stabilising atrio-ventricular conduction at high excitation rates. Here, we characterise structure and electrophysiological function of murine cardiac MΦ and provide a computational model to quantitatively probe the potential relevance of MΦ-CM coupling for cardiac electrophysiology. We find that MΦ are unlikely to have major electrophysiological effects in normal tissue, where they would hasten early and slow late CM-repolarisation. Further work will address potential arrhythmogenicity of MΦ in patho-physiologically remodelled tissue containing elevated MΦ-numbers, incl. non-resident recruited cells.

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

Cardiovasc Res: 05 Apr 2021; epub ahead of print
Simon-Chica A, Fernández MC, Wülfers EM, Lother A, ... Kohl P, Schneider-Warme F
Cardiovasc Res: 05 Apr 2021; epub ahead of print | PMID: 33823533
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prevention of Fibrosis and Pathological Cardiac Remodeling by Salinomycin.

Burke RM, Dirkx RA, Quijada P, Lighthouse JK, ... Ashton J, Small EM
Rationale: Cardiomyopathy is characterized by the deposition of extracellular matrix by activated resident cardiac fibroblasts, called myofibroblasts. There are currently no therapeutic approaches to blunt the development of pathological fibrosis and ventricle chamber stiffening that ultimately leads to heart failure. Objective: We undertook a high-throughput screen to identify small molecule inhibitors of myofibroblast activation that might limit the progression of heart failure. We evaluated the therapeutic efficacy of the polyether ionophore salinomycin in patient derived cardiac fibroblasts and pre-clinical mouse models of ischemic and non-ischemic heart failure.
Methods and results:
Here, we demonstrate that salinomycin displays potent anti-fibrotic activity in cardiac fibroblasts obtained from heart failure patients. In pre-clinical studies, salinomycin prevents cardiac fibrosis and functional decline in mouse models of ischemic and non-ischemic heart disease. Remarkably, interventional treatment with salinomycin attenuates pre-established pathological cardiac remodeling secondary to hypertension, and limits scar expansion when administered after a severe myocardial infarction. Mechanistically, salinomycin inhibits cardiac fibroblast activation by preventing p38/MAPK and Rho signaling. Salinomycin also promotes cardiomyocyte survival and improves coronary vessel density, suggesting that cardioprotection conferred by salinomycin occurs via the integration of multiple mechanisms in multiple relevant cardiac cell types. Conclusions: These data establish salinomycin as an anti-fibrotic agent that targets multiple cardioprotection pathways, thereby holding promise for the treatment of heart failure patients.




Circ Res: 06 Apr 2021; epub ahead of print
Burke RM, Dirkx RA, Quijada P, Lighthouse JK, ... Ashton J, Small EM
Circ Res: 06 Apr 2021; epub ahead of print | PMID: 33825488
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Extracellular histones are a target in myocardial ischaemia reperfusion injury.

Shah M, He Z, Rauf A, Kalkhoran SB, ... Davidson SM, Yellon D
Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). Histones have been described as important Danger Associated Molecular Proteins (DAMPs) in sepsis.
Aims:
The objective of this study was to establish whether extracellular histone release contributes to myocardial infarction. Methods and results Isolated, perfused rat hearts were subject to I/R. Nucleosomes and histone H4 release was detected early during reperfusion. Sodium-β-O-Methyl cellobioside sulfate (mCBS), a newly developed histone-neutralising compound, significantly reduced infarct size whilst also reducing the detectable levels of histones. Histones were directly toxic to primary adult rat cardiomyocytes in vitro. This was prevented by mCBS, or HIPe, a recently described, histone-H4 neutralizing peptide, but not by an inhibitor of TLR4, a receptor previously reported to be involved in DAMP-mediated cytotoxicity. Furthermore, TLR4-reporter HEK293 cells revealed that cytotoxicity of histone H4 was independent of TLR4 and NF-κB. In an in vivo rat model of I/R, HIPe significantly reduced infarct size.
Conclusion:
Histones released from the myocardium are cytotoxic to cardiomyocytes, via a TLR4-independent mechanism. The targeting of extracellular histones provides a novel opportunity to limit cardiomyocyte death during I/R injury of the myocardium. Translational perspective Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). New approaches are needed to prevent cardiomyocyte injury and limit final infarct size. We show that histones released from damaged cells, and histone-H4 in particular, causes rapid cardiomyocyte death during I/R. mCBS, a compounds targeting histones non-specifically, was cardioprotective in ex vivo rat hearts, while HIPe, a targeting histone H4 specifically, was cardioprotective in an in vivo rat model. HIPe may have potential as a therapeutic agent in the setting of acute myocardial infarction.


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

Cardiovasc Res: 19 Apr 2021; epub ahead of print
Shah M, He Z, Rauf A, Kalkhoran SB, ... Davidson SM, Yellon D
Cardiovasc Res: 19 Apr 2021; epub ahead of print | PMID: 33878183
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Arrhythmogenesis in the aged heart following ischaemia-reperfusion: Role of Transient Receptor Potential Vanilloid 4.

Peana D, Polo-Parada L, Domeier TL
Aims
Cardiomyocyte Ca2+ homeostasis is altered with ageing and predisposes the heart to Ca2+ intolerance and arrhythmia. Transient Receptor Potential Vanilloid 4 (TRPV4) is an osmotically-activated cation channel with expression in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in Ca2+ handling and arrhythmogenesis following ischaemia-reperfusion (I/R), a pathological scenario associated with osmotic stress.
Methods and results
Cardiomyocyte membrane potential was monitored prior to and following I/R in Langendorff-perfused hearts of Aged (19-28 month) male and female C57BL/6 mice ± TRPV4 inhibition (1 μM HC067047, HC). Diastolic resting membrane potential was similar between Aged and Aged HC at baseline, but following I/R Aged exhibited depolarized diastolic membrane potential versus Aged HC. The effects of TRPV4 on cardiomyocyte Ca2+ signaling following I/R were examined in isolated hearts of Aged cardiac-specific GCaMP6f mice (±HC) using high-speed confocal fluorescence microscopy, with cardiomyocytes of Aged exhibiting an increased incidence of pro-arrhythmic Ca2+ signaling versus Aged HC. In the isolated cell environment, cardiomyocytes of Aged responded to sustained hypoosmotic stress (250mOsm) with an increase in Ca2+ transient amplitude (fluo-4) and higher incidence of pro-arrhythmic diastolic Ca2+ signals versus Aged HC. Intracardiac electrocardiogram measurements in isolated hearts following I/R revealed an increased arrhythmia incidence, an accelerated time to ventricular arrhythmia, and increased arrhythmia score in Aged versus Aged HC. Aged exhibited depolarized resting membrane potential, increased pro-arrhythmic diastolic Ca2+ signaling, and greater incidence of arrhythmia when compared to Young (3-5 mo).
Conclusions
TRPV4 contributes to pro-arrhythmic cardiomyocyte Ca2+ signaling, electrophysiological abnormalities, and ventricular arrhythmia in the aged mouse heart.
Translational perspective
Aged populations are at high risk for myocardial infarction, I/R injury, and ventricular arrhythmia. The TRPV4 channel contributes to I/R-induced changes in cardiomyocyte Ca2+ handling and promotes ventricular arrhythmia in the aged mouse heart. Pharmacological TRPV4 inhibition may represent a potential anti-arrhythmic strategy for aged populations following myocardial infarction and I/R.

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

Cardiovasc Res: 20 Apr 2021; epub ahead of print
Peana D, Polo-Parada L, Domeier TL
Cardiovasc Res: 20 Apr 2021; epub ahead of print | PMID: 33881517
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Pulmonary embolism at autopsy in cancer patients.

Gimbel IA, Mulder FI, Bosch FTM, Freund JE, ... Büller HR, Middeldorp S
Background
Pulmonary embolism (PE) is a potentially fatal disease, but data on the incidence of fatal PE in cancer patients are scant.
Objective
We sought to estimate the proportion of cancer patients with PE at autopsy.
Methods
For this retrospective cohort study, all autopsy reports of cancer patients were retrieved from PALGA: Dutch Pathology Registry and used for data extraction. The primary outcome was PE at time of autopsy, defined as any clot obstructing a pulmonary artery. The secondary outcome was venous thromboembolism, defined as the composite of thrombotic PE, deep vein thrombosis, splanchnic vein thrombosis, or internal jugular vein thrombosis.
Results
A total of 9571 cancer patients were included. In 1191 (12.4%; 95% confidence interval [CI], 11.8-13.1) patients, one or more PE events were observed at autopsy, of whom 1074 (90.2%) had a thrombotic embolism, 168 (14.1%) a tumor embolism, 9 (0.8%) a septic embolism, 7 (0.6%) a fat tissue embolism, and 3 (0.3%) a bone marrow embolism. Among patients with PE for whom the cause of death was specified in the autopsy report, death was considered PE-related in 642 patients (66.7%), which was 6.7% of the total study population. Venous thromboembolism was observed in 1223 (12.8%; 95% CI, 12.1-13.5) patients.
Conclusion
The proportion of PE in cancer patients at autopsy is substantial. Although the study population is not representative for the total cancer population, it suggests that PE is an important disease complication in cancer 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; 19:1228-1235
Gimbel IA, Mulder FI, Bosch FTM, Freund JE, ... Büller HR, Middeldorp S
J Thromb Haemost: 29 Apr 2021; 19:1228-1235 | PMID: 33501757
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Intrinsic Electrical Remodeling Underlies Atrioventricular Block in Athletes.

Mesirca P, Nakao S, Nissen SD, Forte G, ... Boyett MR, D\'Souza A
Rationale: Athletes present with atrioventricular node (AV node) dysfunction manifesting as AV block. This can necessitate electronic pacemaker implantation, known to be more frequent in athletes with a long training history. Objective: AV block in athletes is attributed to high vagal tone. Here we investigated the alternative hypothesis that electrical remodeling of the AV node is responsible.
Methods and results:
Radio-telemetry ECG data and AV node biopsies were collected in sedentary and trained Standardbred racehorses, a large-animal model of the athlete\'s heart. Trained horses presented with longer PR intervals (that persisted under complete autonomic block) versus sedentary horses, concomitant with reduced expression of key ion channels involved in AV node conduction: L-type Ca2+ channel subunit CaV1.2 and the hyperpolarization-activated cyclic nucleotide gated channel 4 (HCN4). AV node electrophysiology was explored further in mice; prolongation of the PR interval (in vivo and ex vivo), Wenckebach cycle length and AV node refractory period was observed in mice trained by swimming versus sedentary mice. Transcriptional profiling in laser-capture microdissected AV node revealed striking reduction in pacemaking ion channels in trained mice, translating into protein downregulation of CaV1.2 and HCN4. Correspondingly, patch clamp recordings in isolated AV node myocytes demonstrated a training-induced reduction in ICa,L and If density that likely contributed to the observed lower frequency of action potential firing in trained cohorts. microRNA (miR) profiling and in vitro studies revealed miR-211-5p and miR-432 as direct regulators of CaV1.2 and HCN4. In vivo miRs suppression or detraining restored training-induced PR prolongation and ion channel remodeling. Conclusions: Training-induced AV node dysfunction is underscored by likely miR-mediated transcriptional remodeling that translates into reduced current density of key ionic currents involved in impulse generation and conduction. We conclude that electrical remodeling is a key mechanism underlying AV block in athletes.




Circ Res: 13 Apr 2021; epub ahead of print
Mesirca P, Nakao S, Nissen SD, Forte G, ... Boyett MR, D'Souza A
Circ Res: 13 Apr 2021; epub ahead of print | PMID: 33849278
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Predictors of Early Infarct Recurrence in Patients With Symptomatic Intracranial Atherosclerotic Disease.

Prabhakaran S, Liebeskind DS, Cotsonis G, Nizam A, ... Romano JG, MYRIAD Investigators
Background:
and purpose
While prior studies identified risk factors for recurrent stroke in patients with symptomatic intracranial atherosclerotic disease, few have assessed risk factors for early infarct recurrence.
Methods
We performed a post hoc analysis of the MYRIAD study (Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease) of intracranial atherosclerotic disease patients with recent (<21 days) stroke/transient ischemic attack, 50% to 99% stenosis and who underwent 6- to 8-week magnetic resonance imaging (MRI) per protocol. Infarct recurrence was defined as new infarcts in the territory of the symptomatic artery on brain MRI at 6 to 8 weeks compared to index brain MRI. Qualifying events and clinical and imaging outcomes were centrally ascertained by 2 independent reviewers. We assessed the association between baseline clinical and imaging variables and recurrent infarct in bivariate models and multivariable logistic regression to identify independent predictors of infarct recurrence.
Results
Of 105 enrolled patients in MYRIAD, 89 (84.8%) were included in this analysis (mean age, 64±12 years, 54 [60.7%] were male, and 53 [59.6%] were White). The median time from qualifying event to MRI was 51+16 days, on which 22 (24.7%) patients had new or recurrent infarcts. Younger age (57.7 versus 66.0 years; P<0.01), diabetes (32.6% versus 14.6%, P=0.05), index stroke (31.3% versus 4.6%, P=0.01), anterior circulation location of stenosis (29.7% versus 12.0%, P=0.08), number of diffusion-weighted imaging lesions (>1: 40.0%, 1: 26.9% versus 0: 4.4%, P<0.01), and borderzone infarct pattern (63.6% versus 25.0%, P=0.01) on baseline MRI were associated with new or recurrent infarcts. Age (adjusted odds ratio, 0.93 [95% CI, 0.89-0.98], P<0.01) and number of diffusion-weighted imaging lesions (adjusted odds ratio, 3.24 [95% CI, 1.36-7.71], P<0.01) were independently associated with recurrent infarct adjusting for hypertension, diabetes, and stenosis location (anterior versus posterior circulation).
Conclusions
An index multi-infarct pattern is associated with early recurrent infarcts, a finding that might be explained by plaque instability and artery-to-artery embolism. Further investigation of plaque vulnerability in intracranial atherosclerotic disease is needed.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02121028.



Stroke: 18 Apr 2021:STROKEAHA120032676; epub ahead of print
Prabhakaran S, Liebeskind DS, Cotsonis G, Nizam A, ... Romano JG, MYRIAD Investigators
Stroke: 18 Apr 2021:STROKEAHA120032676; epub ahead of print | PMID: 33866818
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Low-intensity pulsed ultrasound ameliorates cardiac diastolic dysfunction in mice: a possible novel therapy for heart failure with preserved left ventricular ejection fraction.

Monma Y, Shindo T, Eguchi K, Kurosawa R, ... Kanai H, Shimokawa H
Aims
Heart failure with preserved left ventricular ejection fraction (HFpEF) is a serious health problem worldwide, as no effective therapy is yet available. We have previously demonstrated that our low-intensity pulsed ultrasound (LIPUS) therapy is effective and safe for angina and dementia. In this study, we aimed to examine whether the LIPUS therapy also ameliorates cardiac diastolic dysfunction in mice.
Methods and results
Twelve-week-old obese diabetic mice (db/db) and their control littermates (db/+) were treated with either the LIPUS therapy [1.875 MHz, 32 cycles, Ispta (spatial peak temporal average intensity) 117-162 mW/cm2, 0.25 W/cm2] or placebo procedure two times a week for 4 weeks. At 20-week-old, transthoracic echocardiography and invasive haemodynamic analysis showed that cardiac diastolic function parameters, such as e\', E/e\', end-diastolic pressure-volume relationship, Tau, and dP/dt min, were all deteriorated in placebo-treated db/db mice compared with db/+ mice, while systolic function was preserved. Importantly, these cardiac diastolic function parameters were significantly ameliorated in the LIPUS-treated db/db mice. We also measured the force (F) and intracellular Ca2+ ([Ca2+]i) in trabeculae dissected from ventricles. We found that relaxation time and [Ca2+]i decay (Tau) were prolonged during electrically stimulated twitch contractions in db/db mice, both of which were significantly ameliorated in the LIPUS-treated db/db mice, indicating that the LIPUS therapy also improves relaxation properties at tissue level. Functionally, exercise capacity was also improved in the LIPUS-treated db/db mice. Histologically, db/db mice displayed progressed cardiomyocyte hypertrophy and myocardial interstitial fibrosis, while those changes were significantly suppressed in the LIPUS-treated db/db mice. Mechanistically, western blot showed that the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-cGMP-protein kinase G (PKG) pathway and Ca2+-handling molecules were up-regulated in the LIPUS-treated heart.
Conclusions
These results indicate that the LIPUS therapy ameliorates cardiac diastolic dysfunction in db/db mice through improvement of eNOS-NO-cGMP-PKG pathway and cardiomyocyte Ca2+-handling system, suggesting its potential usefulness for the treatment of HFpEF patients.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Cardiovasc Res: 22 Apr 2021; 117:1325-1338
Monma Y, Shindo T, Eguchi K, Kurosawa R, ... Kanai H, Shimokawa H
Cardiovasc Res: 22 Apr 2021; 117:1325-1338 | PMID: 32683442
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Recent advances in the role of the adenosinergic system in coronary artery disease.

Paganelli F, Gaudry M, Ruf J, Guieu R
Adenosine is an endogenous nucleoside that plays a major role in the physiology and physiopathology of the coronary artery system, mainly by activating its A2A receptors (A2AR). Adenosine is released by myocardial, endothelial, and immune cells during hypoxia, ischaemia, or inflammation, each condition being present in coronary artery disease (CAD). While activation of A2AR improves coronary blood circulation and leads to anti-inflammatory effects, down-regulation of A2AR has many deleterious effects during CAD. A decrease in the level and/or activity of A2AR leads to: (i) lack of vasodilation, which decreases blood flow, leading to a decrease in myocardial oxygenation and tissue hypoxia; (ii) an increase in the immune response, favouring inflammation; and (iii) platelet aggregation, which therefore participates, in part, in the formation of a fibrin-platelet thrombus after the rupture or erosion of the plaque, leading to the occurrence of acute coronary syndrome. Inflammation contributes to the development of atherosclerosis, leading to myocardial ischaemia, which in turn leads to tissue hypoxia. Therefore, a vicious circle is created that maintains and aggravates CAD. In some cases, studying the adenosinergic profile can help assess the severity of CAD. In fact, inducible ischaemia in CAD patients, as assessed by exercise stress test or fractional flow reserve, is associated with the presence of a reserve of A2AR called spare receptors. The purpose of this review is to present emerging experimental evidence supporting the existence of this adaptive adenosinergic response to ischaemia or inflammation in CAD. We believe that we have achieved a breakthrough in the understanding and modelling of spare A2AR, based upon a new concept allowing for a new and non-invasive CAD management.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Cardiovasc Res: 22 Apr 2021; 117:1284-1294
Paganelli F, Gaudry M, Ruf J, Guieu R
Cardiovasc Res: 22 Apr 2021; 117:1284-1294 | PMID: 32991685
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Genetic and Developmental Contributors to Aortic Stenosis.

Dutta P, James JF, Kazik H, Lincoln J
Aortic stenosis (AS) remains one of the most common forms of valve disease, with significant impact on patient survival. The disease is characterized by left ventricular outflow obstruction and encompasses a series of stenotic lesions starting from the left ventricular outflow tract to the descending aorta. Obstructions may be subvalvar, valvar, or supravalvar and can be present at birth (congenital) or acquired later in life. Bicuspid aortic valve, whereby the aortic valve forms with two instead of three cusps, is the most common cause of AS in younger patients due to primary anatomic narrowing of the valve. In addition, the secondary onset of premature calcification, likely induced by altered hemodynamics, further obstructs left ventricular outflow in bicuspid aortic valve patients. In adults, degenerative AS involves progressive calcification of an anatomically normal, tricuspid aortic valve and is attributed to lifelong exposure to multifactoral risk factors and physiological wear-and-tear that negatively impacts valve structure-function relationships. AS continues to be the most frequent valvular disease that requires intervention, and aortic valve replacement is the standard treatment for patients with severe or symptomatic AS. While the positive impacts of surgical interventions are well documented, the financial burden, the potential need for repeated procedures, and operative risks are substantial. In addition, the clinical management of asymptomatic patients remains controversial. Therefore, there is a critical need to develop alternative approaches to prevent the progression of left ventricular outflow obstruction, especially in valvar lesions. This review summarizes our current understandings of AS cause; beginning with developmental origins of congenital valve disease, and leading into the multifactorial nature of AS in the adult population.



Circ Res: 29 Apr 2021; 128:1330-1343
Dutta P, James JF, Kazik H, Lincoln J
Circ Res: 29 Apr 2021; 128:1330-1343 | PMID: 33914609
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

cAMP Imaging at Ryanodine Receptors Reveals β2-Adrenoceptor Driven Arrhythmias.

Berisha F, Götz K, Wegener JW, Brandenburg S, ... Lehnart SE, Nikolaev VO
Rationale: 3\',5\'-cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger which, upon β-adrenergic receptor (β-AR) stimulation, acts in microdomains to regulate cardiac excitation-contraction coupling by activating phosphorylation of calcium handling proteins. One crucial microdomain is in vicinity of the cardiac ryanodine receptor type 2 (RyR2) which is associated with arrhythmogenic diastolic calcium leak from the sarcoplasmic reticulum (SR) often occurring in heart failure. Objective: We sought to establish a real time live cell imaging approach capable of directly visualizing cAMP in the vicinity of mouse and human RyR2 and to analyze its pathological changes in failing cardiomyocytes under β-AR stimulation.
Methods and results:
We generated a novel targeted fluorescent biosensor Epac1-JNC for RyR2-associated cAMP and expressed it in transgenic mouse hearts as well in human ventricular myocytes using adenoviral gene transfer. In healthy cardiomyocytes, β1-AR but not β2-AR stimulation strongly increased local RyR2-associated cAMP levels. However, already in cardiac hypertrophy induced by aortic banding, there was a marked subcellular redistribution of phosphodiesterases (PDEs) 2, 3 and 4, which included a dramatic loss of the local pool of PDE4. This was also accompanied by measurableβ2-AR/AMP signals in the vicinity of RyR2 in failing mouse and human myocytes, increased β2-AR-dependent RyR2 phosphorylation, SR calcium leak and arrhythmia susceptibility. Conclusions: Our new imaging approach could visualize cAMP levels in the direct vicinity of cardiac RyR2. Unexpectedly, in mouse and human failing myocytes, it could uncover functionally relevant local arrhythmogenic β2-AR/cAMP signals which might be an interesting antiarrhythmic target for heart failure.




Circ Res: 26 Apr 2021; epub ahead of print
Berisha F, Götz K, Wegener JW, Brandenburg S, ... Lehnart SE, Nikolaev VO
Circ Res: 26 Apr 2021; epub ahead of print | PMID: 33902292
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

CAPN1 (Calpain1)-Mediated Impairment of Autophagic Flux Contributes to Cerebral Ischemia-Induced Neuronal Damage.

Liu Y, Che X, Zhang H, Fu X, ... Yang J, Zhou MS
Background:
and purpose
CAPN1 (calpain1)-an intracellular Ca2+-regulated cysteine protease-can be activated under cerebral ischemia. However, the mechanisms by which CAPN1 activation promotes cerebral ischemic injury are not defined.
Methods
In the present study, we used adeno-associated virus-mediated genetic knockdown and pharmacological blockade (MDL-28170) of CAPN1 to investigate the role of CAPN1 in the regulation of the autophagy-lysosomal pathway and neuronal damage in 2 models, rat permanent middle cerebral occlusion in vivo model and oxygen-glucose-deprived primary neuron in vitro model.
Results
CAPN1 was activated in the cortex of permanent middle cerebral occlusion-operated rats and oxygen-glucose deprivation-exposed neurons. Genetic and pharmacological inhibition of CAPN1 significantly attenuated ischemia-induced lysosomal membrane permeabilization and subsequent accumulation of autophagic substrates in vivo and in vitro. Moreover, inhibition of CAPN1 increased autophagosome formation by decreasing the cleavage of the autophagy regulators BECN1 (Beclin1) and ATG (autophagy-related gene) 5. Importantly, the neuron-protective effect of MDL-28170 on ischemic insult was reversed by cotreatment with either class III-PI3K (phosphatidylinositol 3-kinase) inhibitor 3-methyladenine or lysosomal inhibitor chloroquine (chloroquine), suggesting that CAPN1 activation-mediated impairment of autophagic flux is crucial for cerebral ischemia-induced neuronal damage.
Conclusions
The present study demonstrates for the first time that ischemia-induced CAPN1 activation impairs lysosomal function and suppresses autophagosome formation, which contribute to the accumulation of substrates and aggravate the ischemia-induced neuronal cell damage. Our work highlights the vital role of CAPN1 in the regulation of cerebral ischemia-mediated autophagy-lysosomal pathway defects and neuronal damage.



Stroke: 19 Apr 2021:STROKEAHA120032749; epub ahead of print
Liu Y, Che X, Zhang H, Fu X, ... Yang J, Zhou MS
Stroke: 19 Apr 2021:STROKEAHA120032749; epub ahead of print | PMID: 33874744
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

CAPN1 (Calpain1)-Mediated Impairment of Autophagic Flux Contributes to Cerebral Ischemia-Induced Neuronal Damage.

Liu Y, Che X, Zhang H, Fu X, ... Yang J, Zhou MS
Background:
and purpose
CAPN1 (calpain1)-an intracellular Ca2+-regulated cysteine protease-can be activated under cerebral ischemia. However, the mechanisms by which CAPN1 activation promotes cerebral ischemic injury are not defined.
Methods
In the present study, we used adeno-associated virus-mediated genetic knockdown and pharmacological blockade (MDL-28170) of CAPN1 to investigate the role of CAPN1 in the regulation of the autophagy-lysosomal pathway and neuronal damage in 2 models, rat permanent middle cerebral occlusion in vivo model and oxygen-glucose-deprived primary neuron in vitro model.
Results
CAPN1 was activated in the cortex of permanent middle cerebral occlusion-operated rats and oxygen-glucose deprivation-exposed neurons. Genetic and pharmacological inhibition of CAPN1 significantly attenuated ischemia-induced lysosomal membrane permeabilization and subsequent accumulation of autophagic substrates in vivo and in vitro. Moreover, inhibition of CAPN1 increased autophagosome formation by decreasing the cleavage of the autophagy regulators BECN1 (Beclin1) and ATG (autophagy-related gene) 5. Importantly, the neuron-protective effect of MDL-28170 on ischemic insult was reversed by cotreatment with either class III-PI3K (phosphatidylinositol 3-kinase) inhibitor 3-methyladenine or lysosomal inhibitor chloroquine (chloroquine), suggesting that CAPN1 activation-mediated impairment of autophagic flux is crucial for cerebral ischemia-induced neuronal damage.
Conclusions
The present study demonstrates for the first time that ischemia-induced CAPN1 activation impairs lysosomal function and suppresses autophagosome formation, which contribute to the accumulation of substrates and aggravate the ischemia-induced neuronal cell damage. Our work highlights the vital role of CAPN1 in the regulation of cerebral ischemia-mediated autophagy-lysosomal pathway defects and neuronal damage.



Stroke: 19 Apr 2021:STROKEAHA120032749; epub ahead of print
Liu Y, Che X, Zhang H, Fu X, ... Yang J, Zhou MS
Stroke: 19 Apr 2021:STROKEAHA120032749; epub ahead of print | PMID: 33874744
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Transcranial Doppler in Acute COVID-19 Infection: Unexpected Associations.

Ziai WC, Cho SM, Johansen MC, Ergin B, Bahouth MN
Background:
and purpose
Stroke may complicate coronavirus disease 2019 (COVID-19) infection based on clinical hypercoagulability. We investigated whether transcranial Doppler ultrasound has utility for identifying microemboli and clinically relevant cerebral blood flow velocities (CBFVs) in COVID-19.
Methods
We performed transcranial Doppler for a consecutive series of patients with confirmed or suspected COVID-19 infection admitted to 2 intensive care units at a large academic center including evaluation for microembolic signals. Variables specific to hypercoagulability and blood flow including transthoracic echocardiography were analyzed as a part of routine care.
Results
Twenty-six patients were included in this analysis, 16 with confirmed COVID-19 infection. Of those, 2 had acute ischemic stroke secondary to large vessel occlusion. Ten non-COVID stroke patients were included for comparison. Two COVID-negative patients had severe acute respiratory distress syndrome and stroke due to large vessel occlusion. In patients with COVID-19, relatively low CBFVs were observed diffusely at median hospital day 4 (interquartile range, 3-9) despite low hematocrit (29.5% [25.7%-31.6%]); CBFVs in comparable COVID-negative stroke patients were significantly higher compared with COVID-positive stroke patients. Microembolic signals were not detected in any patient. Median left ventricular ejection fraction was 60% (interquartile range, 60%-65%). CBFVs were correlated with arterial oxygen content, and C-reactive protein (Spearman ρ=0.28 [P=0.04]; 0.58 [P<0.001], respectively) but not with left ventricular ejection fraction (ρ=-0.18; P=0.42).
Conclusions
In this cohort of critically ill patients with COVID-19 infection, we observed lower than expected CBFVs in setting of low arterial oxygen content and low hematocrit but not associated with suppression of cardiac output.



Stroke: 20 Apr 2021:STROKEAHA120032150; epub ahead of print
Ziai WC, Cho SM, Johansen MC, Ergin B, Bahouth MN
Stroke: 20 Apr 2021:STROKEAHA120032150; epub ahead of print | PMID: 33878893
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Endothelial Dysfunction in the Brain: Setting the Stage for Stroke and Other Cerebrovascular Complications of COVID-19.

Sashindranath M, Nandurkar HH
The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.



Stroke: 29 Apr 2021; 52:1895-1904
Sashindranath M, Nandurkar HH
Stroke: 29 Apr 2021; 52:1895-1904 | PMID: 33794655
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Thrombolytic strategies for ischemic stroke in the thrombectomy era.

Gauberti M, de Lizarrondo SM, Vivien D
Twenty-five years ago, intravenous thrombolysis has revolutionized the care of patients with acute ischemic stroke. Since 2015, randomized clinical trials have demonstrated that mechanical thrombectomy improves functional outcome in stroke patients over intravenous thrombolysis alone. More recently, three randomized clinical trials have suggested that mechanical thrombectomy alone is non-inferior to a combined strategy with both intravenous thrombolysis and mechanical thrombectomy. In the present review, we will present the last clinical and preclinical studies on the use of thrombolysis in stroke patients in the modern thrombectomy era. At the cost of a potential increased risk of hemorrhagic transformation, thrombolysis may promote arterial recanalization before thrombectomy, improve the rate of successful recanalisation after thrombectomy and restore microcirculation patency downstream of the main thrombus. Besides, new thrombolytic strategies targeting tissue-type plasminogen activator resistant thrombi are being developed, which could strengthen the beneficial effects of thrombolysis without carrying additional pro-hemorrhagic effects. For instance, tenecteplase has shown improved rate of recanalisation compared to tissue-type plasminogen activator (alteplase). Beyond fibrinolysis, DNA and von Willebrand factor targeted thrombolytic strategies have shown promising results in experimental models of ischemic stroke. New combined strategies, improved thrombolytics and dedicated clinical trials in selected patients are eagerly awaited to further improve functional outcome in stroke.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 08 Apr 2021; epub ahead of print
Gauberti M, de Lizarrondo SM, Vivien D
J Thromb Haemost: 08 Apr 2021; epub ahead of print | PMID: 33834615
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Transient Vestibular Symptoms Preceding Posterior Circulation Stroke: A Prospective Multicenter Study.

Kim HA, Oh EH, Choi SY, Choi JH, ... Lee H, Choi KD
Background:
and purpose
The recognition of clinical features of transient vestibular symptoms (TVSs) preceding posterior circulation stroke (PCOS) would be informative to discriminate dizziness/vertigo due to vertebrobasilar transient ischemic attack from the acute transient vestibular syndrome. We sought to determine the prevalence and characteristics of TVSs preceding PCOS.
Methods
We performed a prospective multicenter observational study that had recruited 447 patients with PCOS from referral-based 4 university hospitals in Korea. We investigated the timing, pattern, frequency, duration, and accompanying neurological symptoms of TVSs during the 3 months preceding PCOS.
Results
The prevalence of TVSs preceding PCOS was 12% (55/447) during the previous 3 months. The TVSs preceding PCOS occurred within 1 week (33%), between 1 week and 1 month (16%), or between 1 and 3 months (51%). The TVSs were mostly dizziness/vertigo with (36%) or without (60%) imbalance, while the remaining 4% had an isolated imbalance. The dizziness/vertigo was spinning in 38% and was aggravated during head position in 45%. The duration of TVSs was mostly a few seconds (55%) or minutes (38%). Approximately 72% of the patients with PCOS had TVSs 1 to 5 times, while 16% had >10 times. Accompanying neurological symptoms, including headache, tinnitus, limb weakness, sensory change, dysarthria, visual field defect, and diplopia, were reported in 11%.
Conclusions
Preceding TVSs can occur in 12% of PCOS during the previous 3 months. Isolated dizziness/vertigo of unknown cause needs to be considered as a vertebrobasilar transient ischemic attack symptom, especially in patients with vascular risk factors. The characteristics of isolated vestibular symptom in vertebrobasilar transient ischemic attacks is highly variable and atypical compared with other transient ischemic symptoms.



Stroke: 26 Apr 2021:STROKEAHA120032488; epub ahead of print
Kim HA, Oh EH, Choi SY, Choi JH, ... Lee H, Choi KD
Stroke: 26 Apr 2021:STROKEAHA120032488; epub ahead of print | PMID: 33902298
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Pregnancy outcomes in women with a systemic right ventricle and transposition of the great arteries results from the ESC-EORP Registry of Pregnancy and Cardiac disease (ROPAC).

Tutarel O, Baris L, Budts W, Gamal Abd-El Aziz M, ... Roos-Hesselink JW, ROPAC Investigators Group
Objective
Cardiac disease is a major cause of maternal mortality. Data regarding pregnancy outcomes in women with a systemic right ventricle (sRV) are scarce. We studied pregnancy outcomes in women with an sRV after the atrial switch procedure for transposition of the great arteries (TGA) or congenitally corrected TGA (CCTGA).
Methods
The ESC EORP Registry of Pregnancy and Cardiac Disease is an international prospective registry of pregnant women with cardiac disease. Pregnancy outcomes (maternal/fetal) in all women with an sRV are described. The primary end point was a major adverse cardiac event (MACE) defined as maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischaemic coronary event and other thromboembolic events.
Results
Altogether, 162 women with an sRV (TGA n=121, CCTGA n=41, mean age 28.8±4.6 years) were included. No maternal mortality occurred. In 26 women, at least one MACE occurred, heart failure in 16 (9.8%), arrhythmias (atrial 5, ventricular 6) in 11 (6.7%) and others in 4 (2.5%). Prepregnancy signs of heart failure as well as an sRV ejection fraction <40% were predictors of MACE. One woman experienced fetal loss, while no neonatal mortality was observed. No significant differences were found between women with CCTGA and TGA. In the subset of women who had an echocardiogram before and after pregnancy, no clear deterioration in sRV was observed.
Conclusion
The majority of women with an sRV tolerated pregnancy well with a favourable maternal and fetal outcome. Heart failure and arrhythmias were the most common MACE.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Heart: 27 Apr 2021; epub ahead of print
Tutarel O, Baris L, Budts W, Gamal Abd-El Aziz M, ... Roos-Hesselink JW, ROPAC Investigators Group
Heart: 27 Apr 2021; epub ahead of print | PMID: 33911009
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Successful treatment of vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).

Thaler J, Ay C, Gleixner KV, Hauswirth AW, ... Pabinger I, Knöbl P
Cases of unusual thrombosis and thrombocytopenia after administration of the ChAdOx1 nCoV-19 vaccine (AstraZeneca) have been reported. The term vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) was coined to reflect this new phenomenon. In vitro experiments with VIPIT patient sera indicated that high dose intravenous immunoglobulins (IVIG) competitively inhibit the platelet activating properties of ChAdOx1 nCoV-19 vaccine induced antibodies. Here, we report a case of a 62-year-old woman, who had received this vaccine and developed VIPIT. She visited the emergency ward because of petechiae and hematomas. In the laboratory work-up, thrombocytopenia, low fibrinogen, elevated D-dimer, and positivity in the platelet factor 4/heparin-enzyme-immunoassay were present. Signs and symptoms of thrombosis were absent. Upon immediate therapy with non-heparin anticoagulation, high dose IVIG, and prednisolone laboratory parameters steadily improved and the patient was discharged from hospital without thrombotic complications. We conclude that early initiation of VIPIT treatment results in a swift response without thrombotic complications.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 19 Apr 2021; epub ahead of print
Thaler J, Ay C, Gleixner KV, Hauswirth AW, ... Pabinger I, Knöbl P
J Thromb Haemost: 19 Apr 2021; epub ahead of print | PMID: 33877735
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Treatment-Related Changes in Left Atrial Structure in Atrial Fibrillation: Findings from the CABANA Imaging Substudy.

Rettmann ME, Holmes Iii DR, Monahan KH, Breen JF, ... Robb RA, Packer DL

Background:
- The Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial was a randomized, prospective trial of left atrial catheter ablation versus drug therapy for treatment of atrial fibrillation (AF). As part of CABANA, a prospective imaging sub-study was conducted. The main objectives were to describe the patterns of changes in the dimensions of the left atrium (LA) and pulmonary veins (PVs), and the relationship between these changes with treatment assignment and clinical outcomes. Methods - CT or MRI was acquired at baseline and follow-up in 121 ablation (median follow-up 101 days) and 85 drug patients (median follow-up 97 days). Left atrial volume index (LAVI), mean PV ostial diameter (MPV) , and ostial diameters of each PV separately were computed. We examined the relationship between the change from baseline to follow-up with subsequent clinical outcomes (composite of death, disabling stroke, serious bleeding, or cardiac arrest [CABANA primary endpoint], total mortality or cardiovascular hospitalization, first AF recurrence after the 90 day blanking period, first AF/atrial flutter/ atrial tachycardia after the 90 day blanking period) using Cox proportional-hazards models. Results - The median (25th, 75th) change from baseline for LAVI was -7.8 mL/m2 (-16.4, 0.2), ablation arm and -3.5 mL/m2 (-11.4, 2.6), drug therapy arm. The LAVI decreased in 52.9% of ablation patients versus 40.0% of drug therapy patients. Change for MPV was -2.7 mm (-4.2, -1.3) in the ablation arm versus -0.1 mm (-1.5, 0.8) in the drug therapy arm. Changes in LA and PV dimensions had no consistent relationship with the risk of developing the study primary endpoint. Reductions in LAVI, and in MPV diameter were associated with decreased risk of AF recurrence.
Conclusions:
- Ablation patients demonstrated more frequent and larger atrial structural changes compared with drug patients. These changes suggest a critical relationship between structural features and AF generation.




Circ Arrhythm Electrophysiol: 12 Apr 2021; epub ahead of print
Rettmann ME, Holmes Iii DR, Monahan KH, Breen JF, ... Robb RA, Packer DL
Circ Arrhythm Electrophysiol: 12 Apr 2021; epub ahead of print | PMID: 33848199
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The value of multimodality imaging in hypertensive heart disease.

Saeed S, Tadic M, Grytaas M, Mancia G, Larsen TH
Hypertensive heart disease (HHD) includes left ventricular (LV) functional and structural remodeling. For a long time, this involved only LV diastolic dysfunction and LV hypertrophy. However, development of imaging technique enabled more detailed insights into LV mechanics. Its impairment seems to be the first step in the cascade of HHD. Tissue characterization, obtained by cardiac magnetic resonance, opened a completely new chapter in the assessment of HHD. We report a case of a 47-year-old man who was referred to our department for a newly detected heart failure. CT angiography excluded relevant coronary disease and cardiac magnetic resonance revealed focuses of fibrosis in interventricular septum, in addition severely dilated LV with severely reduced ejection fraction. Considering the fact that the patient had longstanding uncontrolled arterial hypertension and that other causes of cardiac remodeling and dysfunction were excluded, we hypothesized that the multimodality imaging approach enabled prompt diagnosis of HHD.

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 30 Apr 2021; 39:1040-1043
Saeed S, Tadic M, Grytaas M, Mancia G, Larsen TH
J Hypertens: 30 Apr 2021; 39:1040-1043 | PMID: 33239554
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Radiofrequency vs. Cryoballoon Catheter Ablation for Paroxysmal Atrial Fibrillation: Durability of Pulmonary Vein Isolation and Effect on AF Burden: The RACE-AF Randomized Controlled Trial.

Sørensen SK, Johannessen A, Worck R, Hansen ML, Hansen J

Background:
- Recurrent paroxysmal atrial fibrillation (PAF) after catheter ablation is presumably caused by failure to achieve durable pulmonary vein isolation (PVI). The primary methods of PVI are radiofrequency (RF) and cryoballoon (CRYO) catheter ablation, but these methods have not been directly compared with respect to PVI durability and the effect thereof on AF burden (% of time in AF). Methods - Accordingly, we performed a randomized trial including 98 patients (68% male, 61 [55-67] years) with PAF assigned 1:1 to PVI by contact-force sensing, irrigated RF catheter or second-generation CRYO catheter. Implantable cardiac monitors were inserted ≥1 month before PVI for assessment of AF burden and recurrence, and all patients, irrespective of AF recurrence, underwent a second procedure 4-6 months after PVI to determine PVI durability. Results - In the second procedure, 152/199 (76%) pulmonary veins (PVs) were found durably isolated after RF and 161/200 (81%) after CRYO (NS), corresponding to durable isolation of all veins in 47% of patients in both groups (NS). Median AF burden before PVI was 5.4% (interquartile range: 0.5-13.0%) vs. 4.0% (0.6-18.1%), RF vs. CRYO, and reduced to 0.0% (0.0-0.1%) and 0.0% (0.0-0.5%), respectively - a reduction of 99.9% (92.9-100.0%) and 99.3% (85.9-100.0%) (all NS). AF burden after PVI significantly correlated to the number of durably isolated PVs (p < 0.01), but 9/45 (20%) patients with durable isolation of all veins had recurrence of AF within 4-6 months after PVI (excluding a 3-month blanking period).
Conclusions:
- PVI by RF and CRYO catheter ablation produce similar moderate to high PVI durability. Both treatments lead to marked reductions in AF burden, which is related to the number of durably isolated PVs. However, for one fifth of PAF patients, complete and durable PVI was not sufficient to prevent even short-term AF recurrence.




Circ Arrhythm Electrophysiol: 08 Apr 2021; epub ahead of print
Sørensen SK, Johannessen A, Worck R, Hansen ML, Hansen J
Circ Arrhythm Electrophysiol: 08 Apr 2021; epub ahead of print | PMID: 33835823
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiac and renal protective effects of 2,5-dimethylcelecoxib in angiotensin II and high-salt-induced hypertension model mice.

Yamamoto M, Takahashi-Yanaga F, Arioka M, Igawa K, ... Yamaura K, Sasaguri T
Background
We reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative that is unable to inhibit cyclooxygenase-2, prevented cardiac remodeling induced by sarcomeric gene mutation, left ventricular pressure overload, or β-adrenergic receptor stimulation. This effect seemed to be mediated by the inhibition of the canonical Wnt/β-catenin signaling pathway, which has been suggested to play a key role in the development of chronic kidney disease and chronic heart failure.
Method
We investigated the effect of DM-celecoxib on cardiac remodeling and kidney injury in hypertension model mice induced by angiotensin II infusion in the absence or presence of high-salt load.
Results
DM-celecoxib prevented cardiac remodeling and markedly reduced urinary albumin excretion without altering blood pressure in those mice. Moreover, DM-celecoxib prevented podocyte injury, glomerulosclerosis, and interstitial fibrosis in the kidney of mice loaded with angiotensin II and high-salt load. DM-celecoxib reduced the phosphorylation level of Akt and activated glycogen synthase kinase-3, which led to the suppression of the Wnt/β-catenin signal in the heart and kidney. DM-celecoxib also reduced the expression level of snail, a key transcription factor for the epithelial-mesenchymal transition and of which gene is a target of the Wnt/β-catenin signal.
Conclusion
Results of the current study suggested that DM-celecoxib could be beneficial for patients with hypertensive heart and kidney diseases.

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 30 Apr 2021; 39:892-903
Yamamoto M, Takahashi-Yanaga F, Arioka M, Igawa K, ... Yamaura K, Sasaguri T
J Hypertens: 30 Apr 2021; 39:892-903 | PMID: 33252422
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effects of inverted photoperiods on the blood pressure and carotid artery of spontaneously hypertensive rats and Wistar-Kyoto rats.

Wang Y, Zhang T, Zhang Y, Yu Y, ... Zhang H, Chi Y
Objective
The objective of this study was to investigate the effects of inverted photoperiods on the blood pressure and carotid arteries in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats (homologous control group).
Methods and results
This study used two inverted photoperiods [inverted light:dark (ILD)16 : 8 and ILD12 : 12] to create the model. A total of 27 male SHR and 27 male WKY rats were randomly divided into six groups (nine rats per group): SHR (LD12 : 12), SHR (ILD16 : 8), SHR (ILD12 : 12), WKY (LD12 : 12), WKY (ILD16 : 8) and WKY (ILD12 : 12). We recorded the trajectory of the activity rhythm of the rats and performed carotid vascular ultrasound examination, MRI (arterial spin labelling) analysis and carotid biopsy. The results showed that inverted photoperiods increased the blood pressure, carotid intima-media thickness, resistance index and blood flow velocity. In addition, inverted photoperiods led to the development of carotid arterial thrombosis, significantly reduced cerebral blood flow and increased the number of collagen fibres. Moreover, it increased the expression of angiotensin receptor and low-density lipoprotein receptor in the carotid arteries, leading to decreased expression of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase and nitric oxide synthase. Inverted photoperiods induced the formation of atherosclerotic plaque. Multiple results of SHR were worse than those of WKY rats.
Conclusion
Taken together, inverted photoperiods can produce a series of adverse consequences on blood pressure and carotid arteries. Hypertension can aggravate the adverse effects of inverted photoperiods.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 30 Apr 2021; 39:871-879
Wang Y, Zhang T, Zhang Y, Yu Y, ... Zhang H, Chi Y
J Hypertens: 30 Apr 2021; 39:871-879 | PMID: 33824259
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Incidence and prognostic significance of hypoxemia in fibrotic interstitial lung disease: an international cohort study.

Khor YH, Gutman L, Hussein NA, Johannson KA, ... Goh NS, Ryerson CJ
Background
Hypoxemia is a cardinal feature of fibrotic interstitial lung disease (ILD). The incidence, progression, and prognostic significance of hypoxemia in patients with fibrotic ILD is currently unknown.
Research question
What are the epidemiology of hypoxemia and its additive prognostic value in current risk prediction model in fibrotic ILD?
Methods
We identified 848 patients with fibrotic ILD (258 with idiopathic pulmonary fibrosis (IPF)) in five prospective ILD registries from Australia, Canada, and Switzerland. Cumulative incidence of exertional and resting hypoxemia from the time of diagnosis was estimated at 1-year intervals in patients with baseline 6-minute walk tests, adjusted for competing risks of death and lung transplantation. Likelihood ratio tests were used to determine the prognostic significance of exertional and resting hypoxemia for 1-year mortality/transplantation when added to the ILD-GAP model. The cohort was divided into derivation and validation subsets to evaluate performance characteristics of the extended model (the \"ILD-GAP-O2\" model), which included oxygenation status as a predictor.
Results
The 1-, 2-, and 5-year overall cumulative incidence was 6.1%, 17.3%, and 40.1% for exertional hypoxemia, and 2.4%, 5.6%, and 16.5% for resting hypoxemia, which were significantly higher in IPF patients compared to non-IPF patients (p<0.001 for both). Addition of exertional or resting hypoxemia to the ILD-GAP model improved 1-year mortality/transplantation prediction (p<0.001 for both). The ILD-GAP-O2 model had improved discrimination (C-index of 0.80 vs 0.75) and model fit (Akaike information criteria of 400 vs 422) in the validation cohort, with comparable calibration.
Interpretation
IPF patients have higher cumulative incidence of exertional and resting hypoxemia than non-IPF patients. The extended ILD-GAP-O2 model provides additional risk stratification for 1-year prognosis in fibrotic ILD.

Copyright © 2021. Published by Elsevier Inc.

Chest: 23 Apr 2021; epub ahead of print
Khor YH, Gutman L, Hussein NA, Johannson KA, ... Goh NS, Ryerson CJ
Chest: 23 Apr 2021; epub ahead of print | PMID: 33905679
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Glomerular Filtration Rates on Outcomes Following Percutaneous Left Atrial Appendage Closure.

Faroux L, Cruz-González I, Arzamendi D, Freixa X, ... O\'Hara G, Rodés-Cabau J
Scarce data support the prescription of oral anticoagulation in patients with concomitant advanced chronic kidney disease (CKD) and atrial fibrillation, and left atrial appendage closure (LAAC) may provide a favorable risk-benefit ratio in this population. However, outcomes of LAAC in CKD patients are unknown. We aimed to investigate the impact of moderate-to-severe CKD on clinical outcomes following percutaneous LAAC. This was a multicenter study including 1094 patients who underwent LAAC. Moderate-to-severe CKD was defined as an eGFR<45 mL/min. Death, ischemic stroke, severe bleeding (≥BARC 3a) and serious adverse event (SAE; composite of death, stroke or severe bleeding) were recorded. A total of 300 patients (27.4%) had moderate-to-severe CKD. There were no differences between groups in periprocedural complications or device related thrombosis. At a median follow-up of 2 (1 to 3) years, patients with moderate-to-severe CKD did not present an increased risk of ischemic stroke (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.22 to 1.92; p = 0.435) but were at a higher risk of death (HR: 2.84; 95% CI: 2.22 to 3.64; p <0.001), severe bleeding (HR: 1.96; 95% CI: 1.36 to 2.81; p <0.001) and SAE (HR: 2.23; 95% CI: 1.80 to 2.77; p <0.001). By multivariable analysis, an eGFR<45 ml/min (HR: 1.92; 95% CI: 1.34 to 2.76; p <0.001) and previous bleeding (HR: 2.30; 95% CI: 1.27 to 4.17; p = 0.006) were associated with an increased risk of severe bleeding. In conclusion, patients with moderate-to-severe CKD who underwent LAAC had very high thrombotic and bleeding risks. Although the rates of device related thrombosis or ischemic stroke after-LAAC were not influenced by kidney dysfunction, patients with moderate-to-severe CKD remained at higher risk of severe bleeding events.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Apr 2021; 145:77-84
Faroux L, Cruz-González I, Arzamendi D, Freixa X, ... O'Hara G, Rodés-Cabau J
Am J Cardiol: 14 Apr 2021; 145:77-84 | PMID: 33508268
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Glomerular Filtration Rates on Outcomes Following Percutaneous Left Atrial Appendage Closure.

Faroux L, Cruz-González I, Arzamendi D, Freixa X, ... O\'Hara G, Rodés-Cabau J
Scarce data support the prescription of oral anticoagulation in patients with concomitant advanced chronic kidney disease (CKD) and atrial fibrillation, and left atrial appendage closure (LAAC) may provide a favorable risk-benefit ratio in this population. However, outcomes of LAAC in CKD patients are unknown. We aimed to investigate the impact of moderate-to-severe CKD on clinical outcomes following percutaneous LAAC. This was a multicenter study including 1094 patients who underwent LAAC. Moderate-to-severe CKD was defined as an eGFR<45 mL/min. Death, ischemic stroke, severe bleeding (≥BARC 3a) and serious adverse event (SAE; composite of death, stroke or severe bleeding) were recorded. A total of 300 patients (27.4%) had moderate-to-severe CKD. There were no differences between groups in periprocedural complications or device related thrombosis. At a median follow-up of 2 (1 to 3) years, patients with moderate-to-severe CKD did not present an increased risk of ischemic stroke (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.22 to 1.92; p = 0.435) but were at a higher risk of death (HR: 2.84; 95% CI: 2.22 to 3.64; p <0.001), severe bleeding (HR: 1.96; 95% CI: 1.36 to 2.81; p <0.001) and SAE (HR: 2.23; 95% CI: 1.80 to 2.77; p <0.001). By multivariable analysis, an eGFR<45 ml/min (HR: 1.92; 95% CI: 1.34 to 2.76; p <0.001) and previous bleeding (HR: 2.30; 95% CI: 1.27 to 4.17; p = 0.006) were associated with an increased risk of severe bleeding. In conclusion, patients with moderate-to-severe CKD who underwent LAAC had very high thrombotic and bleeding risks. Although the rates of device related thrombosis or ischemic stroke after-LAAC were not influenced by kidney dysfunction, patients with moderate-to-severe CKD remained at higher risk of severe bleeding events.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Apr 2021; 145:77-84
Faroux L, Cruz-González I, Arzamendi D, Freixa X, ... O'Hara G, Rodés-Cabau J
Am J Cardiol: 14 Apr 2021; 145:77-84 | PMID: 33508268
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Glomerular Filtration Rates on Outcomes Following Percutaneous Left Atrial Appendage Closure.

Faroux L, Cruz-González I, Arzamendi D, Freixa X, ... O\'Hara G, Rodés-Cabau J
Scarce data support the prescription of oral anticoagulation in patients with concomitant advanced chronic kidney disease (CKD) and atrial fibrillation, and left atrial appendage closure (LAAC) may provide a favorable risk-benefit ratio in this population. However, outcomes of LAAC in CKD patients are unknown. We aimed to investigate the impact of moderate-to-severe CKD on clinical outcomes following percutaneous LAAC. This was a multicenter study including 1094 patients who underwent LAAC. Moderate-to-severe CKD was defined as an eGFR<45 mL/min. Death, ischemic stroke, severe bleeding (≥BARC 3a) and serious adverse event (SAE; composite of death, stroke or severe bleeding) were recorded. A total of 300 patients (27.4%) had moderate-to-severe CKD. There were no differences between groups in periprocedural complications or device related thrombosis. At a median follow-up of 2 (1 to 3) years, patients with moderate-to-severe CKD did not present an increased risk of ischemic stroke (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.22 to 1.92; p = 0.435) but were at a higher risk of death (HR: 2.84; 95% CI: 2.22 to 3.64; p <0.001), severe bleeding (HR: 1.96; 95% CI: 1.36 to 2.81; p <0.001) and SAE (HR: 2.23; 95% CI: 1.80 to 2.77; p <0.001). By multivariable analysis, an eGFR<45 ml/min (HR: 1.92; 95% CI: 1.34 to 2.76; p <0.001) and previous bleeding (HR: 2.30; 95% CI: 1.27 to 4.17; p = 0.006) were associated with an increased risk of severe bleeding. In conclusion, patients with moderate-to-severe CKD who underwent LAAC had very high thrombotic and bleeding risks. Although the rates of device related thrombosis or ischemic stroke after-LAAC were not influenced by kidney dysfunction, patients with moderate-to-severe CKD remained at higher risk of severe bleeding events.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Apr 2021; 145:77-84
Faroux L, Cruz-González I, Arzamendi D, Freixa X, ... O'Hara G, Rodés-Cabau J
Am J Cardiol: 14 Apr 2021; 145:77-84 | PMID: 33508268
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Comparison of Patients With Nonobstructive Coronary Artery Disease With Versus Without Myocardial Infarction (from the VA Clinical Assessment Reporting and Tracking [CART] Program).

Kovach CP, Hebbe A, O\'Donnell CI, Plomondon ME, ... Waldo SW, Valle JA
Comparisons of the outcomes of patients with myocardial infarction with nonobstructive coronary artery disease (MINOCA) and patients with nonobstructive coronary artery disease (CAD) without myocardial infarction (MI) are limited. Here we compare the outcomes of patients with MINOCA and patients with nonobstructive CAD without MI and assess the influence of medical therapy on outcomes in these patients. Veterans who underwent coronary angiography between 2008 to 2017 with nonobstructive CAD were divided into those with or without pre-procedural troponin elevation. Patients with prior revascularization, heart failure, or who presented with cardiogenic shock, STEMI, or unstable angina were excluded. After propensity matching, outcomes were compared between groups. The primary outcome was major adverse cardiovascular events (MACE: mortality, myocardial infarction, and revascularization) within one year: 3,924 patients with nonobstructive CAD and a troponin obtained prior to angiography were identified (n=1,986 with elevated troponin) and restricted to 1,904 patients after propensity-matching. There was a significantly higher risk of MACE among troponin-positive patients compared with those with a negative troponin (HR 2.37; 95% CI, 1.67 to 3.34). Statin (HR 0.32; 95% CI, 0.22 to 0.49) and ACE inhibitor (HR 0.49; 95% CI, 0.32 to 0.75) therapy after angiography was associated with decreased MACE, while P2Y12 inhibitor, calcium-channel and beta-blocker therapy were not associated with outcomes. In conclusion, Veterans with MINOCA are at increased risk for MACE compared with those with nonobstructive CAD and negative troponin at the time of angiography. Specific medications were associated with a reduction in MACE, suggesting an opportunity to explore novel approaches for secondary prevention in this population.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 30 Apr 2021; 146:1-7
Kovach CP, Hebbe A, O'Donnell CI, Plomondon ME, ... Waldo SW, Valle JA
Am J Cardiol: 30 Apr 2021; 146:1-7 | PMID: 33539858
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Comparison of Patients With Nonobstructive Coronary Artery Disease With Versus Without Myocardial Infarction (from the VA Clinical Assessment Reporting and Tracking [CART] Program).

Kovach CP, Hebbe A, O\'Donnell CI, Plomondon ME, ... Waldo SW, Valle JA
Comparisons of the outcomes of patients with myocardial infarction with nonobstructive coronary artery disease (MINOCA) and patients with nonobstructive coronary artery disease (CAD) without myocardial infarction (MI) are limited. Here we compare the outcomes of patients with MINOCA and patients with nonobstructive CAD without MI and assess the influence of medical therapy on outcomes in these patients. Veterans who underwent coronary angiography between 2008 to 2017 with nonobstructive CAD were divided into those with or without pre-procedural troponin elevation. Patients with prior revascularization, heart failure, or who presented with cardiogenic shock, STEMI, or unstable angina were excluded. After propensity matching, outcomes were compared between groups. The primary outcome was major adverse cardiovascular events (MACE: mortality, myocardial infarction, and revascularization) within one year: 3,924 patients with nonobstructive CAD and a troponin obtained prior to angiography were identified (n=1,986 with elevated troponin) and restricted to 1,904 patients after propensity-matching. There was a significantly higher risk of MACE among troponin-positive patients compared with those with a negative troponin (HR 2.37; 95% CI, 1.67 to 3.34). Statin (HR 0.32; 95% CI, 0.22 to 0.49) and ACE inhibitor (HR 0.49; 95% CI, 0.32 to 0.75) therapy after angiography was associated with decreased MACE, while P2Y12 inhibitor, calcium-channel and beta-blocker therapy were not associated with outcomes. In conclusion, Veterans with MINOCA are at increased risk for MACE compared with those with nonobstructive CAD and negative troponin at the time of angiography. Specific medications were associated with a reduction in MACE, suggesting an opportunity to explore novel approaches for secondary prevention in this population.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 30 Apr 2021; 146:1-7
Kovach CP, Hebbe A, O'Donnell CI, Plomondon ME, ... Waldo SW, Valle JA
Am J Cardiol: 30 Apr 2021; 146:1-7 | PMID: 33539858
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Comparison of Hospitalization Trends and Outcomes in Acute Myocardial Infarction Patients With Versus Without Opioid Use Disorder.

Ranka S, Dalia T, Acharya P, Taduru SS, ... Shah Z, Gupta K
Discrepancies in medical care are well known to adversely affect patients with opioid abuse disorders (OUD), including management and outcomes of acute myocardial infarction (AMI) in patients with OUD. We used the National Inpatient Sample was queried from January 2006 to September 2015 to identify all patients ≥18 years admitted with a primary diagnosis of AMI (weighted N = 13,030; unweighted N = 2,670) and concomitant OUD. Patients using other nonopiate illicit drugs were excluded. Propensity matching (1:1) yielded 2,253 well-matched pairs in which intergroup comparison of invasive revascularization strategies and cardiac outcomes were performed. The prevalence of OUD patients with AMI over the last decade has doubled, from 163 (2006) to 326 cases (2015) per 100,000 admissions for AMI. The OUD group underwent less cardiac catheterization (63.2% vs 72.2%; p <0.001), percutaneous coronary intervention (37.0% vs 48.5%; p <0.001) and drug-eluting stent placement (32.3% vs 19.5%; p <0.001) compared with non-OUD. No differences in in-hospital mortality/cardiogenic shock were noted. Among subgroup of ST-elevation myocardial infarction patients (26.2% of overall cohort), the OUD patients were less likely to receive percutaneous coronary intervention (67.9% vs 75.5%; p = 0.002), drug-eluting stent (31.4% vs 47.9%; p <0.001) with a significantly higher mortality (7.4% vs 4.3%), and cardiogenic shock (11.7% vs 7.9%). No differences in the frequency of coronary bypass grafting were noted in AMI or its subgroups. In conclusion, OUD patients presenting with AMI receive less invasive treatment compared with those without OUD. OUD patients presenting with ST-elevation myocardial infarction have worse in-hospital outcomes with increased mortality and cardiogenic shock.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Apr 2021; 145:18-24
Ranka S, Dalia T, Acharya P, Taduru SS, ... Shah Z, Gupta K
Am J Cardiol: 14 Apr 2021; 145:18-24 | PMID: 33454349
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Comparison of Hospitalization Trends and Outcomes in Acute Myocardial Infarction Patients With Versus Without Opioid Use Disorder.

Ranka S, Dalia T, Acharya P, Taduru SS, ... Shah Z, Gupta K
Discrepancies in medical care are well known to adversely affect patients with opioid abuse disorders (OUD), including management and outcomes of acute myocardial infarction (AMI) in patients with OUD. We used the National Inpatient Sample was queried from January 2006 to September 2015 to identify all patients ≥18 years admitted with a primary diagnosis of AMI (weighted N = 13,030; unweighted N = 2,670) and concomitant OUD. Patients using other nonopiate illicit drugs were excluded. Propensity matching (1:1) yielded 2,253 well-matched pairs in which intergroup comparison of invasive revascularization strategies and cardiac outcomes were performed. The prevalence of OUD patients with AMI over the last decade has doubled, from 163 (2006) to 326 cases (2015) per 100,000 admissions for AMI. The OUD group underwent less cardiac catheterization (63.2% vs 72.2%; p <0.001), percutaneous coronary intervention (37.0% vs 48.5%; p <0.001) and drug-eluting stent placement (32.3% vs 19.5%; p <0.001) compared with non-OUD. No differences in in-hospital mortality/cardiogenic shock were noted. Among subgroup of ST-elevation myocardial infarction patients (26.2% of overall cohort), the OUD patients were less likely to receive percutaneous coronary intervention (67.9% vs 75.5%; p = 0.002), drug-eluting stent (31.4% vs 47.9%; p <0.001) with a significantly higher mortality (7.4% vs 4.3%), and cardiogenic shock (11.7% vs 7.9%). No differences in the frequency of coronary bypass grafting were noted in AMI or its subgroups. In conclusion, OUD patients presenting with AMI receive less invasive treatment compared with those without OUD. OUD patients presenting with ST-elevation myocardial infarction have worse in-hospital outcomes with increased mortality and cardiogenic shock.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Apr 2021; 145:18-24
Ranka S, Dalia T, Acharya P, Taduru SS, ... Shah Z, Gupta K
Am J Cardiol: 14 Apr 2021; 145:18-24 | PMID: 33454349
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Transaortic Valve Intervention for Aortic Stenosis on Myocardial Mechanics.

Harrington CM, Sorour N, Gottbrecht M, Nagy A, ... Chung ES, Aurigemma GP
Chronic afterload excess in aortic stenosis results in compensatory concentric hypertrophy which mitigates the increased systolic load. Surgical aortic valve replacement has been shown to decrease afterload and improve left ventricular (LV) ejection fraction (EF). The extent to which these changes take place in patients undergoing TAVI (transcatheter aortic valve intervention) may be different than what has been observed in the surgical aortic valve replacement patients who were generally younger with few co-morbidities. Accordingly, we analyzed indices of LV structure and ventricular mechanics pre- and 1-year after TAVI in 397 patients (mean age 81±9, 46% women) with severe symptomatic aortic stenosis, complete echocardiographic data was available in 156 patients and these patients compromised our study population. Our principal findings are: (1) LV remodeling occurs after TAVI; (2) afterload decreases significantly; (3) LV chamber and myocardial function, assessed by left ventricular ejection fraction and midwall fractional shortening, and stroke volume, respectively, remain unchanged or decrease. In conclusion, TAVI effects LV remodeling despite significant co-morbidities. Thus, TAVI reduces afterload and leads to LV remodeling. Surprisingly, however, systolic function does not improve. These data run counter to the paradigm that afterload reduction improves systolic function and suggest that the response to afterload reduction is complex in the TAVI population.

Copyright © 2021. Published by Elsevier Inc.

Am J Cardiol: 30 Apr 2021; 146:56-61
Harrington CM, Sorour N, Gottbrecht M, Nagy A, ... Chung ES, Aurigemma GP
Am J Cardiol: 30 Apr 2021; 146:56-61 | PMID: 33529618
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Transaortic Valve Intervention for Aortic Stenosis on Myocardial Mechanics.

Harrington CM, Sorour N, Gottbrecht M, Nagy A, ... Chung ES, Aurigemma GP
Chronic afterload excess in aortic stenosis results in compensatory concentric hypertrophy which mitigates the increased systolic load. Surgical aortic valve replacement has been shown to decrease afterload and improve left ventricular (LV) ejection fraction (EF). The extent to which these changes take place in patients undergoing TAVI (transcatheter aortic valve intervention) may be different than what has been observed in the surgical aortic valve replacement patients who were generally younger with few co-morbidities. Accordingly, we analyzed indices of LV structure and ventricular mechanics pre- and 1-year after TAVI in 397 patients (mean age 81±9, 46% women) with severe symptomatic aortic stenosis, complete echocardiographic data was available in 156 patients and these patients compromised our study population. Our principal findings are: (1) LV remodeling occurs after TAVI; (2) afterload decreases significantly; (3) LV chamber and myocardial function, assessed by left ventricular ejection fraction and midwall fractional shortening, and stroke volume, respectively, remain unchanged or decrease. In conclusion, TAVI effects LV remodeling despite significant co-morbidities. Thus, TAVI reduces afterload and leads to LV remodeling. Surprisingly, however, systolic function does not improve. These data run counter to the paradigm that afterload reduction improves systolic function and suggest that the response to afterload reduction is complex in the TAVI population.

Copyright © 2021. Published by Elsevier Inc.

Am J Cardiol: 30 Apr 2021; 146:56-61
Harrington CM, Sorour N, Gottbrecht M, Nagy A, ... Chung ES, Aurigemma GP
Am J Cardiol: 30 Apr 2021; 146:56-61 | PMID: 33529618
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Meta-Analysis of Valve-in-Valve Transcatheter Aortic Valve Implantation Versus Redo-surgical Aortic Valve Replacement in Failed Bioprosthetic Aortic Valve.

Al-Abcha A, Saleh Y, Boumegouas M, Prasad R, ... Rayamajhi S, Abela GS
This meta-analysis was conducted to compare clinical outcomes of valve-in-valve transcatheter aortic valve implantation (ViV-TAVI) versus redo-surgical aortic valve replacement (Redo-SAVR) in failed bioprosthetic aortic valves. We conducted a comprehensive review of previous publications of all relevant studies through August 2020. Twelve observational studies were included with a total of 8,430 patients, and a median-weighted follow-up period of 1.74 years. A pooled analysis of the data showed no significant difference in all-cause mortality (OR 1.15; 95% CI 0.93 to 1.43; p = 0.21), cardiovascular mortality, myocardial infarction, permanent pacemaker implantation, and the rate of moderate to severe paravalvular leakage between ViV-TAVI and Redo-SAVR groups. The rate of major bleeding (OR 0.36; 95% CI 0.16 to 0.83, p = 0.02), procedural mortality (OR 0.41; 95% CI 0.18 to 0.96, p = 0.04), 30-day mortality (OR 0.58; 95% CI 0.45 to 0.74, p <0.0001), and the rate of stroke (OR 0.65; 95% CI 0.52 to 0.81, p = 0.0001) were significantly lower in the ViV- TAVI arm when compared with Redo-SAVR arm. The mean transvalvular pressure gradient was significantly higher post-implantation in the ViV-TAVI group when compared with the Redo-SAVR arm (Mean difference 3.92; 95% CI 1.97 to 5.88, p < 0.0001). In conclusion, compared with Redo-SAVR, ViV-TAVI is associated with a similar risk of all-cause mortality, cardiovascular mortality, myocardial infarction, permanent pacemaker implantation, and the rate of moderate to severe paravalvular leakage. However, the rate of major bleeding, stroke, procedural mortality and 30-day mortality were significantly lower in the ViV-TAVI group when compared with Redo-SAVR.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 30 Apr 2021; 146:74-81
Al-Abcha A, Saleh Y, Boumegouas M, Prasad R, ... Rayamajhi S, Abela GS
Am J Cardiol: 30 Apr 2021; 146:74-81 | PMID: 33529615
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Meta-Analysis of Valve-in-Valve Transcatheter Aortic Valve Implantation Versus Redo-surgical Aortic Valve Replacement in Failed Bioprosthetic Aortic Valve.

Al-Abcha A, Saleh Y, Boumegouas M, Prasad R, ... Rayamajhi S, Abela GS
This meta-analysis was conducted to compare clinical outcomes of valve-in-valve transcatheter aortic valve implantation (ViV-TAVI) versus redo-surgical aortic valve replacement (Redo-SAVR) in failed bioprosthetic aortic valves. We conducted a comprehensive review of previous publications of all relevant studies through August 2020. Twelve observational studies were included with a total of 8,430 patients, and a median-weighted follow-up period of 1.74 years. A pooled analysis of the data showed no significant difference in all-cause mortality (OR 1.15; 95% CI 0.93 to 1.43; p = 0.21), cardiovascular mortality, myocardial infarction, permanent pacemaker implantation, and the rate of moderate to severe paravalvular leakage between ViV-TAVI and Redo-SAVR groups. The rate of major bleeding (OR 0.36; 95% CI 0.16 to 0.83, p = 0.02), procedural mortality (OR 0.41; 95% CI 0.18 to 0.96, p = 0.04), 30-day mortality (OR 0.58; 95% CI 0.45 to 0.74, p <0.0001), and the rate of stroke (OR 0.65; 95% CI 0.52 to 0.81, p = 0.0001) were significantly lower in the ViV- TAVI arm when compared with Redo-SAVR arm. The mean transvalvular pressure gradient was significantly higher post-implantation in the ViV-TAVI group when compared with the Redo-SAVR arm (Mean difference 3.92; 95% CI 1.97 to 5.88, p < 0.0001). In conclusion, compared with Redo-SAVR, ViV-TAVI is associated with a similar risk of all-cause mortality, cardiovascular mortality, myocardial infarction, permanent pacemaker implantation, and the rate of moderate to severe paravalvular leakage. However, the rate of major bleeding, stroke, procedural mortality and 30-day mortality were significantly lower in the ViV-TAVI group when compared with Redo-SAVR.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 30 Apr 2021; 146:74-81
Al-Abcha A, Saleh Y, Boumegouas M, Prasad R, ... Rayamajhi S, Abela GS
Am J Cardiol: 30 Apr 2021; 146:74-81 | PMID: 33529615
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Acute Chylopericardium With Tamponade and Cardiac Arrest With Pseudomyxoma Peritonei.

Milandt N, Birkelund T, Engholm M
A 51-year-old woman with pseudomyxoma peritonei developed cardiac arrest 5 days after surgery. Acute echocardiography demonstrated pericardial tamponade. Emergency pericardiocentesis evacuated milky fluid and circulation was re-established. Analysis of the pericardial fluid suggested chylopericardium. In conclusion, this case demonstrates that chylopericardium may be life-threatening and underlines the importance of acute echocardiography in critical management of patients with unexplained shock.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 30 Apr 2021; 146:134-136
Milandt N, Birkelund T, Engholm M
Am J Cardiol: 30 Apr 2021; 146:134-136 | PMID: 33548186
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Acute Chylopericardium With Tamponade and Cardiac Arrest With Pseudomyxoma Peritonei.

Milandt N, Birkelund T, Engholm M
A 51-year-old woman with pseudomyxoma peritonei developed cardiac arrest 5 days after surgery. Acute echocardiography demonstrated pericardial tamponade. Emergency pericardiocentesis evacuated milky fluid and circulation was re-established. Analysis of the pericardial fluid suggested chylopericardium. In conclusion, this case demonstrates that chylopericardium may be life-threatening and underlines the importance of acute echocardiography in critical management of patients with unexplained shock.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 30 Apr 2021; 146:134-136
Milandt N, Birkelund T, Engholm M
Am J Cardiol: 30 Apr 2021; 146:134-136 | PMID: 33548186
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Percutaneous Coronary Intervention Versus Coronary Artery Bypass Graftinge Among Patients with Unprotected Left Main Coronary Artery Disease in the New-Generation Drug-Eluting Stents Era (From the CREDO-Kyoto PCI/CABG Registry Cohort-3).

Yamamoto K, Shiomi H, Morimoto T, Kadota K, ... Kimura T, CREDO-Kyoto PCI/CABG Registry Cohort-3 investigators
Long-term safety of percutaneous coronary intervention (PCI) as compared with coronary artery bypass grafting (CABG) is still controversial in patients with unprotected left main coronary artery disease (ULMCAD), and there is a scarcity of real-world data on the comparative long-term clinical outcomes between PCI and CABG for ULMCAD in new-generation drug-eluting stents era. The CREDO-Kyoto PCI/CABG registry Cohort-3 enrolled 14927 consecutive patients undergoing first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013, and we identified 855 patients with ULMCAD (PCI: N = 383 [45%], and CABG: N = 472 [55%]). The primary outcome measure was all-cause death. Median follow-up duration was 5.5 (interquartile range: 3.9 to 6.6) years. The cumulative 5-year incidence of all-cause death was not significantly different between the PCI and CABG groups (21.9% vs 17.6%, Log-rank p = 0.13). After adjusting confounders, the excess risk of PCI relative to CABG remained insignificant for all-cause death (HR, 1.00; 95% CI, 0.68 to 1.47; p = 0.99). There were significant excess risks of PCI relative to CABG for myocardial infarction and any coronary revascularization (HR, 2.07; 95% CI, 1.30 to 3.37; p = 0.002, and HR, 2.96; 95% CI, 1.96 to 4.46; p < 0.001), whereas there was no significant excess risk of PCI relative to CABG for stroke (HR, 0.85; 95% CI, 0.50 to 1.41; p = 0.52). In conclusion, there was no excess long-term mortality risk of PCI relative to CABG, while the excess risks of PCI relative to CABG were significant for myocardial infarction and any coronary revascularization in the present study population reflecting real-world clinical practice in Japan.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Apr 2021; 145:47-57
Yamamoto K, Shiomi H, Morimoto T, Kadota K, ... Kimura T, CREDO-Kyoto PCI/CABG Registry Cohort-3 investigators
Am J Cardiol: 14 Apr 2021; 145:47-57 | PMID: 33454345
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Percutaneous Coronary Intervention Versus Coronary Artery Bypass Graftinge Among Patients with Unprotected Left Main Coronary Artery Disease in the New-Generation Drug-Eluting Stents Era (From the CREDO-Kyoto PCI/CABG Registry Cohort-3).

Yamamoto K, Shiomi H, Morimoto T, Kadota K, ... Kimura T, CREDO-Kyoto PCI/CABG Registry Cohort-3 investigators
Long-term safety of percutaneous coronary intervention (PCI) as compared with coronary artery bypass grafting (CABG) is still controversial in patients with unprotected left main coronary artery disease (ULMCAD), and there is a scarcity of real-world data on the comparative long-term clinical outcomes between PCI and CABG for ULMCAD in new-generation drug-eluting stents era. The CREDO-Kyoto PCI/CABG registry Cohort-3 enrolled 14927 consecutive patients undergoing first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013, and we identified 855 patients with ULMCAD (PCI: N = 383 [45%], and CABG: N = 472 [55%]). The primary outcome measure was all-cause death. Median follow-up duration was 5.5 (interquartile range: 3.9 to 6.6) years. The cumulative 5-year incidence of all-cause death was not significantly different between the PCI and CABG groups (21.9% vs 17.6%, Log-rank p = 0.13). After adjusting confounders, the excess risk of PCI relative to CABG remained insignificant for all-cause death (HR, 1.00; 95% CI, 0.68 to 1.47; p = 0.99). There were significant excess risks of PCI relative to CABG for myocardial infarction and any coronary revascularization (HR, 2.07; 95% CI, 1.30 to 3.37; p = 0.002, and HR, 2.96; 95% CI, 1.96 to 4.46; p < 0.001), whereas there was no significant excess risk of PCI relative to CABG for stroke (HR, 0.85; 95% CI, 0.50 to 1.41; p = 0.52). In conclusion, there was no excess long-term mortality risk of PCI relative to CABG, while the excess risks of PCI relative to CABG were significant for myocardial infarction and any coronary revascularization in the present study population reflecting real-world clinical practice in Japan.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Apr 2021; 145:47-57
Yamamoto K, Shiomi H, Morimoto T, Kadota K, ... Kimura T, CREDO-Kyoto PCI/CABG Registry Cohort-3 investigators
Am J Cardiol: 14 Apr 2021; 145:47-57 | PMID: 33454345
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Mitral Regurgitation on Thrombotic Risk in Patients With Nonrheumatic Atrial Fibrillation: A New CHADS-VASc Score Risk Modifier?

Van Laer SL, Verreyen S, Winkler KM, Miljoen H, ... Heidbuchel H, Claeys MJ
The current study assessed the effect of mitral regurgitation (MR) on thrombotic risk in nonrheumatic atrial fibrillation (AF). AF carries a thrombotic risk related to left atrial blood stasis. The prevalence of atrial thrombosis, defined as the presence of left atrial appendage thrombus and/or left atrial spontaneous echo contrast grade >2, was determined in 686 consecutive nonrheumatic AF patients without (adequate) anticoagulation scheduled for transesophageal echocardiography before electrical cardioversion and was related to the severity of MR adjusted for the CHA2DS2-VASc score. A total of 103 (15%) patients had severe MR, 210 (31%) had moderate MR, and 373 (54%) had no-mild MR; the median CHA2DS2-VASc score was 3.0 (interquartile range 2.0 to 4.0). Atrial thrombosis was observed in 118 patients (17%). The prevalence of atrial thrombosis decreased with increasing MR severity: 19.9% versus 15.2% versus 11.6% for no-mild, moderate, and severe MR, respectively (p value for trend = 0.03). Patients with moderate and severe MR had a lower risk of atrial thrombosis than patients with no-mild MR, with adjusted odds ratios of 0.51 (95% confidence interval 0.31 to 0.84) and 0.24 (95% confidence interval 0.11 to 0.49), respectively. The protective effect of MR was present across all levels of the CHA2DS2-VASc risk score and the presence of moderate-severe MR in patients with an intermediate CHA2DS2-VASc score (2 to 3) lowered the atrial thrombotic risk to the level of patients with a low CHA2DS2-VASc score (0 to 1). In conclusion, our data show that the presence of MR attenuated the atrial thrombotic risk by more than 50% in patients with nonrheumatic AF.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Apr 2021; 145:69-76
Van Laer SL, Verreyen S, Winkler KM, Miljoen H, ... Heidbuchel H, Claeys MJ
Am J Cardiol: 14 Apr 2021; 145:69-76 | PMID: 33454347
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Mitral Regurgitation on Thrombotic Risk in Patients With Nonrheumatic Atrial Fibrillation: A New CHADS-VASc Score Risk Modifier?

Van Laer SL, Verreyen S, Winkler KM, Miljoen H, ... Heidbuchel H, Claeys MJ
The current study assessed the effect of mitral regurgitation (MR) on thrombotic risk in nonrheumatic atrial fibrillation (AF). AF carries a thrombotic risk related to left atrial blood stasis. The prevalence of atrial thrombosis, defined as the presence of left atrial appendage thrombus and/or left atrial spontaneous echo contrast grade >2, was determined in 686 consecutive nonrheumatic AF patients without (adequate) anticoagulation scheduled for transesophageal echocardiography before electrical cardioversion and was related to the severity of MR adjusted for the CHA2DS2-VASc score. A total of 103 (15%) patients had severe MR, 210 (31%) had moderate MR, and 373 (54%) had no-mild MR; the median CHA2DS2-VASc score was 3.0 (interquartile range 2.0 to 4.0). Atrial thrombosis was observed in 118 patients (17%). The prevalence of atrial thrombosis decreased with increasing MR severity: 19.9% versus 15.2% versus 11.6% for no-mild, moderate, and severe MR, respectively (p value for trend = 0.03). Patients with moderate and severe MR had a lower risk of atrial thrombosis than patients with no-mild MR, with adjusted odds ratios of 0.51 (95% confidence interval 0.31 to 0.84) and 0.24 (95% confidence interval 0.11 to 0.49), respectively. The protective effect of MR was present across all levels of the CHA2DS2-VASc risk score and the presence of moderate-severe MR in patients with an intermediate CHA2DS2-VASc score (2 to 3) lowered the atrial thrombotic risk to the level of patients with a low CHA2DS2-VASc score (0 to 1). In conclusion, our data show that the presence of MR attenuated the atrial thrombotic risk by more than 50% in patients with nonrheumatic AF.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Apr 2021; 145:69-76
Van Laer SL, Verreyen S, Winkler KM, Miljoen H, ... Heidbuchel H, Claeys MJ
Am J Cardiol: 14 Apr 2021; 145:69-76 | PMID: 33454347
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Relation of Antecedent Symptoms to the Likelihood of Detecting Subclinical Atrial Fibrillation With Inserted Cardiac Monitors.

Reiffel JA, Verma A, Kowey PR, Halperin JL, ... Ziegler PD, REVEAL AF Investigators
Atrial fibrillation (AF) comes to attention clinically during an evaluation of symptoms, an evaluation of its adverse outcomes, or because of incidental detection during a routine examination or electrocardiogram. However, a notable number of additional individuals have AF that has not yet been clinically apparent or suspect-subclinical AF (SCAF). SCAF has been recognized during interrogation of pacemakers and defibrillators. More recently, SCAF has been demonstrated in prospective studies with long-term monitors-both external and implanted. The REVEAL AF trial enrolled a demographically \"enriched\" population that underwent monitoring for up to 3 years with an insertable cardiac monitor. SCAF was noted in 40% by 30 months. None of these patients had AF known before the study; however, some had nonspecific symptoms common to patients with known AF. The current study assessed whether patients with versus without such symptoms were more likely to have SCAF detected. We found that only palpitations had an association with AF detection when controlling for other baseline symptoms (hazard ratio 1.61 (95% confidence interval 1.12 to 2.32; p = 0.011). No other prescreening symptoms evaluated were associated with an increased likelihood of SCAF detection although patients without detected SCAF had an even higher frequency of symptoms than those with detected SCAF. Thus, REVEAL AF demonstrated that the presence of palpitations is associated with an increased likelihood of SCAF whereas other common symptoms are not; and, symptoms, per se, may more likely be consequent to associated disorders than they are a direct consequence of SCAF.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Apr 2021; 145:64-68
Reiffel JA, Verma A, Kowey PR, Halperin JL, ... Ziegler PD, REVEAL AF Investigators
Am J Cardiol: 14 Apr 2021; 145:64-68 | PMID: 33497655
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Relation of Antecedent Symptoms to the Likelihood of Detecting Subclinical Atrial Fibrillation With Inserted Cardiac Monitors.

Reiffel JA, Verma A, Kowey PR, Halperin JL, ... Ziegler PD, REVEAL AF Investigators
Atrial fibrillation (AF) comes to attention clinically during an evaluation of symptoms, an evaluation of its adverse outcomes, or because of incidental detection during a routine examination or electrocardiogram. However, a notable number of additional individuals have AF that has not yet been clinically apparent or suspect-subclinical AF (SCAF). SCAF has been recognized during interrogation of pacemakers and defibrillators. More recently, SCAF has been demonstrated in prospective studies with long-term monitors-both external and implanted. The REVEAL AF trial enrolled a demographically \"enriched\" population that underwent monitoring for up to 3 years with an insertable cardiac monitor. SCAF was noted in 40% by 30 months. None of these patients had AF known before the study; however, some had nonspecific symptoms common to patients with known AF. The current study assessed whether patients with versus without such symptoms were more likely to have SCAF detected. We found that only palpitations had an association with AF detection when controlling for other baseline symptoms (hazard ratio 1.61 (95% confidence interval 1.12 to 2.32; p = 0.011). No other prescreening symptoms evaluated were associated with an increased likelihood of SCAF detection although patients without detected SCAF had an even higher frequency of symptoms than those with detected SCAF. Thus, REVEAL AF demonstrated that the presence of palpitations is associated with an increased likelihood of SCAF whereas other common symptoms are not; and, symptoms, per se, may more likely be consequent to associated disorders than they are a direct consequence of SCAF.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Apr 2021; 145:64-68
Reiffel JA, Verma A, Kowey PR, Halperin JL, ... Ziegler PD, REVEAL AF Investigators
Am J Cardiol: 14 Apr 2021; 145:64-68 | PMID: 33497655
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Electrocardiogram Criteria to Diagnose Cardiac Amyloidosis in Men With a Bundle Branch Block.

Sharma S, Labib SB, Shah SP
Diagnosing cardiac amyloidosis is challenging and requires a high index of suspicion in patients with an increased left ventricular wall thickness (LVWT). Low QRS voltage on electrocardiogram (ECG) has been regarded as the hallmark ECG finding in cardiac amyloidosis; however, the presence of low voltage can range from 20-74% and the voltage/mass ratio carries a greater diagnostic accuracy than QRS voltage alone. Patients with cardiac amyloidosis can have conduction system infiltration and this may result in a BBB. Therefore, the ECG or mass/voltage criteria established for patients with a narrow QRS in the diagnosis of cardiac amyloidosis may not be applicable in patients with a BBB. We sought to identify criteria to aid in the diagnosis of cardiac amyloidosis in patients with increased LVWT on echocardiogram and with a BBB on ECG. We calculated the total QRS score/LVWT, limb lead QRS score/LVWT, R in lead aVL/LVWT, R in lead I/LVWT, and Sokolow index/LVWT. In patients with an increase in LVWT and BBB, total QRS voltage that is indexed to wall thickness can help distinguish between patients with increased wall thickness who have cardiac amyloidosis from those who have LVH related to a pressure overload state. A unique index of Total QRS Score/LVWT is the best predictor of cardiac amyloidosis with a cutoff value of 92.5 mV/cm which is 100% sensitive and 83% specific for the diagnosis of cardiac amyloidosis. This may be a useful screening tool in patients with an increased wall thickness to raise diagnostic suspicion for cardiac amyloidosis.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 30 Apr 2021; 146:89-94
Sharma S, Labib SB, Shah SP
Am J Cardiol: 30 Apr 2021; 146:89-94 | PMID: 33529617
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

In-Hospital Outcomes and Trends of Endovascular Intervention vs Surgical Revascularization in Octogenarians With Peripheral Artery Disease.

Pacha HM, Al-Khadra Y, Darmoch F, Soud M, ... Shishehbor MH, Alraies MC
It is unknown whether endovascular intervention (EVI) is associated with superior outcomes when compared with surgical revascularization in octogenarian. National Inpatient Sample (NIS) database was used to compare the outcomes of limb revascularization in octogenarians who had surgical revascularization versus EVI. The NIS database\'s information on PAD patients ≥80-year-old who underwent limb revascularization between 2002 and 2014 included 394,504 octogenarian patients, of which 184,926 underwent surgical revascularization (46.9%) and 209,578 underwent EVI (53.1%). Multivariate analysis was performed to examine in-hospital outcomes. Trend over time in limb revascularization utilization was examined using Cochrane-Armitage test. EVI group had lower odds of in-hospital mortality (adjusted odds ratio [aOR]: 0.61 [95% CI: 0.58 to 0.63], myocardial infarction (aOR: 0.84 [95% CI: 0.81 to 0.87]), stroke (aOR: 0.93 [95% CI: 0.89 to 0.96]), acute kidney injury (aOR: 0.79 [95% CI: 0.77 to 0.81]), and limb amputation (aOR: 0.77 [95% CI: 0.74 to 0.79]) compared with surgical group (p < 0.001 for all). EVI group had higher risk of bleeding (aOR: 1.20 [95% CI: 1.18 to 1.23]) and vascular complications (3.2% vs 2.7%, aOR: 1.25 [95% CI: 1.19 to 1.30]) compared with surgical group (p < 0.001 for all). Within study period, EVI utilization increased in octogenarian patients from 2.6% to 8.9% (ptrend < 0.001); whereas use of surgical revascularization decreased from 11.6% to 5.2% (ptrend < 0.001). In conclusion, the utilization of EVI in octogenarians is increasing, and associated with lower risk of in-hospital mortality and adverse cardiovascular and limb outcomes as compared with surgical revascularization.

Copyright © 2021. Published by Elsevier Inc.

Am J Cardiol: 14 Apr 2021; 145:143-150
Pacha HM, Al-Khadra Y, Darmoch F, Soud M, ... Shishehbor MH, Alraies MC
Am J Cardiol: 14 Apr 2021; 145:143-150 | PMID: 33460607
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Older ...

This program is still in alpha version.