Topic: Journal Club Selection

Abstract

Empagliflozin in Heart Failure with a Preserved Ejection Fraction.

Anker SD, Butler J, Filippatos G, Ferreira JP, ... Packer M, EMPEROR-Preserved Trial Investigators
Background
Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain.
Methods
In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure.
Results
Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin.
Conclusions
Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 26 Aug 2021; epub ahead of print
Anker SD, Butler J, Filippatos G, Ferreira JP, ... Packer M, EMPEROR-Preserved Trial Investigators
N Engl J Med: 26 Aug 2021; epub ahead of print | PMID: 34449189
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Abstract

Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR.

Van Mieghem NM, Unverdorben M, Hengstenberg C, Möllmann H, ... Dangas GD, ENVISAGE-TAVI AF Investigators
Background
The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied.
Methods
We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding.
Results
A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P = 0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P = 0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11).
Conclusions
In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 27 Aug 2021; epub ahead of print
Van Mieghem NM, Unverdorben M, Hengstenberg C, Möllmann H, ... Dangas GD, ENVISAGE-TAVI AF Investigators
N Engl J Med: 27 Aug 2021; epub ahead of print | PMID: 34449183
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Abstract

Early Convalescent Plasma for High-Risk Outpatients with Covid-19.

Korley FK, Durkalski-Mauldin V, Yeatts SD, Schulman K, ... Callaway CW, SIREN-C3PO Investigators
Background
Early administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19.
Methods
In this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression. In addition, all the patients presented to the emergency department within 7 days after symptom onset and were in stable condition for outpatient management. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included the worst severity of illness on an 8-category ordinal scale, hospital-free days within 30 days after randomization, and death from any cause.
Results
A total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, -6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups.
Conclusions
The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression. (SIREN-C3PO ClinicalTrials.gov number, NCT04355767.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 17 Aug 2021; epub ahead of print
Korley FK, Durkalski-Mauldin V, Yeatts SD, Schulman K, ... Callaway CW, SIREN-C3PO Investigators
N Engl J Med: 17 Aug 2021; epub ahead of print | PMID: 34407339
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Abstract

Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.

Choueiri TK, Tomczak P, Park SH, Venugopal B, ... Powles T, KEYNOTE-564 Investigators
Background
Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence.
Methods
In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator\'s assessment. Overall survival was a key secondary end point. Safety was a secondary end point.
Results
A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred.
Conclusions
Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 18 Aug 2021; 385:683-694
Choueiri TK, Tomczak P, Park SH, Venugopal B, ... Powles T, KEYNOTE-564 Investigators
N Engl J Med: 18 Aug 2021; 385:683-694 | PMID: 34407342
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Abstract

AV junction ablation and cardiac resynchronization for patients with permanent atrial fibrillation and narrow QRS: the APAF-CRT mortality trial.

Brignole M, Pentimalli F, Palmisano P, Landolina M, ... Rienstra M, Van Gelder IC
Aims 
In patients with atrial fibrillation (AF) and heart failure (HF), strict and regular rate control with atrioventricular junction ablation and biventricular pacemaker (Ablation + CRT) has been shown to be superior to pharmacological rate control in reducing HF hospitalizations. However, whether it also improves survival is unknown.
Methods and results 
In this international, open-label, blinded outcome trial, we randomly assigned patients with severely symptomatic permanent AF >6 months, narrow QRS (≤110 ms) and at least one HF hospitalization in the previous year to Ablation + CRT or to pharmacological rate control. We hypothesized that Ablation + CRT is superior in reducing the primary endpoint of all-cause mortality. A total of 133 patients were randomized. The mean age was 73 ± 10 years, and 62 (47%) were females. The trial was stopped for efficacy at interim analysis after a median of 29 months of follow-up per patient. The primary endpoint occurred in 7 patients (11%) in the Ablation + CRT arm and in 20 patients (29%) in the Drug arm [hazard ratio (HR) 0.26, 95% confidence interval (CI) 0.10-0.65; P = 0.004]. The estimated death rates at 2 years were 5% and 21%, respectively; at 4 years, 14% and 41%. The benefit of Ablation + CRT of all-cause mortality was similar in patients with ejection fraction (EF) ≤35% and in those with >35%. The secondary endpoint combining all-cause mortality or HF hospitalization was significantly lower in the Ablation + CRT arm [18 (29%) vs. 36 (51%); HR 0.40, 95% CI 0.22-0.73; P = 0.002].
Conclusions 
Ablation + CRT was superior to pharmacological therapy in reducing mortality in patients with permanent AF and narrow QRS who were hospitalized for HF, irrespective of their baseline EF.
Study registration
ClinicalTrials.gov Identifier: NCT02137187.

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

Eur Heart J: 27 Aug 2021; epub ahead of print
Brignole M, Pentimalli F, Palmisano P, Landolina M, ... Rienstra M, Van Gelder IC
Eur Heart J: 27 Aug 2021; epub ahead of print | PMID: 34453840
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Abstract

Cryoballoon Ablation as Initial Treatment for Atrial Fibrillation: JACC State-of-the-Art Review.

Andrade JG, Wazni OM, Kuniss M, Hawkins NM, ... Wells GA, Turgeon RD
Atrial fibrillation (AF), the most common sustained arrhythmia observed in clinical practice, is a chronic and progressive disorder characterized by exacerbations and remissions. Guidelines recommend antiarrhythmic drugs as the initial therapy for the maintenance of sinus rhythm; however, antiarrhythmic drugs have modest efficacy to maintain sinus rhythm and can be associated with significant adverse effects. An initial treatment strategy of cryoballoon catheter ablation in patients with treatment-naïve AF has been shown to significantly improve arrhythmia outcomes (freedom from any, or symptomatic atrial tachyarrhythmia), produce clinically meaningful improvements in patient-reported outcomes (symptoms and quality of life), and significantly reduce subsequent health care resource use (hospitalization), and it does not increase the risk of serious or any adverse events compared with initial antiarrhythmic drug therapy. These findings are relevant to inform patients, providers, and health care systems regarding the initial choice of rhythm-control therapy in patients with treatment-naïve AF.

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

J Am Coll Cardiol: 30 Aug 2021; 78:914-930
Andrade JG, Wazni OM, Kuniss M, Hawkins NM, ... Wells GA, Turgeon RD
J Am Coll Cardiol: 30 Aug 2021; 78:914-930 | PMID: 34446164
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Abstract

The Characteristics and Outcomes of Native Aortic Valve Thrombosis: A Systematic Review.

Alajaji W, Hornick JM, Malek E, Klein AL
Background
There is a lack of knowledge in the current medical literature about native aortic valve thrombosis.
Objectives
The aim of this systematic review was to summarize the characteristics, presentations, underlying etiologies, and outcomes of native aortic valve thrombosis and to present a meta-analysis of the best available data.
Methods
The authors performed a literature search, identified published cases of patients with native aortic valve thrombosis, and pooled the data in this meta-analysis. The statistical analysis included calculations of the prevalence of the various presentations, underlying etiologies, aortic cusp involvement, as well as choices of diagnostic testing. They calculated the sensitivities of the various diagnostic testing as well as in-hospital mortality event rates and the univariate ORs of the risk factors for poor outcomes.
Results
The search strategy and screening process yielded 74 cases of native aortic valve thrombosis, which are included in this meta-analysis. The data revealed that the most common presentation was myocardial infarction in 36%, and the most common underlying etiology was hypercoagulable state in 30%. In-hospital clinical deterioration after presentation including recurrent embolism occurred in ∼38%, and in-hospital mortality rate was ∼20%.
Conclusions
Native aortic valve thrombosis is clinically relevant, especially in patients presenting with embolic events. Awareness about native aortic valve or root thrombosis as well as its underlying etiologies, diagnostic work-up, and management is essential, because this condition can be associated with poor outcomes.

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

J Am Coll Cardiol: 23 Aug 2021; 78:811-824
Alajaji W, Hornick JM, Malek E, Klein AL
J Am Coll Cardiol: 23 Aug 2021; 78:811-824 | PMID: 34412815
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Abstract

De-Escalation of Dual Antiplatelet Therapy in Patients With Acute Coronary Syndromes.

Shoji S, Kuno T, Fujisaki T, Takagi H, ... Latib A, Kohsaka S
Background
Balancing the effects of dual antiplatelet therapy (DAPT) in the era of potent P2Y12 inhibitors has become a cornerstone of acute coronary syndrome (ACS) management. Recent randomized controlled trials (RCTs) have investigated DAPT de-escalation to decrease the risk of bleeding outcomes.
Objectives
The aim of this study was to compare the efficacy and safety outcomes of various DAPT strategies in patients with ACS, including de-escalation from a potent P2Y12 inhibitor to clopidogrel or low-dose prasugrel.
Methods
MEDLINE and EMBASE were searched through January 2021 for RCTs investigating the efficacy and safety of DAPT in patients with ACS, and a network meta-analysis was conducted. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, and stroke. The primary bleeding outcome was trial-defined major or minor bleeding.
Results
Our search identified 15 eligible RCTs, including 55,798 patients with ACS. De-escalation therapy was associated with reduced risk of primary bleeding outcomes (HR: 0.48 [95% CI: 0.30-0.77] vs clopidogrel; HR: 0.32 [95% CI: 0.20-0.52] vs ticagrelor; HR: 0.36 [95% CI: 0.24-0.55] vs standard-dose prasugrel; and HR: 0.40 [95% CI: 0.22-0.75] vs low-dose prasugrel) without negatively affecting primary efficacy outcomes. There were no significant differences in ischemic or bleeding outcomes between de-escalation to clopidogrel or low-dose prasugrel.
Conclusions
Compared with other established uses of DAPT, de-escalation was the most effective strategy for ACS treatment, resulting in fewer bleeding events without increasing ischemic events.

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

J Am Coll Cardiol: 23 Aug 2021; 78:763-777
Shoji S, Kuno T, Fujisaki T, Takagi H, ... Latib A, Kohsaka S
J Am Coll Cardiol: 23 Aug 2021; 78:763-777 | PMID: 34275697
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Abstract

Statin associated lower cancer risk and related mortality in patients with heart failure.

Ren QW, Yu SY, Teng TK, Li X, ... Lam CSP, Yiu KH
Aims 
Patients with heart failure (HF) have an increased risk of incident cancer. Data relating to the association of statin use with cancer risk and cancer-related mortality among patients with HF are sparse.
Methods and results 
Using a previously validated territory-wide clinical information registry, statin use was ascertained among all eligible patients with HF (n = 87 102) from 2003 to 2015. Inverse probability of treatment weighting was used to balance baseline covariates between statin nonusers (n = 50 926) with statin users (n = 36 176). Competing risk regression with Cox proportional-hazard models was performed to estimate the risk of cancer and cancer-related mortality associated with statin use. Of all eligible subjects, the mean age was 76.5 ± 12.8 years, and 47.8% was male. Over a median follow-up of 4.1 years (interquartile range: 1.6-6.8), 11 052 (12.7%) were diagnosed with cancer. Statin use (vs. none) was associated with a 16% lower risk of cancer incidence [multivariable adjusted subdistribution hazard ratio (SHR) = 0.84; 95% confidence interval (CI), 0.80-0.89]. This inverse association with risk of cancer was duration dependent; as compared with short-term statin use (3 months to <2 years), the adjusted SHR was 0.99 (95% CI, 0.87-1.13) for 2 to <4 years of use, 0.82 (95% CI, 0.70-0.97) for 4 to <6 years of use, and 0.78 (95% CI, 0.65-0.93) for ≥6 years of use. Ten-year cancer-related mortality was 3.8% among statin users and 5.2% among nonusers (absolute risk difference, -1.4 percentage points [95% CI, -1.6% to -1.2%]; adjusted SHR = 0.74; 95% CI, 0.67-0.81).
Conclusion 
Our study suggests that statin use is associated with a significantly lower risk of incident cancer and cancer-related mortality in HF, an association that appears to be duration dependent.

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

Eur Heart J: 20 Aug 2021; 42:3049-3059
Ren QW, Yu SY, Teng TK, Li X, ... Lam CSP, Yiu KH
Eur Heart J: 20 Aug 2021; 42:3049-3059 | PMID: 34157723
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Abstract

HINT1 (Histidine Triad Nucleotide-Binding Protein 1) Attenuates Cardiac Hypertrophy Via Suppressing HOXA5 (Homeobox A5) Expression.

Zhang Y, Da Q, Cao S, Yan K, ... Xie L, Ji Y
Background
Cardiac hypertrophy is an important prepathology of, and will ultimately lead to, heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. This study aims to elucidate the effects and mechanisms of HINT1 (histidine triad nucleotide-binding protein 1) in cardiac hypertrophy and heart failure.
Methods
HINT1 was downregulated in human hypertrophic heart samples compared with nonhypertrophic samples by mass spectrometry analysis. Hint1 knockout mice were challenged with transverse aortic constriction surgery. Cardiac-specific overexpression of HINT1 mice by intravenous injection of adeno-associated virus 9 (AAV9)-encoding Hint1 under the cTnT (cardiac troponin T) promoter were subjected to transverse aortic construction. Unbiased transcriptional analyses were used to identify the downstream targets of HINT1. AAV9 bearing shRNA against Hoxa5 (homeobox A5) was administrated to investigate whether the effects of HINT1 on cardiac hypertrophy were HOXA5-dependent. RNA sequencing analysis was performed to recapitulate possible changes in transcriptome profile.Coimmunoprecipitation assays and cellular fractionation analyses were conducted to examine the mechanism by which HINT1 regulates the expression of HOXA5.
Results
The reduction of HINT1 expression was observed in the hearts of hypertrophic patients and pressure overloaded-induced hypertrophic mice, respectively. In Hint1-deficient mice, cardiac hypertrophy deteriorated after transverse aortic construction. Conversely, cardiac-specific overexpression of HINT1 alleviated cardiac hypertrophy and dysfunction. Unbiased profiler polymerase chain reaction array showed HOXA5 is 1 target for HINT1, and the cardioprotective role of HINT1 was abolished by HOXA5 knockdown in vivo. Hoxa5 was identified to affect hypertrophy through the TGF-β (transforming growth factor β) signal pathway. Mechanically, HINT1 inhibited PKCβ1 (protein kinase C β type 1) membrane translocation and phosphorylation via direct interaction, attenuating the MEK/ERK/YY1 (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/yin yang 1) signal pathway, downregulating HOXA5 expression, and eventually attenuating cardiac hypertrophy.
Conclusions
HINT1 protects against cardiac hypertrophy through suppressing HOXA5 expression. These findings indicate that HINT1 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.



Circulation: 23 Aug 2021; 144:638-654
Zhang Y, Da Q, Cao S, Yan K, ... Xie L, Ji Y
Circulation: 23 Aug 2021; 144:638-654 | PMID: 34098726
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Abstract

Polymorphic Ventricular Tachycardia: Terminology, Mechanism, Diagnosis, and Emergency Therapy.

Viskin S, Chorin E, Viskin D, Hochstadt A, Schwartz AL, Rosso R
Polymorphic ventricular tachyarrhythmias are highly lethal arrhythmias. Several types of polymorphic ventricular tachycardia have similar electrocardiographic characteristics but have different modes of therapy. In fact, medications considered the treatment of choice for one form of polymorphic ventricular tachycardia, are contraindicated for the other. Yet confusion about terminology, and thus diagnosis and therapy, continues. We present an in-depth review of the different forms of polymorphic ventricular tachycardia and propose a practical step-by-step approach for distinguishing these malignant arrhythmias.



Circulation: 06 Sep 2021; 144:823-839
Viskin S, Chorin E, Viskin D, Hochstadt A, Schwartz AL, Rosso R
Circulation: 06 Sep 2021; 144:823-839 | PMID: 34491774
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Abstract

PKM1 Exerts Critical Roles in Cardiac Remodeling Under Pressure Overload in the Heart.

Li Q, Li C, Elnwasany A, Sharma G, ... Fu G, Wang ZV
Background
Metabolic remodeling precedes most alterations during cardiac hypertrophic growth under hemodynamic stress. The elevation of glucose utilization has been recognized as a hallmark of metabolic remodeling. However, its role in cardiac hypertrophic growth and heart failure in response to pressure overload remains to be fully illustrated. Here, we aimed to dissect the role of cardiac PKM1 (pyruvate kinase muscle isozyme 1) in glucose metabolic regulation and cardiac response under pressure overload.
Methods
Cardiac-specific deletion of PKM1 was achieved by crossing the floxed PKM1 mouse model with the cardiomyocyte-specific Cre transgenic mouse. PKM1 transgenic mice were generated under the control of tetracycline response elements, and cardiac-specific overexpression of PKM1 was induced by doxycycline administration in adult mice. Pressure overload was triggered by transverse aortic constriction. Primary neonatal rat ventricular myocytes were used to dissect molecular mechanisms. Moreover, metabolomics and nuclear magnetic resonance spectroscopy analyses were conducted to determine cardiac metabolic flux in response to pressure overload.
Results
We found that PKM1 expression is reduced in failing human and mouse hearts. It is important to note that cardiomyocyte-specific deletion of PKM1 exacerbates cardiac dysfunction and fibrosis in response to pressure overload. Inducible overexpression of PKM1 in cardiomyocytes protects the heart against transverse aortic constriction-induced cardiomyopathy and heart failure. At the mechanistic level, PKM1 is required for the augmentation of glycolytic flux, mitochondrial respiration, and ATP production under pressure overload. Furthermore, deficiency of PKM1 causes a defect in cardiomyocyte growth and a decrease in pyruvate dehydrogenase complex activity at both in vitro and in vivo levels.
Conclusions
These findings suggest that PKM1 plays an essential role in maintaining a homeostatic response in the heart under hemodynamic stress.



Circulation: 30 Aug 2021; 144:712-727
Li Q, Li C, Elnwasany A, Sharma G, ... Fu G, Wang ZV
Circulation: 30 Aug 2021; 144:712-727 | PMID: 34102853
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Abstract

Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Dependent Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

Satoh T, Wang L, Espinosa-Diez C, Wang B, ... McTiernan CF, Gladwin MT
Background
Many patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells.
Methods
We used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC β1 subunit (sGCβ1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress.
Results
Obese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCβ1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCβ1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH.
Conclusions
In heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCβ1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCβ1-cGMP signaling and ameliorate EIPH.



Circulation: 23 Aug 2021; 144:615-637
Satoh T, Wang L, Espinosa-Diez C, Wang B, ... McTiernan CF, Gladwin MT
Circulation: 23 Aug 2021; 144:615-637 | PMID: 34157861
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Abstract

Outcome and durability of mitral valve annuloplasty in atrial secondary mitral regurgitation.

Deferm S, Bertrand PB, Verhaert D, Dauw J, ... Vandervoort PM, Rega F
Objectives
Atrial secondary mitral regurgitation (ASMR) is a clinically distinct form of Carpentier type I mitral regurgitation (MR), rooted in excessive atrial and mitral annular dilation in the absence of left ventricular dysfunction. Mitral valve annuloplasty (MVA) is expected to provide a more durable solution for ASMR than for ventricular secondary MR (VSMR). Yet data on MR recurrence and outcome after MVA for ASMR are scarce. This study sought to investigate surgical outcomes and repair durability in patients with ASMR, as compared with a contemporary group of patients with VSMR.
Methods
Clinical and echocardiographic data from consecutive patients who underwent MVA to treat ASMR or VSMR in an academic centre were retrospectively analysed. Patient characteristics, operative outcomes, time to recurrence of ≥moderate MR and all-cause mortality were compared between patients with ASMR versus VSMR.
Results
Of the 216 patients analysed, 97 had ASMR opposed to 119 with VSMR and subvalvular leaflet tethering. Patients with ASMR were typically female (68.0% vs 33.6% in VSMR, p<0.001), with a history of atrial fibrillation (76.3% vs 33.6% in VSMR, p<0.001), paralleling a larger left atrial size (p<0.033). At a median follow-up of 3.3 (IQR 1.0-7.3) years, recurrence of ≥moderate MR was significantly lower in ASMR versus VSMR (7% vs 25% at 2 years, overall log-rank p=0.001), also when accounting for all-cause death as competing risk (subdistribution HR 0.50 in ASMR, 95% CI 0.29 to 0.88, p=0.016). Moreover, ASMR was associated with better overall survival compared with VSMR (adjusted HR 0.43 95% CI 0.22 to 0.82, p=0.011), independent from baseline European System for Cardiac Operative Risk Evaluation II surgical risk score.
Conclusion
Prognosis following MVA to treat ASMR is better, compared with VSMR as reflected by lower all-cause mortality and MR recurrence. Early distinction of secondary MR towards underlying ventricular versus atrial disease has important therapeutic implications.

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

Heart: 30 Aug 2021; 107:1503-1509
Deferm S, Bertrand PB, Verhaert D, Dauw J, ... Vandervoort PM, Rega F
Heart: 30 Aug 2021; 107:1503-1509 | PMID: 34415852
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Impact:
Abstract

Independent Association of Fatty Liver Index With Left Ventricular Diastolic Dysfunction in Subjects Without Medication.

Furuhashi M, Muranaka A, Yuda S, Tanaka M, ... Shimamoto K, Miura T
Nonalcoholic fatty liver disease has been reported to be potentially linked to cardiovascular disease. Fatty liver index (FLI) is a noninvasive and simple predictor of nonalcoholic fatty liver disease. However, little is known about the relationship between FLI and cardiac function, especially in a general population. We investigated the relationships of FLI with echocardiographic parameters in 185 subjects (men/women: 79/106) of the Tanno-Sobetsu Study, a population-based cohort, who were not being treated with any medication and who underwent echocardiography. FLI was negatively correlated with high-density lipoprotein cholesterol and peak myocardial velocity during early diastole (e\'; r = -0.342, p <0.001), an index of left ventricular (LV) diastolic function, and ratio of peak mitral velocities during early and late diastole (E/A) and was positively correlated with age, systolic and diastolic blood pressures, creatinine, uric acid, homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein, ratio of mitral to myocardial early diastolic peak velocity (E/e\'), left atrial volume index and LV mass index. No significant correlation was found between FLI and LV ejection fraction. Stepwise multivariable regression analysis showed that FLI was independently and negatively associated with e\' after adjustment of age, gender, high-density lipoprotein cholesterol, homeostasis model assessment of insulin resistance, and high-sensitivity C-reactive protein. Conversely, e\' was independently and negatively associated with FLI after adjustment of age, gender, systolic blood pressure, and LV ejection fraction. In conclusion, elevated FLI is independently associated with LV diastolic dysfunction in a general population without medication. FLI would be a novel marker of LV diastolic dysfunction as an early sign of myocardial injury.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 30 Aug 2021; epub ahead of print
Furuhashi M, Muranaka A, Yuda S, Tanaka M, ... Shimamoto K, Miura T
Am J Cardiol: 30 Aug 2021; epub ahead of print | PMID: 34474907
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Abstract

Analysis of Differences in Assessment of Left Ventricular Function on Echocardiography and Nuclear Perfusion Imaging.

Jacobson AF, Narula J, Tijssen J
Two widely used methods for left ventricular (LV) ejection fraction (EF) determination, echocardiography (echo) and gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), often have wide limits of agreement. Factors influencing discrepancies between core laboratory echo and MPI LVEF determinations were examined in a large series of heart failure (HF) subjects and normal controls. 879 HF and 101 control subjects had core lab analyses of echo and MPI (mean time between procedures 7-8 days). LVEF differences were analyzed using one-way analysis of variance and Bland-Altman plots. Relationships between LVEF differences and patient characteristics and outcome endpoints (mortality and arrhythmias) were explored with logistic regression, Cox proportional hazards models, and Kaplan-Meier survival analyses. There was a systematic difference between the 2 modalities; echo LVEF was higher with more severe LV dysfunction, MPI LVEF higher when systolic function was normal. LVEF results were within ±5% in only 37% of HF and 23% of control subjects. Considering discordance around the LVEF threshold 35%, there was disagreement between the 2 methods in 305 HF subjects (35%). Male gender (odds ratio (OR) = 0.200), atrial fibrillation (OR = 2.314), higher body mass index (OR = 1.051) and lower LV end-diastolic volume (OR = 0.985) were the strongest predictors of methodologic discordance. Cardiac event rates were highest if both LVEF values were ≤35% and lowest when both LVEF values were >35%. In conclusion, substantial disagreements between LVEF results by echo and MPI are common. HF patients with LVEF ≤35% by both techniques have the highest 2-year event risk.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 30 Sep 2021; 156:85-92
Jacobson AF, Narula J, Tijssen J
Am J Cardiol: 30 Sep 2021; 156:85-92 | PMID: 34344513
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Abstract

Screening of Native Valvular Heart Disease using a Pocket-Sized Transthoracic Echocardiography Device.

Kikoïne J, Hauguel-Moreau M, Hergault H, Aidan V, ... Szymanski C, Mansencal N
Aims
We assessed the performance of pocket-sized transthoracic echocardiography (pTTE) compared to standard transthoracic echocardiography (sTTE) and auscultation for an early screening of valvular heart disease (VHD). Early diagnosis of significant VHD is a real challenge, and enables appropriate follow-up and implementation of the best therapeutic strategy.
Methods
STTE, pTTE and auscultation were performed by three different experienced physicians in 284 unselected patients. All cases of VHD detected by each of these three techniques were noted. sTTE was the gold standard. Each physician performed one examination and was blinded to the results of other exams.
Results
We diagnosed a total of 301 VHD cases with a large predominance of regurgitant lesions: 269 (89.3%) of regurgitant VHD and 32 (10.7%) of stenotic VHD. pTTE was highly sensitive (85.7%) and specific (97.9%) for screening VHD, while auscultation detected only 54.1%. All significant VHD cases (at least mild severity) were detected by pTTE. The weighted Kappa between pTTE and sTTE for the assessment of mitral regurgitation was 0.71 (95% CI, 0.70-0.72), indicating good agreement. The weighted Kappa between pTTE and sTTE for the assessment of aortic regurgitation and aortic stenosis was 0.97 (95% CI, 0.96-0.98) and 0.98 (95% CI, 0.97-0.99), respectively, indicating excellent agreement.
Conclusion
PTTE performed by physicians with a level III competency in echocardiography is reliable for identifying significant VHD and should be proposed as a new screening tool.

Copyright © 2021. Published by Elsevier Inc.

J Am Soc Echocardiogr: 26 Aug 2021; epub ahead of print
Kikoïne J, Hauguel-Moreau M, Hergault H, Aidan V, ... Szymanski C, Mansencal N
J Am Soc Echocardiogr: 26 Aug 2021; epub ahead of print | PMID: 34461249
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Abstract

Three-Dimensional Echocardiographic Left Atrial Appendage Volumetric Analysis.

Meltzer SN, Phatak PM, Fazlalizadeh H, Chang I, ... Kumar P, Medvedofsky D
Background
Left atrial appendage (LAA) echocardiographic assessment is difficult because of the complex shape and relatively small size of the LAA. Three-dimensional (3D) echocardiographic imaging can overcome the limitations of two-dimensional imaging. Pulsed-wave Doppler is the only currently standard LAA functional parameter. The aim of this study was to test a new approach for 3D echocardiographic volumetric analysis to obtain LAA ejection fraction (EF), its size and shape.
Methods
Transesophageal two-dimensional and 3D LAA images were prospectively obtained in 159 consecutive patients. LAA volumes were measured from 3D echocardiographic images using available software. Pulsed-wave Doppler was considered the reference value for LAA function and was used for comparison with LAA EF. Comparison with cardiac computed tomography was performed in a subgroup of 32 patients. Comparisons included linear regression and Bland-Altman analyses. Repeated measurements were performed to assess measurement variability.
Results
Nine patients were excluded because of suboptimal image quality (94% feasibility). Three-dimensional LAA calculated EF was in good agreement with LAA pulsed-wave measurements. Three-dimensional morphologic evaluation showed that 43% of the patients had \"chicken wing,\" 33% \"cactus,\" 19% \"windsock,\" and 5% cauliflower shapes. At the time of data acquisition, patients with atrial fibrillation had nonsignificantly larger LAA end-systolic and end-diastolic volumes, leading to lower calculated EFs. Three-dimensional echocardiographic LAA end-systolic volumes were in good agreement with cardiac computed tomography (r = 0.75), with small biases (mean, -2.5 ± 3.9 ml). Reproducibility was better for larger LAA volumes.
Conclusions
A novel 3D echocardiographic approach can determine the geometry, size, and function of the LAA. A new parameter, LAA EF, provides functional quantitation.

Copyright © 2021 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

J Am Soc Echocardiogr: 30 Aug 2021; 34:987-995
Meltzer SN, Phatak PM, Fazlalizadeh H, Chang I, ... Kumar P, Medvedofsky D
J Am Soc Echocardiogr: 30 Aug 2021; 34:987-995 | PMID: 33775733
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This program is still in alpha version.