Topic: Journal Club Selection

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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Impact:
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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Impact:
Abstract

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19.

Weinreich DM, Sivapalasingam S, Norton T, Ali S, ... Yancopoulos GD, Trial Investigators
Background
In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern.
Methods
In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated.
Results
Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log10 copies per milliliter (95% confidence interval [CI], -0.90 to -0.53) in the 1200-mg group and -0.86 log10 copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups.
Conclusions
REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 28 Sep 2021; epub ahead of print
Weinreich DM, Sivapalasingam S, Norton T, Ali S, ... Yancopoulos GD, Trial Investigators
N Engl J Med: 28 Sep 2021; epub ahead of print | PMID: 34587383
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Impact:
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

Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation.

Andrade JG, Wells GA, Deyell MW, Bennett M, ... Verma A, EARLY-AF Investigators
Background
Guidelines recommend a trial of one or more antiarrhythmic drugs before catheter ablation is considered in patients with atrial fibrillation. However, first-line ablation may be more effective in maintaining sinus rhythm.
Methods
We randomly assigned 303 patients with symptomatic, paroxysmal, untreated atrial fibrillation to undergo catheter ablation with a cryothermy balloon or to receive antiarrhythmic drug therapy for initial rhythm control. All the patients received an implantable cardiac monitoring device to detect atrial tachyarrhythmia. The follow-up period was 12 months. The primary end point was the first documented recurrence of any atrial tachyarrhythmia (atrial fibrillation, atrial flutter, or atrial tachycardia) between 91 and 365 days after catheter ablation or the initiation of an antiarrhythmic drug. The secondary end points included freedom from symptomatic arrhythmia, the atrial fibrillation burden, and quality of life.
Results
At 1 year, a recurrence of atrial tachyarrhythmia had occurred in 66 of 154 patients (42.9%) assigned to undergo ablation and in 101 of 149 patients (67.8%) assigned to receive antiarrhythmic drugs (hazard ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66; P<0.001). Symptomatic atrial tachyarrhythmia had recurred in 11.0% of the patients who underwent ablation and in 26.2% of those who received antiarrhythmic drugs (hazard ratio, 0.39; 95% CI, 0.22 to 0.68). The median percentage of time in atrial fibrillation was 0% (interquartile range, 0 to 0.08) with ablation and 0.13% (interquartile range, 0 to 1.60) with antiarrhythmic drugs. Serious adverse events occurred in 5 patients (3.2%) who underwent ablation and in 6 patients (4.0%) who received antiarrhythmic drugs.
Conclusions
Among patients receiving initial treatment for symptomatic, paroxysmal atrial fibrillation, there was a significantly lower rate of atrial fibrillation recurrence with catheter cryoballoon ablation than with antiarrhythmic drug therapy, as assessed by continuous cardiac rhythm monitoring. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 Jan 2021; 384:305-315
Andrade JG, Wells GA, Deyell MW, Bennett M, ... Verma A, EARLY-AF Investigators
N Engl J Med: 27 Jan 2021; 384:305-315 | PMID: 33197159
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Impact:
Abstract

Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation.

Wazni OM, Dandamudi G, Sood N, Hoyt R, ... Nissen SE, STOP AF First Trial Investigators
Background
In patients with symptomatic paroxysmal atrial fibrillation that has not responded to medication, catheter ablation is more effective than antiarrhythmic drug therapy for maintaining sinus rhythm. However, the safety and efficacy of cryoballoon ablation as initial first-line therapy have not been established.
Methods
We performed a multicenter trial in which patients 18 to 80 years of age who had paroxysmal atrial fibrillation for which they had not previously received rhythm-control therapy were randomly assigned (1:1) to receive treatment with antiarrhythmic drugs (class I or III agents) or pulmonary vein isolation with a cryoballoon. Arrhythmia monitoring included 12-lead electrocardiography conducted at baseline and at 1, 3, 6, and 12 months; patient-activated telephone monitoring conducted weekly and when symptoms were present during months 3 through 12; and 24-hour ambulatory monitoring conducted at 6 and 12 months. The primary efficacy end point was treatment success (defined as freedom from initial failure of the procedure or atrial arrhythmia recurrence after a 90-day blanking period to allow recovery from the procedure or drug dose adjustment, evaluated in a Kaplan-Meier analysis). The primary safety end point was assessed in the ablation group only and was a composite of several procedure-related and cryoballoon system-related serious adverse events.
Results
Of the 203 participants who underwent randomization and received treatment, 104 underwent ablation, and 99 initially received drug therapy. In the ablation group, initial success of the procedure was achieved in 97% of patients. The Kaplan-Meier estimate of the percentage of patients with treatment success at 12 months was 74.6% (95% confidence interval [CI], 65.0 to 82.0) in the ablation group and 45.0% (95% CI, 34.6 to 54.7) in the drug-therapy group (P<0.001 by log-rank test). Two primary safety end-point events occurred in the ablation group (Kaplan-Meier estimate of the percentage of patients with an event within 12 months, 1.9%; 95% CI, 0.5 to 7.5).
Conclusions
Cryoballoon ablation as initial therapy was superior to drug therapy for the prevention of atrial arrhythmia recurrence in patients with paroxysmal atrial fibrillation. Serious procedure-related adverse events were uncommon. (Supported by Medtronic; STOP AF First ClinicalTrials.gov number, NCT03118518.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 Jan 2021; 384:316-324
Wazni OM, Dandamudi G, Sood N, Hoyt R, ... Nissen SE, STOP AF First Trial Investigators
N Engl J Med: 27 Jan 2021; 384:316-324 | PMID: 33197158
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Impact:
Abstract

Macrophage NFATc3 prevents foam cell formation and atherosclerosis: evidence and mechanisms.

Liu X, Guo JW, Lin XC, Tuo YH, ... Zhou JG, Liang SJ
Aims
Our previous study demonstrated that Ca2+ influx through the Orai1 store-operated Ca2+ channel in macrophages contributes to foam cell formation and atherosclerosis via the calcineurin-ASK1 pathway, not the classical calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Moreover, up-regulation of NFATc3 in macrophages inhibits foam cell formation, suggesting that macrophage NFATc3 is a negative regulator of atherogenesis. Hence, this study investigated the precise role of macrophage NFATc3 in atherogenesis.
Methods and results
Macrophage-specific NFATc3 knockout mice were generated to determine the effect of NFATc3 on atherosclerosis in a mouse model of adeno-associated virus-mutant PCSK9-induced atherosclerosis. NFATc3 expression was decreased in macrophages within human and mouse atherosclerotic lesions. Moreover, NFATc3 levels in peripheral blood mononuclear cells from atherosclerotic patients were negatively associated with plaque instability. Furthermore, macrophage-specific ablation of NFATc3 in mice led to the atherosclerotic plaque formation, whereas macrophage-specific NFATc3 transgenic mice exhibited the opposite phenotype. NFATc3 deficiency in macrophages promoted foam cell formation by potentiating SR-A- and CD36-meditated lipid uptake. NFATc3 directly targeted and transcriptionally up-regulated miR-204 levels. Mature miR-204-5p suppressed SR-A expression via canonical regulation. Unexpectedly, miR-204-3p localized in the nucleus and inhibited CD36 transcription. Restoration of miR-204 abolished the proatherogenic phenotype observed in the macrophage-specific NFATc3 knockout mice, and blockade of miR-204 function reversed the beneficial effects of NFATc3 in macrophages.
Conclusion
Macrophage NFATc3 up-regulates miR-204 to reduce SR-A and CD36 levels, thereby preventing foam cell formation and atherosclerosis, indicating that the NFATc3/miR-204 axis may be a potential therapeutic target against atherosclerosis.

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: 26 Sep 2021; epub ahead of print
Liu X, Guo JW, Lin XC, Tuo YH, ... Zhou JG, Liang SJ
Eur Heart J: 26 Sep 2021; epub ahead of print | PMID: 34570211
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Abstract

Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism.

Haghikia A, Zimmermann F, Schumann P, Jasina A, ... Haghikia A, Landmesser U
Aims
Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism.
Methods and results
Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels.
Conclusion
Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.

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: 30 Sep 2021; epub ahead of print
Haghikia A, Zimmermann F, Schumann P, Jasina A, ... Haghikia A, Landmesser U
Eur Heart J: 30 Sep 2021; epub ahead of print | PMID: 34597388
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Impact:
Abstract

The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart \'OMics\' in AGEing (HOMAGE) randomized clinical trial.

Cleland JGF, Ferreira JP, Mariottoni B, Pellicori P, ... Zannad F, HOMAGE Trial Committees and Investigators
Aims 
To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure.
Methods and results 
Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): -0.15; 95% confidence interval (CI) -0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: -8.1; 95% CI -11.9 to -4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: -2.9; 95% CI -4.3 to -1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: -10; 95% CI -13 to -7 mmHg; P < 0.0001), left atrial volume (mdiff: -1; 95% CI -2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: -57; 95% CI -81 to -33 ng/L; P < 0.0001) were reduced in those assigned spironolactone.
Conclusions 
Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 10 Feb 2021; 42:684-696
Cleland JGF, Ferreira JP, Mariottoni B, Pellicori P, ... Zannad F, HOMAGE Trial Committees and Investigators
Eur Heart J: 10 Feb 2021; 42:684-696 | PMID: 33215209
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Impact:
Abstract

Troponin-Guided Coronary Computed Tomographic Angiography After Exclusion of Myocardial Infarction.

Lee KK, Bularga A, O\'Brien R, Ferry AV, ... Gray AJ, Mills NL
Background
Patients with suspected acute coronary syndrome in whom myocardial infarction has been excluded are at risk of future adverse cardiac events.
Objectives
This study evaluated the usefulness of high-sensitivity cardiac troponin I (hs-cTnI) to select patients for further investigation after myocardial infarction has been excluded.
Methods
This is a prospective cohort study of patients presenting to the emergency department with suspected acute coronary syndrome and hs-cTnI concentrations below the sex-specific 99th percentile. Patients were recruited in a 2:1 fashion, stratified by peak hs-cTnI concentration above and below the risk stratification threshold of 5 ng/L. All patients underwent coronary computed tomography angiography (CCTA) after hospital discharge.
Results
Overall, 250 patients were recruited (61.4 ± 12.2 years 31% women) in whom 62.4% (156 of 250 patients) had coronary artery disease (CAD). Patients with intermediate hs-cTnI concentrations (between 5 ng/L and the sex-specific 99th percentile) were more likely to have CAD than those with hs-cTnI concentrations <5 ng/L (71.9% [120 of 167 patients] vs 43.4% [36 of 83 patients]; odds ratio: 3.33; 95% CI: 1.92-5.78). Conversely, there was no association between anginal symptoms and CAD (63.2% [67 of 106 patients] vs 61.8% [89 of 144 patients]; odds ratio: 0.92; 95% CI: 0.48-1.76). Most patients with CAD did not have a previous diagnosis (53.2%; 83 of 156 patients) and were not on antiplatelet and statin therapies (63.5%; 99 of 156 patients) before they underwent CCTA.
Conclusions
In patients who had myocardial infarction excluded, CAD was 3× more likely in those with intermediate hs-cTnI concentrations compared with low hs-cTnI concentrations. In such patients, CCTA could help to identify those with occult CAD and to target preventative treatments, thereby improving clinical outcomes.

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

J Am Coll Cardiol: 04 Oct 2021; 78:1407-1417
Lee KK, Bularga A, O'Brien R, Ferry AV, ... Gray AJ, Mills NL
J Am Coll Cardiol: 04 Oct 2021; 78:1407-1417 | PMID: 34593122
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Impact:
Abstract

Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

Teerlink JR, Diaz R, Felker GM, McMurray JJV, ... Kurtz CE, GALACTIC-HF Investigators
Background
The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown.
Methods
We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes.
Results
During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups.
Conclusions
Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 13 Jan 2021; 384:105-116
Teerlink JR, Diaz R, Felker GM, McMurray JJV, ... Kurtz CE, GALACTIC-HF Investigators
N Engl J Med: 13 Jan 2021; 384:105-116 | PMID: 33185990
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Impact:
Abstract

3\' untranslated region of Ckip-1 inhibits cardiac hypertrophy independently of its cognate protein.

Zhao Y, Ling S, Li J, Zhong G, ... Chang YZ, Li Y
Aims
3\' untranslated region (3\' UTR) of mRNA is more conserved than other non-coding sequences in vertebrate genomes, and its sequence space has substantially expanded during the evolution of higher organisms, which substantiates their significance in biological regulation. However, the independent role of 3\' UTR in cardiovascular disease was largely unknown.
Methods and results
Using bioinformatics, RNA fluorescent in situ hybridization and quantitative real-time polymerase chain reaction, we found that 3\' UTR and coding sequence regions of Ckip-1 mRNA exhibited diverse expression and localization in cardiomyocytes. We generated cardiac-specific Ckip-1 3\' UTR overexpression mice under wild type and casein kinase 2 interacting protein-1 (CKIP-1) knockout background. Cardiac remodelling was assessed by histological, echocardiography, and molecular analyses at 4 weeks after transverse aortic constriction (TAC) surgery. The results showed that cardiac Ckip-1 3\' UTR significantly inhibited TAC-induced cardiac hypertrophy independent of CKIP-1 protein. To determine the mechanism of Ckip-1 3\' UTR in cardiac hypertrophy, we performed transcriptome and metabolomics analyses, RNA immunoprecipitation, biotin-based RNA pull-down, and reporter gene assays. We found that Ckip-1 3\' UTR promoted fatty acid metabolism through AMPK-PPARα-CPT1b axis, leading to its protection against pathological cardiac hypertrophy. Moreover, Ckip-1 3\' UTR RNA therapy using adeno-associated virus obviously alleviates cardiac hypertrophy and improves heart function.
Conclusions
These findings disclose that Ckip-1 3\' UTR inhibits cardiac hypertrophy independently of its cognate protein. Ckip-1 3\' UTR is an effective RNA-based therapy tool for treating cardiac hypertrophy and heart failure.

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: 20 Sep 2021; 42:3786-3799
Zhao Y, Ling S, Li J, Zhong G, ... Chang YZ, Li Y
Eur Heart J: 20 Sep 2021; 42:3786-3799 | PMID: 34347073
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Impact:
Abstract

Stress Cardiac Magnetic Resonance Myocardial Perfusion Imaging: JACC Review Topic of the Week.

Patel AR, Salerno M, Kwong RY, Singh A, Heydari B, Kramer CM
Stress cardiovascular magnetic resonance imaging (CMR) is a cost-effective, noninvasive test that accurately assesses myocardial ischemia, myocardial viability, and cardiac function without the need for ionizing radiation. There is a large body of literature, including randomized controlled trials, validating its diagnostic performance, risk stratification capabilities, and ability to guide appropriate use of coronary intervention. Specifically, stress CMR has shown higher diagnostic sensitivity than single-photon emission computed tomography imaging in detecting angiographically significant coronary artery disease. Stress CMR is particularly valuable for the evaluation of patients with moderate to high pretest probability of having stable ischemic heart disease and for patients known to have challenging imaging characteristics, including women, individuals with prior revascularization, and those with left ventricular dysfunction. This paper reviews the basics principles of stress CMR, the data supporting its clinical use, the added-value of myocardial blood flow quantification, and the assessment of myocardial function and viability routinely obtained during a stress CMR study.

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

J Am Coll Cardiol: 18 Oct 2021; 78:1655-1668
Patel AR, Salerno M, Kwong RY, Singh A, Heydari B, Kramer CM
J Am Coll Cardiol: 18 Oct 2021; 78:1655-1668 | PMID: 34649703
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Abstract

COVID-19 in Adults With Congenital Heart Disease.

Broberg CS, Kovacs AH, Sadeghi S, Rosenbaum MS, ... Cotts TB, Aboulhosn JA
Background
Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications.
Objectives
This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes.
Methods
Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide. Data collection included anatomic diagnosis and subsequent interventions, comorbidities, medications, echocardiographic findings, presenting symptoms, course of illness, and outcomes. Predictors of death or severe infection were determined.
Results
From 58 adult CHD centers, the study included 1,044 infected patients (age: 35.1 ± 13.0 years; range 18 to 86 years; 51% women), 87% of whom had laboratory-confirmed coronavirus infection. The cohort included 118 (11%) patients with single ventricle and/or Fontan physiology, 87 (8%) patients with cyanosis, and 73 (7%) patients with pulmonary hypertension. There were 24 COVID-related deaths (case/fatality: 2.3%; 95% confidence interval: 1.4% to 3.2%). Factors associated with death included male sex, diabetes, cyanosis, pulmonary hypertension, renal insufficiency, and previous hospital admission for heart failure. Worse physiological stage was associated with mortality (p = 0.001), whereas anatomic complexity or defect group were not.
Conclusions
COVID-19 mortality in adults with CHD is commensurate with the general population. The most vulnerable patients are those with worse physiological stage, such as cyanosis and pulmonary hypertension, whereas anatomic complexity does not appear to predict infection severity.

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

J Am Coll Cardiol: 05 Jan 2021; 77:1644-1655
Broberg CS, Kovacs AH, Sadeghi S, Rosenbaum MS, ... Cotts TB, Aboulhosn JA
J Am Coll Cardiol: 05 Jan 2021; 77:1644-1655 | PMID: 33795039
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Abstract

Clinical Risk Prediction in Patients With Left Ventricular Myocardial Noncompaction.

Casas G, Limeres J, Oristrell G, Gutierrez-Garcia L, ... Ferreira-González I, Rodríguez-Palomares JF
Background
Left ventricular noncompaction (LVNC) is a heterogeneous entity with uncertain prognosis.
Objectives
This study sought to develop and validate a prediction model of major adverse cardiovascular events (MACE) and to identify LVNC cases without events during long-term follow-up.
Methods
This is a retrospective longitudinal multicenter cohort study of consecutive patients fulfilling LVNC criteria by echocardiography or cardiovascular magnetic resonance. MACE were defined as heart failure (HF), ventricular arrhythmias (VAs), systemic embolisms, or all-cause mortality.
Results
A total of 585 patients were included (45 ± 20 years of age, 57% male). LV ejection fraction (LVEF) was 48% ± 17%, and 18% presented late gadolinium enhancement (LGE). After a median follow-up of 5.1 years, MACE occurred in 223 (38%) patients: HF in 110 (19%), VAs in 87 (15%), systemic embolisms in 18 (3%), and 34 (6%) died. LVEF was the main variable independently associated with MACE (P < 0.05). LGE was associated with HF and VAs in patients with LVEF >35% (P < 0.05). A prediction model of MACE was developed using Cox regression, composed by age, sex, electrocardiography, cardiovascular risk factors, LVEF, and family aggregation. C-index was 0.72 (95% confidence interval: 0.67-0.75) in the derivation cohort and 0.72 (95% confidence interval: 0.71-0.73) in an external validation cohort. Patients with no electrocardiogram abnormalities, LVEF ≥50%, no LGE, and negative family screening presented no MACE at follow-up.
Conclusions
LVNC is associated with an increased risk of heart failure and ventricular arrhythmias. LVEF is the variable most strongly associated with MACE; however, LGE confers additional risk in patients without severe systolic dysfunction. A risk prediction model is developed and validated to guide management.

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

J Am Coll Cardiol: 16 Aug 2021; 78:643-662
Casas G, Limeres J, Oristrell G, Gutierrez-Garcia L, ... Ferreira-González I, Rodríguez-Palomares JF
J Am Coll Cardiol: 16 Aug 2021; 78:643-662 | PMID: 34384546
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Abstract

Predictors of Device-Related Thrombus Following Percutaneous Left Atrial Appendage Occlusion.

Simard T, Jung RG, Lehenbauer K, Piayda K, ... Holmes DR, Alkhouli M
Background
Device-related thrombus (DRT) has been considered an Achilles\' heel of left atrial appendage occlusion (LAAO). However, data on DRT prediction remain limited.
Objectives
This study constructed a DRT registry via a multicenter collaboration aimed to assess outcomes and predictors of DRT.
Methods
Thirty-seven international centers contributed LAAO cases with and without DRT (device-matched and temporally related to the DRT cases). This study described the management patterns and mid-term outcomes of DRT and assessed patient and procedural predictors of DRT.
Results
A total of 711 patients (237 with and 474 without DRT) were included. Follow-up duration was similar in the DRT and no-DRT groups, median 1.8 years (interquartile range: 0.9-3.0 years) versus 1.6 years (interquartile range: 1.0-2.9 years), respectively (P = 0.76). DRTs were detected between days 0 to 45, 45 to 180, 180 to 365, and >365 in 24.9%, 38.8%, 16.0%, and 20.3% of patients. DRT presence was associated with a higher risk of the composite endpoint of death, ischemic stroke, or systemic embolization (HR: 2.37; 95% CI, 1.58-3.56; P < 0.001) driven by ischemic stroke (HR: 3.49; 95% CI: 1.35-9.00; P = 0.01). At last known follow-up, 25.3% of patients had DRT. Discharge medications after LAAO did not have an impact on DRT. Multivariable analysis identified 5 DRT risk factors: hypercoagulability disorder (odds ratio [OR]: 17.50; 95% CI: 3.39-90.45), pericardial effusion (OR: 13.45; 95% CI: 1.46-123.52), renal insufficiency (OR: 4.02; 95% CI: 1.22-13.25), implantation depth >10 mm from the pulmonary vein limbus (OR: 2.41; 95% CI: 1.57-3.69), and non-paroxysmal atrial fibrillation (OR: 1.90; 95% CI: 1.22-2.97). Following conversion to risk factor points, patients with ≥2 risk points for DRT had a 2.1-fold increased risk of DRT compared with those without any risk factors.
Conclusions
DRT after LAAO is associated with ischemic events. Patient- and procedure-specific factors are associated with the risk of DRT and may aid in risk stratification of patients referred for LAAO.

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

J Am Coll Cardiol: 26 Jul 2021; 78:297-313
Simard T, Jung RG, Lehenbauer K, Piayda K, ... Holmes DR, Alkhouli M
J Am Coll Cardiol: 26 Jul 2021; 78:297-313 | PMID: 34294267
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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
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Abstract

Single Nuclei Sequencing Reveals Novel Insights Into the Regulation of Cellular Signatures in Children With Dilated Cardiomyopathy.

Nicin L, Abplanalp WT, Schänzer A, Sprengel A, ... Rupp S, Dimmeler S
Background
Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent, and large cohort studies are lacking. Progress may be achieved through personalized therapy that takes age- and disease-related pathophysiology, pathology, and molecular fingerprints into account. We present single nuclei RNA sequencing from pediatric patients with DCM as the next step in identifying cellular signatures.
Methods
We performed single nuclei RNA sequencing with heart tissues from 6 children with DCM with an age of 0.5, 0.75, 5, 6, 12, and 13 years. Unsupervised clustering of 18 211 nuclei led to the identification of 14 distinct clusters with 6 major cell types.
Results
The number of nuclei in fibroblast clusters increased with age in patients with DCM, a finding that was confirmed by histological analysis and was consistent with an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging. Fibroblasts of patients with DCM >6 years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans, switch in thrombospondin isoforms, and signatures of fibroblast activation. In addition, a population of cardiomyocytes with a high proregenerative profile was identified in infant patients with DCM but was absent in children >6 years of age. This cluster showed high expression of cell cycle activators such as cyclin D family members, increased glycolytic metabolism and antioxidative genes, and alterations in ß-adrenergic signaling genes.
Conclusions
Novel insights into the cellular transcriptomes of hearts from pediatric patients with DCM provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched proregenerative signatures in infants.



Circulation: 26 Apr 2021; 143:1704-1719
Nicin L, Abplanalp WT, Schänzer A, Sprengel A, ... Rupp S, Dimmeler S
Circulation: 26 Apr 2021; 143:1704-1719 | PMID: 33618539
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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

Move more - be happier? Physical Activity and Health-Related Quality of Life in Children with Congenital Heart Disease.

Brudy L, Meyer M, Oberhoffer R, Ewert P, Müller J
Objective
This cross-sectional study aimed to determine whether there is an association between objectively assessed physical activity (PA) and health-related quality of life (HRQoL) in children with CHD.
Patients and methods
From September 2017 to January 2021, 343 children with CHD (12.1 ± 3.3 years, 135 girls) provided valid PA data after a 7-day objective PA assessment. PA was evaluated as average daily steps and moderate-to-vigorous physical activity (MVPA) minutes assessed via wearable bracelet Garmin vivofit® Jr. These children also completed the KINDL® - a 24 Likert-scaled item questionnaire assessing HRQoL in the six dimensions physical well-being, emotional well-being, self-esteem, family, friends and everyday functioning.
Results
Daily Steps (r=.166, p=.003) and daily MVPA minutes (r=.134, p=.017,) were both correlated to total KINDL® score. Furthermore, both steps and MVPA were associated with the subscales physical well-being (steps: r=.165 p=.003; MVPA: r=.129, p=.022), friends (steps: r=.210, p<.001, MVPA: r=.179, p=.001), and steps also to everyday functioning (r=.142, p=.012). Logistic regression showed each MVPA minute increase conferred to a 1% increase in reporting better HRQoL (OR: 1.009 [95% CI: 1.002 - 1.017], p=.019).
Conclusions
PA was positively associated with HRQoL in children with CHD. Patients who move more are more likely to report better HRQoL. While the magnitude of this association needs to be further understood, continuous encouragement towards more PA seems to be crucial in a holistic approach to medical aftercare in children with CHD.

Copyright © 2021. Published by Elsevier Inc.

Am Heart J: 17 Jul 2021; epub ahead of print
Brudy L, Meyer M, Oberhoffer R, Ewert P, Müller J
Am Heart J: 17 Jul 2021; epub ahead of print | PMID: 34289343
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Abstract

Association of maternal dietary intakes and CBS gene polymorphisms with congenital heart disease in offspring.

Li Y, Diao J, Li J, Luo L, ... Zhu P, Qin J
Background
Although it is generally acknowledged that genetic and environmental factors are associated with risk of congenital heart disease (CHD), the causes are not fully understood. This study aimed at assessing the association of maternal dietary intakes, genetic variants of cystathionine beta synthase (CBS) gene and their interactions with risk of CHDs in offspring.
Method
A hospital-based case-control study of 464 mothers with CHD infants and 504 control mothers of health infant was performed. The exposures of interest were maternal dietary intakes in early pregnancy, single nucleotide polymorphisms (SNPs) of CBS gene.
Results
More frequent intake of pickled vegetables (adjusted odds ratio[aOR] = 1.81; 95% confidence interval[CI]: 1.38-2.37), smoked foods (aOR = 2.00; 95%CI: 1.53-2.60), barbecued foods (aOR = 1.63; 95%CI: 1.19-2.25) and fried foods (aOR = 1.57; 95%CI: 1.22-2.03) were associated with higher risk of CHD, while salted eggs (aOR = 0.20; 95%CI: 0.12-0.33), fish and shrimp (aOR = 0.34; 95%CI: 0.27-0.44), fresh fruits (aOR = 0.49; 95%CI: 0.37-0.66), and milk products (aOR = 0.54; 95%CI: 0.45-0.65) were associated with lower risk of CHD. The SNPs of CBS gene at rs2851391 (T/T vs C/C: aOR = 1.91, 95%CI: 1.15-3.15) and rs234714 (T/T vs C/C: aOR = 2.22, 95%CI: 1.32-3.73) significantly increased the risk of CHD. Additionally, significant interaction effects between maternal dietary intakes and CBS genetic variants on CHD risks were observed.
Conclusions
Maternal dietary factors, CBS genetic variants and their interactions were significantly associated with risk of CHD in offspring. However, it is still unclear how these factors jointly work in the development of CHD, and more studies with larger samples and prospective design are required.

Copyright © 2020 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Dec 2020; 322:121-128
Li Y, Diao J, Li J, Luo L, ... Zhu P, Qin J
Int J Cardiol: 31 Dec 2020; 322:121-128 | PMID: 32800907
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This program is still in alpha version.