Journal: J Am Coll Cardiol

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Abstract

Gaining Efficiency in Clinical Trials With Cardiac Biomarkers: JACC Review Topic of the Week.

Januzzi JL, Canty JM, Das S, DeFilippi CR, ... Zabka TS, Seltzer JH
The momentum of cardiovascular drug development has slowed dramatically. Use of validated cardiac biomarkers in clinical trials could accelerate development of much-needed therapies, but biomarkers have been used less for cardiovascular drug development than in therapeutic areas such as oncology. Moreover, there are inconsistences in biomarker use in clinical trials, such as sample type, collection times, analytical methods, and storage for future research. With these needs in mind, participants in a Cardiac Safety Research Consortium Think Tank proposed the development of international guidance in this area, together with improved quality assurance and analytical methods, to determine what biomarkers can reliably show. Participants recommended the development of systematic methods for sample collection, and the archiving of samples in all cardiovascular clinical trials (including creation of a biobank or repository). The academic and regulatory communities also agreed to work together to ensure that published information is fully and clearly expressed.

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

J Am Coll Cardiol: 19 Apr 2021; 77:1922-1933
Januzzi JL, Canty JM, Das S, DeFilippi CR, ... Zabka TS, Seltzer JH
J Am Coll Cardiol: 19 Apr 2021; 77:1922-1933 | PMID: 33858628
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Abstract

Endovascular Aortic Repair in Nonagenarian Patients.

Prendes CF, Dayama A, Panneton JM, Stana J, ... Wanhainen A, Tsilimparis N
Background
The increasing proportion of elderly patients being treated for abdominal aortic aneurysm (AAA) in the endovascular era is controversial.
Objectives
This study compared 30-day outcomes of endovascular aortic repair (EVAR) in nonagenarians (NAs) with non-nonagenarians (NNAs).
Methods
This retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program database included EVAR procedures performed from 2011 to 2017. Multivariate logistic regression in the unadjusted cohort, followed by propensity-score matching (PSM), was performed. Primary outcomes were 30-day mortality and 30-day major adverse events.
Results
A total of 12,267 patients were included (365 NAs). Ruptured aneurysms accounted for 6.7% (n = 819): 15.7% (n = 57) in NAs versus 6.5% (n = 762) in NNAs (p < 0.001). Mean aneurysm diameter was 6.5 ± 1.8 cm in NAs versus 5.8 ± 1.7 cm in NNAs (p < 0.001). The unadjusted 30-day mortality was 9.9% in NA versus 2.2% in NNAs (p < 0.001). Multivariate analysis revealed age ≥90 years (odds ratio [OR]: 3.36), male sex (OR: 1.78), functional status (OR: 4.22), pre-operative ventilator dependency (OR: 3.80), bleeding disorders (OR: 1.52), dialysis (OR: 2.56), and ruptured aneurysms (OR: 17.21) as independent predictors of mortality. After PSM, no differences in 30-day mortality (intact AAA [iAAA]: 5.3% NA vs. 3% NNA [p = 0.15]; ruptured AAA [rAAA]: 38% NA vs. 28.6% NNA [p = 0.32]) or 30-day major adverse events (iAAA: 7% NA vs. 4.6% NNA [p = 0.22]; rAAA: 28% NA vs. 36.7% NNA [p = 0.35]) were observed.
Conclusions
Age was identified as an independent predictor of 30-day mortality after EVAR on multivariate analysis. However, no differences were found after PSM, suggesting that being ≥90 years of age but with similar comorbidities to younger patients is not associated with a higher short-term mortality after EVAR. Age ≥90 years alone should not exclude patients from EVAR, and tailored indications and carefully balanced risk assessment are advised.

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

J Am Coll Cardiol: 19 Apr 2021; 77:1891-1899
Prendes CF, Dayama A, Panneton JM, Stana J, ... Wanhainen A, Tsilimparis N
J Am Coll Cardiol: 19 Apr 2021; 77:1891-1899 | PMID: 33858626
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Abstract

Effects of Fluoroquinolones on Outcomes of Patients With Aortic Dissection or Aneurysm.

Chen SW, Chan YH, Chien-Chia Wu V, Cheng YT, ... Chu PH, Chou AH
Background
Recent population-based studies have revealed that the use of fluoroquinolones (FQs) is associated with an increased risk of aortic dissection (AD) and aneurysm (AA). However, no evidence is available on whether FQs increase adverse events in patients who had been diagnosed with AD or AA.
Objectives
This study investigated whether the use of FQs increases the risk of aortic-related adverse events and death in this high-risk population.
Methods
A retrospective cohort study was conducted by using the Taiwan National Health Insurance Research Database. A total of 31,570 adult patients who survived after admission for AD or AA between 2001 and 2013 were identified. We divided each calendar year into 6 data units (2 months) for each patient and each year during follow-up. Covariates and exposure of interest (FQs) were reassessed every 2 months. We used another common antibiotic, amoxicillin, as a negative control exposure.
Results
Exposure to FQs was associated with a higher risk of all-cause death (adjusted hazard ratio: 1.61; 95% confidence interval: 1.50 to 1.73), aortic death (adjusted hazard ratio: 1.80; 95% confidence interval: 1.50 to 2.15), and later aortic surgery. However, amoxicillin exposure was not significantly associated with risk of any of the outcomes. A subgroup analysis revealed that the effect of FQs was not significantly different between the AD and AA groups.
Conclusions
Relative to amoxicillin use, FQ exposure in patients with AD or AA was associated with a higher risk of adverse outcomes. FQs should not be used by high-risk patients unless no other treatment options are available.

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

J Am Coll Cardiol: 19 Apr 2021; 77:1875-1887
Chen SW, Chan YH, Chien-Chia Wu V, Cheng YT, ... Chu PH, Chou AH
J Am Coll Cardiol: 19 Apr 2021; 77:1875-1887 | PMID: 33858624
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Abstract

Long-Term Outcomes of Patients With Late Presentation of ST-Segment Elevation Myocardial Infarction.

Cho KH, Han X, Ahn JH, Hyun DY, ... Jeong MH, KAMIR-NIH Investigators
Background
Real-world data on baseline characteristics, clinical practice, and outcomes of late presentation (12 to 48 h of symptom onset) in patients with ST-segment elevation myocardial infarction (STEMI) are limited.
Objectives
This study aimed to investigate real-world features of STEMI late presenters in the contemporary percutaneous coronary intervention (PCI) era.
Methods
Of 13,707 patients from the Korea Acute Myocardial Infarction Registry-National Institutes of Health database, 5,826 consecutive patients diagnosed with STEMI within 48 h of symptom onset during 2011 to 2015 were categorized as late (12 to 48 h; n = 624) or early (<12 h; n = 5,202) presenters. Coprimary outcomes were 180-day and 3-year all-cause mortality.
Results
Late presenters had remarkably worse clinical outcomes than early presenters (180-day mortality: 10.7% vs. 6.8%; 3-year mortality: 16.2% vs. 10.6%; both log-rank p < 0.001), whereas presentation at ≥12 h of symptom onset was not independently associated with increased mortality after STEMI. The use of invasive interventional procedures abruptly decreased from the first (<12 h) to the second (12 to 24 h) 12-h interval of symptom-to-door time (\"no primary PCI strategy\" increased from 4.9% to 12.4%, and \"no PCI\" from 2.3% to 6.6%; both p < 0.001). Mortality rates abruptly increased from the first to the second 12-h interval of symptom-to-door time (from 6.8% to 11.2% for 180-day mortality; from 10.6% to 17.3% for 3-year mortality; all p < 0.05).
Conclusions
Data from a nationwide prospective Korean registry reveal that inverse steep differences in the use of invasive interventional procedures and mortality rates were found between early and late presenters after STEMI. A multidisciplinary approach is required in identifying late presenters of STEMI who can benefit from invasive interventional procedures until further studied.

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

J Am Coll Cardiol: 19 Apr 2021; 77:1859-1870
Cho KH, Han X, Ahn JH, Hyun DY, ... Jeong MH, KAMIR-NIH Investigators
J Am Coll Cardiol: 19 Apr 2021; 77:1859-1870 | PMID: 33858622
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Abstract

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

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

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

J Am Coll Cardiol: 19 Apr 2021; 77:1845-1855
Broch K, Anstensrud AK, Woxholt S, Sharma K, ... Aukrust P, Gullestad L
J Am Coll Cardiol: 19 Apr 2021; 77:1845-1855 | PMID: 33858620
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Abstract

Contraception and Reproductive Planning for Women With Cardiovascular Disease: JACC Focus Seminar 5/5.

Lindley KJ, Bairey Merz CN, Davis MB, Madden T, ... Bello NA, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
The majority of reproductive-age women with cardiovascular disease are sexually active. Early and accurate counseling by the cardiovascular team regarding disease-specific contraceptive safety and effectiveness is imperative to preventing unplanned pregnancies in this high-risk group of patients. This document, the final of a 5-part series, provides evidence-based recommendations regarding contraceptive options for women with, or at high risk for, cardiovascular disease as well as recommendations regarding pregnancy termination for women at excessive cardiovascular mortality risk due to pregnancy.

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

J Am Coll Cardiol: 12 Apr 2021; 77:1823-1834
Lindley KJ, Bairey Merz CN, Davis MB, Madden T, ... Bello NA, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
J Am Coll Cardiol: 12 Apr 2021; 77:1823-1834 | PMID: 33832608
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Abstract

Diagnostic Cardiovascular Imaging and Therapeutic Strategies in Pregnancy: JACC Focus Seminar 4/5.

Bello NA, Bairey Merz CN, Brown H, Davis MB, ... Lindley KJ, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
The prevalence of cardiovascular disease (CVD) in pregnancy, both diagnosed and previously unknown, is rising, and CVD is a leading cause of maternal morbidity and mortality. Historically, women of child-bearing potential have been underrepresented in research, leading to lasting knowledge gaps in the cardiovascular care of pregnant and lactating women. Despite these limitations, clinicians should be familiar with the safety of frequently used diagnostic and therapeutic interventions to adequately care for this at-risk population. This review, the fourth of a 5-part series, provides evidence-based recommendations regarding the use of common cardiovascular diagnostic tests and medications in pregnant and lactating women.

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

J Am Coll Cardiol: 12 Apr 2021; 77:1813-1822
Bello NA, Bairey Merz CN, Brown H, Davis MB, ... Lindley KJ, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
J Am Coll Cardiol: 12 Apr 2021; 77:1813-1822 | PMID: 33832607
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Abstract

Management of Women With Acquired Cardiovascular Disease From Pre-Conception Through Pregnancy and Postpartum: JACC Focus Seminar 3/5.

Park K, Bairey Merz CN, Bello NA, Davis M, ... Lindley KJ, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
Acquired cardiovascular conditions are a leading cause of maternal morbidity and mortality. A growing number of pregnant women have acquired and heritable cardiovascular conditions and cardiovascular risk factors. As the average age of childbearing women increases, the prevalence of acute coronary syndromes, cardiomyopathy, and other cardiovascular complications in pregnancy are also expected to increase. This document, the third of a 5-part series, aims to provide practical guidance on the management of such conditions encompassing pre-conception through acute management and considerations for delivery.

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J Am Coll Cardiol: 12 Apr 2021; 77:1799-1812
Park K, Bairey Merz CN, Bello NA, Davis M, ... Lindley KJ, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
J Am Coll Cardiol: 12 Apr 2021; 77:1799-1812 | PMID: 33832606
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Abstract

Management of Women With Congenital or Inherited Cardiovascular Disease From Pre-Conception Through Pregnancy and Postpartum: JACC Focus Seminar 2/5.

Lindley KJ, Bairey Merz CN, Asgar AW, Bello NA, ... Pepine CJ, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
Maternal morbidity and mortality continue to rise in the United States, with cardiovascular disease as the leading cause of maternal deaths. Congenital heart disease is now the most common cardiovascular condition encountered during pregnancy, and its prevalence will continue to grow. In tandem with these trends, maternal cardiovascular health is becoming increasingly complex. The identification of women at highest risk for cardiovascular complications is essential, and a team-based approach is recommended to optimize maternal and fetal outcomes. This document, the second of a 5-part series, will provide practical guidance from pre-conception through postpartum for cardiovascular conditions that are predominantly congenital or heritable in nature, including aortopathies, congenital heart disease, pulmonary hypertension, and valvular heart disease.

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

J Am Coll Cardiol: 12 Apr 2021; 77:1778-1798
Lindley KJ, Bairey Merz CN, Asgar AW, Bello NA, ... Pepine CJ, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
J Am Coll Cardiol: 12 Apr 2021; 77:1778-1798 | PMID: 33832605
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Abstract

Team-Based Care of Women With Cardiovascular Disease From Pre-Conception Through Pregnancy and Postpartum: JACC Focus Seminar 1/5.

Davis MB, Arendt K, Bello NA, Brown H, ... Lindley KJ, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
The specialty of cardio-obstetrics has emerged in response to the rising rates of maternal morbidity and mortality related to cardiovascular disease (CVD) during pregnancy. Women of childbearing age with or at risk for CVD should receive appropriate counseling regarding maternal and fetal risks of pregnancy, medical optimization, and contraception advice. A multidisciplinary cardio-obstetrics team should ensure appropriate monitoring during pregnancy, plan for labor and delivery, and ensure close follow-up during the postpartum period when CVD complications remain common. The hemodynamic changes throughout pregnancy and during labor and delivery should be considered with respect to the individual cardiac disease of the patient. The fourth trimester refers to the 12 weeks after delivery and is a key time to address contraception, mental health, cardiovascular risk factors, and identify any potential postpartum complications. Women with adverse pregnancy outcomes are at increased risk of long-term CVD and should receive appropriate education and longitudinal follow-up.

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

J Am Coll Cardiol: 12 Apr 2021; 77:1763-1777
Davis MB, Arendt K, Bello NA, Brown H, ... Lindley KJ, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
J Am Coll Cardiol: 12 Apr 2021; 77:1763-1777 | PMID: 33832604
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Abstract

Clonal Hematopoiesis and Risk of Progression of Heart Failure With Reduced Left Ventricular Ejection Fraction.

Pascual-Figal DA, Bayes-Genis A, Díez-Díez M, Hernández-Vicente Á, ... Sánchez-Cabo F, Fuster JJ
Background
Clonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown.
Objectives
The purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology.
Methods
The study cohort comprised 62 patients with HF and LVEF <45% (age 74 ± 7 years, 74% men, 52% nonischemic, and LVEF 30 ± 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction >2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization.
Results
CHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio [HR]: 2.79; 95% confidence interval [CI]: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p < 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p < 0.001). In single gene-specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p < 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology.
Conclusions
Somatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology.

Copyright © 2021. Published by Elsevier Inc.

J Am Coll Cardiol: 12 Apr 2021; 77:1747-1759
Pascual-Figal DA, Bayes-Genis A, Díez-Díez M, Hernández-Vicente Á, ... Sánchez-Cabo F, Fuster JJ
J Am Coll Cardiol: 12 Apr 2021; 77:1747-1759 | PMID: 33832602
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Abstract

Myocardial Angiotensin Metabolism in End-Stage Heart Failure.

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

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

J Am Coll Cardiol: 12 Apr 2021; 77:1731-1743
Pavo N, Prausmüller S, Spinka G, Goliasch G, ... Zuckermann A, Hülsmann M
J Am Coll Cardiol: 12 Apr 2021; 77:1731-1743 | PMID: 33832600
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Abstract

Long-Term Cardiovascular Outcomes in Systemic Lupus Erythematosus.

Yafasova A, Fosbøl EL, Schou M, Baslund B, ... Køber L, Butt JH
Background
Data on long-term cardiovascular outcomes in systemic lupus erythematosus (SLE) are sparse.
Objectives
This study sought to examine the long-term risk and prognosis associated with cardiovascular outcomes, including heart failure (HF), in patients with SLE.
Methods
Using Danish administrative registries, risks of outcomes were compared between SLE patients (diagnosed 1996 to 2018, no history of cardiovascular disease) and age-, sex-, and comorbidity-matched control subjects from the background population (matched 1:4). Furthermore, mortality following HF diagnosis was compared between SLE patients developing HF and age- and sex-matched non-SLE control subjects with HF (matched 1:4).
Results
A total of 3,411 SLE patients (median age: 44.6 years [25th to 75th percentile: 31.9 to 57.0 years]; 14.1% men) were matched with 13,644 control subjects. The median follow-up was 8.5 years (25th to 75th percentile: 4.0 to 14.4 years). Absolute 10-year risks of outcomes were: HF, 3.71% (95% confidence interval [CI]: 3.02% to 4.51%) for SLE patients, 1.94% (95% CI: 1.68% to 2.24%) for control subjects; atrial fibrillation, 4.35% (95% CI: 3.61% to 5.18%) for SLE patients, 2.82% (95% CI: 2.50% to 3.16%) for control subjects; ischemic stroke, 3.75% (95% CI: 3.06% to 4.54%) for SLE patients, 1.92% (95% CI: 1.66% to 2.20%) for control subjects; myocardial infarction, 2.17% (95% CI: 1.66% to 2.80%) for SLE patients, 1.49% (95% CI: 1.26% to 1.75%) for control subjects; venous thromboembolism, 6.03% (95% CI: 5.17% to 6.98%) for SLE patients, 1.68% (95% CI: 1.44% to 1.95%) for control subjects; and the composite of implantable cardioverter-defibrillator implantation/ventricular arrhythmias/cardiac arrest, 0.89% (95% CI: 0.58% to 1.31%) for SLE patients, 0.30% (95% CI: 0.20% to 0.43%) for control subjects. SLE with subsequent HF was associated with higher mortality compared with HF without SLE (adjusted hazard ratio: 1.50; 95% CI: 1.08 to 2.08).
Conclusions
SLE patients had a higher associated risk of HF and other cardiovascular outcomes compared with matched control subjects. Among patients developing HF, a history of SLE was associated with higher mortality.

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

J Am Coll Cardiol: 12 Apr 2021; 77:1717-1727
Yafasova A, Fosbøl EL, Schou M, Baslund B, ... Køber L, Butt JH
J Am Coll Cardiol: 12 Apr 2021; 77:1717-1727 | PMID: 33832598
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Abstract

Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Rheumatic Aortic Stenosis.

Mentias A, Saad M, Desai MY, Krishnaswamy A, ... Kapadia S, Sarrazin MV
Background
Patients with rheumatic aortic stenosis (AS) were excluded from transcatheter aortic valve replacement (TAVR) trials.
Objectives
The authors sought to examine outcomes with TAVR versus surgical aortic valve replacement (SAVR) in patients with rheumatic AS, and versus TAVR in nonrheumatic AS.
Methods
The authors identified Medicare beneficiaries who underwent TAVR or SAVR from October 2015 to December 2017, and then identified patients with rheumatic AS using prior validated International Classification of Diseases, Version 10 codes. Overlap propensity score weighting analysis was used to adjust for measured confounders. The primary study outcome was all-cause mortality. Multiple secondary outcomes were also examined.
Results
The final study cohort included 1,159 patients with rheumatic AS who underwent aortic valve replacement (SAVR, n = 554; TAVR, n = 605), and 88,554 patients with nonrheumatic AS who underwent TAVR. Patients in the SAVR group were younger and with lower prevalence of most comorbidities and frailty scores. After median follow-up of 19 months (interquartile range: 13 to 26 months), there was no difference in all-cause mortality with TAVR versus SAVR (11.2 vs. 7.0 per 100 person-year; adjusted hazard ratio: 1.53; 95% confidence interval: 0.84 to 2.79; p = 0.2). Compared with TAVR in nonrheumatic AS, TAVR for rheumatic AS was associated with similar mortality (15.2 vs. 17.7 deaths per 100 person-years (adjusted hazard ratio: 0.87; 95% confidence interval: 0.68 to 1.09; p = 0.2) after median follow-up of 17 months (interquartile range: 11 to 24 months). None of the rheumatic TAVR patients, <11 SAVR patients, and 242 nonrheumatic TAVR patients underwent repeat aortic valve replacement (124 redo-TAVR and 118 SAVR) at follow-up.
Conclusions
Compared with SAVR, TAVR could represent a viable and possibly durable option for patients with rheumatic AS.

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

J Am Coll Cardiol: 12 Apr 2021; 77:1703-1713
Mentias A, Saad M, Desai MY, Krishnaswamy A, ... Kapadia S, Sarrazin MV
J Am Coll Cardiol: 12 Apr 2021; 77:1703-1713 | PMID: 33832596
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Abstract

Therapeutic Potential of Ketone Bodies for Patients With Cardiovascular Disease: JACC State-of-the-Art Review.

Yurista SR, Chong CR, Badimon JJ, Kelly DP, de Boer RA, Westenbrink BD
Metabolic perturbations underlie a variety of cardiovascular disease states; yet, metabolic interventions to prevent or treat these disorders are sparse. Ketones carry a negative clinical stigma as they are involved in diabetic ketoacidosis. However, evidence from both experimental and clinical research has uncovered a protective role for ketones in cardiovascular disease. Although ketones may provide supplemental fuel for the energy-starved heart, their cardiovascular effects appear to extend far beyond cardiac energetics. Indeed, ketone bodies have been shown to influence a variety of cellular processes including gene transcription, inflammation and oxidative stress, endothelial function, cardiac remodeling, and cardiovascular risk factors. This paper reviews the bioenergetic and pleiotropic effects of ketone bodies that could potentially contribute to its cardiovascular benefits based on evidence from animal and human studies.

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

J Am Coll Cardiol: 05 Apr 2021; 77:1660-1669
Yurista SR, Chong CR, Badimon JJ, Kelly DP, de Boer RA, Westenbrink BD
J Am Coll Cardiol: 05 Apr 2021; 77:1660-1669 | PMID: 33637354
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Abstract

Cardiovascular Risk in Patients With Psoriasis: JACC Review Topic of the Week.

Garshick MS, Ward NL, Krueger JG, Berger JS
Psoriasis is a chronic inflammatory skin disease that affects 2% to 3% of the U.S. population. The immune response in psoriasis includes enhanced activation of T cells and myeloid cells, platelet activation, and up-regulation of interferons, tumor necrosis factor-α, and interleukins (ILs) IL-23, IL-17, and IL-6, which are linked to vascular inflammation and atherosclerosis development. Patients with psoriasis are up to 50% more likely to develop cardiovascular disease (CV) disease, and this CV risk increases with skin severity. Major society guidelines now advocate incorporating a psoriasis diagnosis into CV risk prediction and prevention strategies. Although registry data suggest treatment targeting psoriasis skin disease reduces vascular inflammation and coronary plaque burden, and may reduce CV risk, randomized placebo-controlled trials are inconclusive to date. Further studies are required to define traditional CV risk factor goals, the optimal role of lipid-lowering and antiplatelet therapy, and targeted psoriasis therapies on CV risk.

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

J Am Coll Cardiol: 05 Apr 2021; 77:1670-1680
Garshick MS, Ward NL, Krueger JG, Berger JS
J Am Coll Cardiol: 05 Apr 2021; 77:1670-1680 | PMID: 33795041
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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 Apr 2021; 77:1644-1655
Broberg CS, Kovacs AH, Sadeghi S, Rosenbaum MS, ... Cotts TB, Aboulhosn JA
J Am Coll Cardiol: 05 Apr 2021; 77:1644-1655 | PMID: 33795039
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Abstract

Infective Endocarditis in Patients on Chronic Hemodialysis.

Pericàs JM, Llopis J, Jiménez-Exposito MJ, Kourany WM, ... Miró JM, ICE Investigators
Background
Infective endocarditis (IE) is a common and serious complication in patients receiving chronic hemodialysis (HD).
Objectives
This study sought to investigate whether there are significant differences in complications, cardiac surgery, relapses, and mortality between IE cases in HD and non-HD patients.
Methods
Prospective cohort study (International Collaboration on Endocarditis databases, encompassing 7,715 IE episodes from 2000 to 2006 and from 2008 to 2012). Descriptive analysis of baseline characteristics, epidemiological and etiological features, complications and outcomes, and their comparison between HD and non-HD patients was performed. Risk factors for major embolic events, cardiac surgery, relapses, and in-hospital and 6-month mortality were investigated in HD-patients using multivariable logistic regression.
Results
A total of 6,691 patients were included and 553 (8.3%) received HD. North America had a higher HD-IE proportion than the other regions. The predominant microorganism was Staphylococcus aureus (47.8%), followed by enterococci (15.4%). Both in-hospital and 6-month mortality were significantly higher in HD versus non-HD-IE patients (30.4% vs. 17% and 39.8% vs. 20.7%, respectively; p < 0.001). Cardiac surgery was less frequently performed among HD patients (30.6% vs. 46.2%; p < 0.001), whereas relapses were higher (9.4% vs. 2.7%; p < 0.001). Risk factors for 6-month mortality included Charlson score (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 1.11 to 1.44; p = 0.001), CNS emboli and other emboli (HR: 3.11; 95% CI: 1.84 to 5.27; p < 0.001; and HR: 1.73; 95% CI: 1.02 to 2.93; p = 0.04, respectively), persistent bacteremia (HR: 1.79; 95% CI: 1.11 to 2.88; p = 0.02), and acute onset heart failure (HR: 2.37; 95% CI: 1.49 to 3.78; p < 0.001).
Conclusions
HD-IE is a health care-associated infection chiefly caused by S. aureus, with increasing rates of enterococcal IE. Mortality and relapses are very high and significantly larger than in non-HD-IE patients, whereas cardiac surgery is less frequently performed.

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

J Am Coll Cardiol: 05 Apr 2021; 77:1629-1640
Pericàs JM, Llopis J, Jiménez-Exposito MJ, Kourany WM, ... Miró JM, ICE Investigators
J Am Coll Cardiol: 05 Apr 2021; 77:1629-1640 | PMID: 33795037
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Abstract

Long Working Hours and Risk of Recurrent Coronary Events.

Trudel X, Brisson C, Talbot D, Gilbert-Ouimet M, Milot A
Background
Evidence from prospective studies has suggested that long working hours are associated with incident coronary heart disease (CHD) events. However, no previous study has examined whether long working hours are associated with an increased risk of recurrent CHD events among patients returning to work after a first myocardial infarction (MI).
Objectives
The purpose of this study was to examine the effect of long working hours on the risk of recurrent CHD events.
Methods
This is a prospective cohort study of 967 men and women age 35 to 59 years who returned to work after a first MI. Patients were recruited from 30 hospitals across the province of Quebec, Canada. The mean follow-up duration was 5.9 years. Long working hours were assessed on average 6 weeks after their return to work. Incident CHD events (fatal or nonfatal MI and unstable angina) occurring during follow-up were determined using patients\' medical files. Hazard ratios were estimated using Cox proportional hazard regression models. Splines and fractional polynomial regressions were used for flexible exposure and time modeling.
Results
Recurrent CHD events occurred among 205 patients. Participants working long hours (≥55 h/week) had a higher risk of recurrent CHD events after controlling for sociodemographics, lifestyle-related risk factors, clinical risk factors, work environment factors, and personality factors (hazard ratio vs. 35 to 40 h/week: 1.67; 95% confidence interval: 1.10 to 2.53). These results showed a linear risk increase after 40 h/week and a stronger effect after the first 4 years of follow-up and when long working hours are combined with job strain.
Conclusions
Among patients returning to work after a first MI, longer working hours per week is associated with an increased risk of recurrent CHD events. Secondary prevention interventions aiming to reduce the number of working hours among these patients may lower the risk of CHD recurrence.

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

J Am Coll Cardiol: 05 Apr 2021; 77:1616-1625
Trudel X, Brisson C, Talbot D, Gilbert-Ouimet M, Milot A
J Am Coll Cardiol: 05 Apr 2021; 77:1616-1625 | PMID: 33795035
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Abstract

Eruptive Calcified Nodules as a Potential Mechanism of Acute Coronary Thrombosis and Sudden Death.

Torii S, Sato Y, Otsuka F, Kolodgie FD, ... Finn AV, Virmani R
Background
Calcified nodule (CN) has a unique plaque morphology, in which an area of nodular calcification causes disruption of the fibrous cap with overlying luminal thrombus. CN is reported to be the least frequent cause of acute coronary thrombosis, and the pathogenesis of CN has not been well studied.
Objectives
The purpose of this study is to provide a comprehensive morphologic assessment of the CN in addition to providing an evolutionary perspective as to how CN causes acute coronary thrombosis in patients with acute coronary syndromes.
Methods
A total of 26 consecutive CN lesions from 25 subjects from our autopsy registry were evaluated. Detailed morphometric analysis was performed to understand the plaque characteristics of CN and nodular calcification.
Results
The mean age was 70 years, with a high prevalence of diabetes and chronic kidney disease. CNs were equally distributed between men and women, with 61.5% of CNs found in the right coronary artery (n = 16), mainly within its mid-portion (56%). All CNs demonstrated surface nonocclusive luminal thrombus, consisting of multiple nodular fragments of calcification, protruding and disrupting the overlying fibrous cap, with evidence of endothelial cell loss. The degree of circumferential sheet calcification was significantly less in the culprit section (89° [interquartile range: 54° to 177°]) than in the adjacent proximal (206° [interquartile range: 157° to 269°], p = 0.0034) and distal (240° [interquartile range: 178° to 333°], p = 0.0004) sections. Polarized picrosirius red staining showed the presence of necrotic core calcium at culprit sites of CNs, whereas collagen calcium was more prevalent at the proximal and distal regions of CNs.
Conclusions
Our study suggests that fibrous cap disruption in CN with overlying thrombosis is initiated through the fragmentation of necrotic core calcifications, which is flanked-proximally and distally-by hard, collagen-rich calcification in coronary arteries, which are susceptible to mechanical stress.

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 05 Apr 2021; 77:1599-1611
Torii S, Sato Y, Otsuka F, Kolodgie FD, ... Finn AV, Virmani R
J Am Coll Cardiol: 05 Apr 2021; 77:1599-1611 | PMID: 33795033
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Abstract

Emerging RNA Therapeutics to Lower Blood Levels of Lp(a): JACC Focus Seminar 2/4.

Tsimikas S, Moriarty PM, Stroes ES
Lipoprotein(a) [Lp(a)] has risen to the level of an accepted cardiovascular disease risk factor, but final proof of causality awaits a randomized trial of Lp(a) lowering. Inhibiting apolipoprotein(a) production in the hepatocyte with ribonucleic acid therapeutics has emerged as an elegant and effective solution to reduce plasma Lp(a) levels. Phase 2 clinical trials have shown that the antisense oligonucleotide pelacarsen reduced mean Lp(a) levels by 80%, allowing 98% of subjects to reach on-treatment levels of <125 nmol/l (∼50 mg/dl). The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently enrolling approximately 7,680 patients with history of myocardial infarction, ischemic stroke, and symptomatic peripheral arterial disease and controlled low-density lipoprotein cholesterol to pelacarsen versus placebo. The co-primary endpoints are major adverse cardiovascular events in subjects with Lp(a) >70 mg/dl and >90 mg/dl, in which either of the two being positive will lead to a successful trial. Additional ribonucleic acid-targeted therapies to lower Lp(a) are in preclinical and clinical development. The testing of the Lp(a) hypothesis will provide proof whether Lp(a)-mediated risk can be abolished by potent Lp(a) lowering.

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

J Am Coll Cardiol: 29 Mar 2021; 77:1576-1589
Tsimikas S, Moriarty PM, Stroes ES
J Am Coll Cardiol: 29 Mar 2021; 77:1576-1589 | PMID: 33766265
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Abstract

New and Emerging Therapies for Reduction of LDL-Cholesterol and Apolipoprotein B: JACC Focus Seminar 1/4.

Nurmohamed NS, Navar AM, Kastelein JJP
Adding to the foundation of statins, ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), novel, emerging low-density lipoprotein cholesterol (LDL-C)-lowering therapies are under development for the prevention of cardiovascular disease. Inclisiran, a small interfering RNA molecule that inhibits PCSK9, only needs to be dosed twice a year and has the potential to help overcome current barriers to persistence and adherence to lipid-lowering therapies. Bempedoic acid, which lowers LDL-C upstream from statins, provides a novel alternative for patients with statin intolerance. Angiopoetin-like 3 protein (ANGPTL3) inhibitors have been shown to provide potent LDL-C lowering in patients with homozygous familial hypercholesterolemia without major adverse effects as seen with lomitapide and mipomersen, and may reduce the need for apheresis. Finally, CETP inhibitors may yet be effective with the development of obicetrapib. These novel agents provide the clinician the tools to effectively lower LDL-C across the entire range of LDL-C-induced elevation of cardiovascular risk, from primary prevention and secondary prevention to null-null homozygous familial hypercholesterolemia patients.

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

J Am Coll Cardiol: 29 Mar 2021; 77:1564-1575
Nurmohamed NS, Navar AM, Kastelein JJP
J Am Coll Cardiol: 29 Mar 2021; 77:1564-1575 | PMID: 33766264
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Abstract

Statistical Inference in Abstracts Published in Cardiovascular Journals.

Stang A, Deckert M, Stolpe S
Background
In 2016, the American Statistical Association stated that the use of statistical significance leads to distortion of the scientific process. The principal alternative to significance or null hypothesis testing (NHT) is estimation with point estimates and confidence intervals (CIs).
Objectives
The aim of this study was to determine the time trend of statistical inference and statistical reporting style in abstracts in major cardiovascular journals.
Methods
A total of 84,250 abstracts published from 1975 to 2019 in 9 high-ranking cardiovascular journals (Circulation, Circulation Research, European Heart Journal, European Heart Journal: Cardiovascular Imaging, European Journal of Heart Failure, Journal of the American College of Cardiology, JACC: Cardiovascular Imaging, JACC: Cardiovascular Interventions, and JAMA Cardiology) were reviewed; in particular, proportions of abstracts containing statistical inference and its major variants (NHT, significance testing) were compared over time and among journals.
Results
Overall, 49,924 abstracts (59%) contained statistical inference. Among these abstracts, NHT was the most frequent reporting style of statistical inference (79% among all journals). Journals differed considerably in the prevalence of CI reporting (1% to 78% in 2017-2019). With the exception of 2 journals, the proportion of abstracts containing CIs was higher in the more recent period. From 2013-2015 to 2017-2019, the proportion of abstracts containing only CIs increased by 5 (95% CI: 0 to 10), 18 (95% CI: 15 to 21), and 9 (95% CI: 3 to 15) percentage points in the European Heart Journal, the Journal of the American College of Cardiology, and JACC: Cardiovascular Imaging, respectively.
Conclusions
NHT is still the prevailing reporting style of statistical inference in major cardiovascular journals. Reporting of CIs in abstracts of major cardiovascular journals appears to be growing more popular.

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

J Am Coll Cardiol: 29 Mar 2021; 77:1554-1561
Stang A, Deckert M, Stolpe S
J Am Coll Cardiol: 29 Mar 2021; 77:1554-1561 | PMID: 33766262
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Abstract

Association of Phosphodiesterase-5 Inhibitors Versus Alprostadil With Survival in Men With Coronary Artery Disease.

Andersson DP, Landucci L, Lagerros YT, Grotta A, ... Lehtihet M, Holzmann MJ
Background
Phosphodiesterase 5 inhibitor (PDE5i) treatment is associated with reduced mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI).
Objectives
This study sought to investigate the association between treatment with PDE5i or alprostadil and outcomes in men with stable coronary artery disease.
Methods
All Swedish men with a prior MI or revascularization who received PDE5i or alprostadil during 2006 through 2013 at >6 months after the event were included, using the Swedish Patient Register and the Swedish Prescribed Drug Register. Cox regression was used to estimate adjusted hazard ratios with 95% confidence intervals for all-cause mortality, MI, heart failure, cardiovascular mortality, noncardiovascular mortality, cardiac revascularization, peripheral arterial disease, and stroke in men treated with PDE5i versus alprostadil.
Results
This study included 16,548 men treated with PDE5i and 1,994 treated with alprostadil. The mean follow-up was 5.8 years, with 2,261 deaths (14%) in the PDE5i group and 521 (26%) in the alprostadil group. PDE5i compared with alprostadil treatment was associated with lower mortality (hazard ratio: 0.88; 95% confidence interval: 0.79 to 0.98) and with similar associations for MI, heart failure, cardiovascular mortality, and revascularization. When quintiles (q) of filled PDE5i prescriptions were compared using q1 as reference, patients in q3, q4, and q5 had lower all-cause mortality. Among alprostadil users, those in q5 had a lower all-cause mortality compared to q1.
Conclusions
In men with stable coronary artery disease, treatment with PDE5i is associated with lower risks of death, MI, heart failure, and revascularization compared with alprostadil treatment. Although the decrease in all-cause mortality was PDE5i dose dependent, the data do not permit the inference of causality or any clinical benefits of PDE5i because of the observational study design.

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

J Am Coll Cardiol: 29 Mar 2021; 77:1535-1550
Andersson DP, Landucci L, Lagerros YT, Grotta A, ... Lehtihet M, Holzmann MJ
J Am Coll Cardiol: 29 Mar 2021; 77:1535-1550 | PMID: 33766260
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Abstract

Ultra-Processed Foods and Incident Cardiovascular Disease in the Framingham Offspring Study.

Juul F, Vaidean G, Lin Y, Deierlein AL, Parekh N
Background
Ultra-processed foods provide 58% of total energy in the U.S. diet, yet their association with cardiovascular disease (CVD) remains understudied.
Objectives
The authors investigated the associations between ultra-processed foods and CVD incidence and mortality in the prospective Framingham Offspring Cohort.
Methods
The analytical sample included 3,003 adults free from CVD with valid dietary data at baseline. Data on diet, measured by food frequency questionnaire, anthropometric measures, and sociodemographic and lifestyle factors were collected quadrennially from 1991 to 2008. Data regarding CVD incidence and mortality were available until 2014 and 2017, respectively. Ultra-processed foods were defined according to the NOVA framework. The authors used Cox proportional hazards models to determine the multivariable association between ultra-processed food intake (energy-adjusted servings per day) and incident hard CVD, hard coronary heart disease (CHD), overall CVD, and CVD mortality. Multivariable models were adjusted for age, sex, education, alcohol consumption, smoking, and physical activity.
Results
During follow-up (1991 to 2014/2017), the authors identified 251, 163, and 648 cases of incident hard CVD, hard CHD, and overall CVD, respectively. On average, participants consumed 7.5 servings per day of ultra-processed foods at baseline. Each additional daily serving of ultra-processed foods was associated with a 7% (95% confidence interval [CI]: 1.03 to 1.12), 9% (95% CI: 1.04 to 1.15), 5% (95% CI: 1.02 to 1.08), and 9% (95% CI: 1.02 to 1.16) increase in the risk of hard CVD, hard CHD, overall CVD, and CVD mortality, respectively.
Conclusions
The current findings support that higher consumption of ultra-processed foods is associated with increased risk of CVD incidence and mortality. Although additional research in ethnically diverse populations is warranted, these findings suggest cardiovascular benefits of limiting ultra-processed foods.

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

J Am Coll Cardiol: 29 Mar 2021; 77:1520-1531
Juul F, Vaidean G, Lin Y, Deierlein AL, Parekh N
J Am Coll Cardiol: 29 Mar 2021; 77:1520-1531 | PMID: 33766258
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Abstract

Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor-Associated Myocarditis.

Thavendiranathan P, Zhang L, Zafar A, Drobni ZD, ... Fradley MG, Neilan TG
Background
Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited.
Objectives
This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis.
Methods
In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block.
Results
Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across all patients, mean z-scores for T1 and T2 values were 2.9 ± 1.9 (p < 0.001) and 2.2 ± 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1 (1,079.0 ± 55.5 ms vs. 1,000.3 ± 22.1 ms; p < 0.001) and T2 (56.2 ± 4.9 ms vs. 49.8 ± 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91 (95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE.
Conclusions
The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis.

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

J Am Coll Cardiol: 29 Mar 2021; 77:1503-1516
Thavendiranathan P, Zhang L, Zafar A, Drobni ZD, ... Fradley MG, Neilan TG
J Am Coll Cardiol: 29 Mar 2021; 77:1503-1516 | PMID: 33766256
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Abstract

Discordance of High-Sensitivity Troponin Assays in Patients With Suspected Acute Coronary Syndromes.

Karády J, Mayrhofer T, Ferencik M, Nagurney JT, ... Koenig W, Hoffmann U
Background
High-sensitivity cardiac troponin (hs-cTn) assays have different analytic characteristics.
Objectives
The goal of this study was to quantify differences between assays for common analytical benchmarks and to determine whether they may result in differences in the management of patients with suspected acute coronary syndrome (ACS).
Methods
The authors included patients with suspected ACS enrolled in the ROMICAT (Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography) I and II trials, with blood samples taken at emergency department presentation (ROMICAT-I and -II) or at 2 and 4 h thereafter (ROMICAT-II). hs-cTn concentrations were measured using 3 assays (Roche Diagnostics, Elecsys 2010 platform; Abbott Diagnostics, ARCHITECT i2000SR; Siemens Diagnostics, HsVista). Per blood sample, we determined concordance across analytic benchmarks (<limit of detection [<LOD]/LOD-99th percentile/>99th percentile). Per-patient, the authors determined concordance of management recommendations (rule-out/observe/rule-in) per the 0/2-h algorithm, and their association with diagnostic test findings (coronary artery stenosis >50% on coronary computed tomography angiography or inducible ischemia on perfusion imaging) and ACS.
Results
Among 1,027 samples from 624 patients (52.8 ± 10.0 years; 39.4% women), samples were classified as <LOD (56.3% vs. 10.4% vs. 41.2%; p < 0.001), LOD-99th percentile (36.5% vs. 83.5% vs. 52.6; p < 0.001), >99th percentile (7.2% vs. 6.0% vs. 6.2%) by Roche, Abbott, and Siemens, respectively. A total of 37.4% (n = 384 of 1,027) of blood samples were classified into the same analytical benchmark category, with low concordance across benchmarks (<LOD 11.1%; LOD-99th percentile 29.3%; >99th percentile 43.6%). Serial samples were available in 242 patients (40.1% women; mean age: 52.8 ± 8.0 years). The concordance of management recommendations across assays was 74.8% (n = 181 of 242) considering serial hs-cTn measurements. Of patients who were recommended to discharge, 19.6% to 21.1% had positive diagnostic test findings and 2.8% to 4.3% had ACS at presentation.
Conclusions
Caregivers should be aware that there are significant differences between hs-cTn assays in stratifying individual samples and patients with intermediate likelihood of ACS according to analytical benchmarks that may result in different management recommendations. (Rule Out Myocardial Infarction by Computer Assisted Tomography [ROMICAT]; NCT00990262) (Multicenter Study to Rule Out Myocardial Infarction by Cardiac Computed Tomography [ROMICAT-II]; NCT01084239).

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

J Am Coll Cardiol: 29 Mar 2021; 77:1487-1499
Karády J, Mayrhofer T, Ferencik M, Nagurney JT, ... Koenig W, Hoffmann U
J Am Coll Cardiol: 29 Mar 2021; 77:1487-1499 | PMID: 33766254
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Abstract

A Personalized Approach to Chronic Kidney Disease and Cardiovascular Disease: JACC Review Topic of the Week.

Lai AC, Bienstock SW, Sharma R, Skorecki K, ... Fuster V, Goldman ME
Cardiovascular disease is the most common cause of death in patients with end-stage renal disease (ESRD). The initiation of dialysis for treatment of ESRD exacerbates chronic electrolyte and hemodynamic perturbations. Rapid large shifts in effective intravascular volume and electrolyte concentrations ultimately lead to subendocardial ischemia, increased left ventricular wall mass, and diastolic dysfunction, and can precipitate serious arrhythmias through a complex pathophysiological process. These factors, unique to advanced kidney disease and its treatment, increase the overall incidence of acute coronary syndrome and sudden cardiac death. To date, risk prediction models largely fail to incorporate the observed cardiovascular mortality in the CKD population; however, multimodality imaging may provide an additional prognostication and risk stratification. This comprehensive review discusses the cardiovascular risks associated with hemodialysis, and explores the pathophysiology and the novel utilization of multimodality imaging in CKD to promote a personalized approach for these patients with implications for future research.

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

J Am Coll Cardiol: 22 Mar 2021; 77:1470-1479
Lai AC, Bienstock SW, Sharma R, Skorecki K, ... Fuster V, Goldman ME
J Am Coll Cardiol: 22 Mar 2021; 77:1470-1479 | PMID: 33736830
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Abstract

Cardiac Rehabilitation for Patients With Heart Failure: JACC Expert Panel.

Bozkurt B, Fonarow GC, Goldberg LR, Guglin M, ... Wolfel E, ACC’s Heart Failure and Transplant Section and Leadership Council
Cardiac rehabilitation is defined as a multidisciplinary program that includes exercise training, cardiac risk factor modification, psychosocial assessment, and outcomes assessment. Exercise training and other components of cardiac rehabilitation (CR) are safe and beneficial and result in significant improvements in quality of life, functional capacity, exercise performance, and heart failure (HF)-related hospitalizations in patients with HF. Despite outcome benefits, cost-effectiveness, and strong practice guideline recommendations, CR remains underused. Clinicians, health care leaders, and payers should prioritize incorporating CR as part of the standard of care for patients with HF.

Published by Elsevier Inc.

J Am Coll Cardiol: 22 Mar 2021; 77:1454-1469
Bozkurt B, Fonarow GC, Goldberg LR, Guglin M, ... Wolfel E, ACC’s Heart Failure and Transplant Section and Leadership Council
J Am Coll Cardiol: 22 Mar 2021; 77:1454-1469 | PMID: 33736829
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Abstract

Apolipoprotein B and Non-HDL Cholesterol Better Reflect Residual Risk Than LDL Cholesterol in Statin-Treated Patients.

Johannesen CDL, Mortensen MB, Langsted A, Nordestgaard BG
Background
In cholesterol guidelines, low-density lipoprotein (LDL) cholesterol remains the primary target while apolipoprotein B (apoB) and non-high-density lipoprotein (non-HDL) cholesterol are secondary targets.
Objectives
This study sought to determine if elevated apoB and/or non-HDL cholesterol are superior to elevated LDL cholesterol in identifying statin-treated patients at residual risk of all-cause mortality and myocardial infarction.
Methods
In total, 13,015 statin-treated patients from the Copenhagen General Population Study were included with 8 years median follow-up. Cox regressions among apoB, non-HDL cholesterol, and LDL cholesterol, respectively, and all-cause mortality or myocardial infarction were examined on continuous scales by restricted cubic splines and by categories of concordant and discordant values defined by medians.
Results
High apoB and non-HDL cholesterol were associated with increased risk of all-cause mortality and myocardial infarction, whereas no such associations were found for high LDL cholesterol. Compared with concordant values below medians, discordant apoB above the median with LDL cholesterol below yielded hazard ratios of 1.21 (95% confidence interval [CI]: 1.07 to 1.36) for all-cause mortality and 1.49 (95% CI: 1.15 to 1.92) for myocardial infarction. Corresponding values for high non-HDL cholesterol with low LDL cholesterol were 1.18 (95% CI: 1.02 to 1.36) and 1.78 (95% CI: 1.35 to 2.34). In contrast, discordant high LDL cholesterol with low apoB or non-HDL cholesterol was not associated with increased risk of all-cause mortality or myocardial infarction. Also, discordant high apoB with low non-HDL cholesterol yielded hazard ratios of 1.21 (95% CI: 1.03 to 1.41) for all-cause mortality and of 0.93 (95% CI: 0.62 to 1.40) for myocardial infarction. Furthermore, dual discordant apoB and non-HDL cholesterol above the medians with LDL cholesterol below presented hazard ratios of 1.23 (95% CI: 1.07 to 1.43) for all-cause mortality and 1.82 (95% CI: 1.37 to 2.42) for myocardial infarction.
Conclusions
In statin-treated patients, elevated apoB and non-HDL cholesterol, but not LDL cholesterol, are associated with residual risk of all-cause mortality and myocardial infarction. Discordance analysis demonstrates that apoB is a more accurate marker of all-cause mortality risk in statin-treated patients than LDL cholesterol or non-HDL cholesterol, and apoB in addition is a more accurate marker of risk of myocardial infarction than LDL cholesterol.

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

J Am Coll Cardiol: 22 Mar 2021; 77:1439-1450
Johannesen CDL, Mortensen MB, Langsted A, Nordestgaard BG
J Am Coll Cardiol: 22 Mar 2021; 77:1439-1450 | PMID: 33736827
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Abstract

Atherosclerotic Carotid Plaque Composition and Incident Stroke and Coronary Events.

Bos D, Arshi B, van den Bouwhuijsen QJA, Ikram MK, ... Kavousi M, van der Lugt A
Background
Increasing evidence suggests that atherosclerotic plaque composition rather than plaque size is linked to ischemic cardiovascular events, yet largescale population-based data in asymptomatic individuals remain scarce.
Objectives
This study sought to investigate carotid plaque composition in relation to incident stroke and coronary heart disease (CHD) in a population-based setting.
Methods
Between 2007 and 2012, 1,349 persons (mean age 72 years, 49.5% women) from the population-based Rotterdam Study who were free from a history of stroke or CHD, in whom carotid ultrasonography showed subclinical atherosclerosis, and who underwent high-resolution magnetic resonance imaging of the carotid arteries to assess plaque characteristics. These included the presence of specific plaque components (intraplaque hemorrhage [IPH], lipid-rich necrotic core, and calcification), and measures of plaque size (maximum plaque thickness and presence of stenosis of more than 30%). Individuals were continuously followed for the occurrence of stroke or CHD until January 1, 2015. The authors used Cox regression models to assess the association of the plaque characteristics with the incidence of stroke and CHD, with adjustments for age, sex, and cardiovascular risk factors.
Results
During a median of 5.1 years\' follow-up for stroke and 4.8 years for CHD, 51 individuals had a stroke and 83 developed CHD. Independent of maximum plaque thickness and cardiovascular risk factors, the presence of IPH was associated with incident stroke and CHD (fully adjusted hazard ratio: 2.42 [95% confidence interval: 1.30 to 4.50], and 1.95 [95% confidence interval: 1.20 to 3.14]). Presence of a lipid-rich necrotic core and calcification were not associated with stroke or CHD.
Conclusions
The presence of IPH in the carotid atherosclerotic plaque is an independent risk factor for stroke and CHD. These findings indicate the promise of IPH as a marker of plaque vulnerability in healthy persons with subclinical atherosclerosis.

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

J Am Coll Cardiol: 22 Mar 2021; 77:1426-1435
Bos D, Arshi B, van den Bouwhuijsen QJA, Ikram MK, ... Kavousi M, van der Lugt A
J Am Coll Cardiol: 22 Mar 2021; 77:1426-1435 | PMID: 33736825
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Abstract

Long-Term Outcomes of Patients Undergoing the Ross Procedure.

Aboud A, Charitos EI, Fujita B, Stierle U, ... Sievers HH, Ensminger S
Background
Treatment of aortic-valve disease in young patients still poses challenges. The Ross procedure offers several potential advantages that may translate to improved long-term outcomes.
Objectives
This study reports long-term outcomes after the Ross procedure.
Methods
Adult patients who were included in the Ross Registry between 1988 and 2018 were analyzed. Endpoints were overall survival, reintervention, and major adverse events at maximum follow-up. Multivariable regression analyses were performed to identify risk factors for survival and the need of Ross-related reintervention.
Results
There were 2,444 adult patients with a mean age of 44.1 ± 11.7 years identified. Early mortality was 1.0%. Estimated survival after 25 years was 75.8% and did not statistically differ from the general population (p = 0.189). The risk for autograft reintervention was 0.69% per patient-year and 0.62% per patient-year for right-ventricular outflow tract (RVOT) reintervention. Larger aortic annulus diameter (hazard ratio [HR]: 1.12/mm; 95% confidence interval [CI]: 1.05 to 1.19/mm; p < 0.001) and pre-operative presence of pure aortic insufficiency (HR: 1.74; 95% CI: 1.13 to 2.68; p = 0.01) were independent predictors for autograft reintervention, whereas the use of a biological valve (HR: 8.09; 95% CI: 5.01 to 13.08; p < 0.001) and patient age (HR: 0.97 per year; 95% CI: 0.96 to 0.99; p = 0.001) were independent predictors for RVOT reintervention. Major bleeding, valve thrombosis, permanent stroke, and endocarditis occurred with an incidence of 0.15% per patient-year, 0.07% per patient-year, 0.13%, and 0.36% per patient-year, respectively.
Conclusions
The Ross procedure provides excellent survival over a follow-up period of up to 25 years. The rates of reintervention, anticoagulation-related morbidity, and endocarditis were very low. This procedure should therefore be considered as a very suitable treatment option in young patients suffering from aortic-valve disease. (Long-Term Follow-up After the Autograft Aortic Valve Procedure [Ross Operation]; NCT00708409).

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

J Am Coll Cardiol: 22 Mar 2021; 77:1412-1422
Aboud A, Charitos EI, Fujita B, Stierle U, ... Sievers HH, Ensminger S
J Am Coll Cardiol: 22 Mar 2021; 77:1412-1422 | PMID: 33736823
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Abstract

Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced.

Ferreira JP, Zannad F, Pocock SJ, Anker SD, ... Schueler E, Packer M
Background
Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors favorably influence the clinical course of patients with heart failure and reduced ejection fraction.
Objectives
This study sought to study the mutual influence of empagliflozin and MRAs in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).
Methods
Secondary analysis that compared the effects of empagliflozin versus placebo in 3,730 patients with heart failure and a reduced ejection fraction, of whom 71% used MRAs at randomization.
Results
The effects of empagliflozin on the primary endpoint, on most efficacy endpoints, and on safety were similar in patients receiving or not receiving an MRA (interaction p > 0.20). For cardiovascular death, the hazard ratios for the effect of empagliflozin versus placebo were 0.82 (95% confidence interval [CI]: 0.65 to 1.05) in MRA users and 1.19 (95% CI: 0.82 to 1.71) in MRA nonusers (interaction p = 0.10); a similar pattern was seen for all-cause mortality (interaction p = 0.098). Among MRA nonusers at baseline, patients in the empagliflozin group were 35% less likely than those in the placebo group to initiate treatment with an MRA following randomization (hazard ratio: 0.65; 95% CI: 0.49 to 0.85). Among MRA users at baseline, patients in the empagliflozin group were 22% less likely than those in the placebo group to discontinue treatment with an MRA following randomization (hazard ratio: 0.78; 95% CI: 0.64 to 0.96). Severe hyperkalemia was less common in the empagliflozin group.
Conclusions
In EMPEROR-Reduced, the use of MRAs did not influence the effect of empagliflozin to reduce adverse heart failure and renal outcomes. Treatment with empagliflozin was associated with less discontinuation of MRAs. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

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

J Am Coll Cardiol: 22 Mar 2021; 77:1397-1407
Ferreira JP, Zannad F, Pocock SJ, Anker SD, ... Schueler E, Packer M
J Am Coll Cardiol: 22 Mar 2021; 77:1397-1407 | PMID: 33736821
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Abstract

Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.

Packer M, Anker SD, Butler J, Filippatos G, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
Background
Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention.
Objectives
This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload.
Methods
This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment.
Results
Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients.
Conclusions
Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

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

J Am Coll Cardiol: 22 Mar 2021; 77:1381-1392
Packer M, Anker SD, Butler J, Filippatos G, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
J Am Coll Cardiol: 22 Mar 2021; 77:1381-1392 | PMID: 33736819
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Abstract

A Test in Context: Interpretation of High-Sensitivity Cardiac Troponin Assays in Different Clinical Settings.

Raber I, McCarthy CP, Januzzi JL
High-sensitivity cardiac troponin (hs-cTn) assays have the ability to detect minute troponin concentrations and resolve minor changes in biomarker concentrations. Clinically, this allows for the ability to rapidly identify or exclude acute myocardial injury in the setting of acute chest discomfort-thus providing more rapid evaluation for acute myocardial infarction-but the improvements in troponin assays also create avenues for other applications where troponin release from the cardiomyocyte might confer prognostic information. These situations include cardiovascular risk assessment across a wide range of clinical circumstances, including apparently-well individuals, those at risk for heart disease, and those with prevalent cardiovascular disorders. The optimal hs-cTn threshold for each circumstance varies by the assay used and by the population assessed. This review will provide context for how hs-cTn assays might be interpreted depending on the application sought, reviewing results from studies leveraging hs-cTn for applications beyond \"acute myocardial infarction diagnostic evaluation.\"

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

J Am Coll Cardiol: 15 Mar 2021; 77:1357-1367
Raber I, McCarthy CP, Januzzi JL
J Am Coll Cardiol: 15 Mar 2021; 77:1357-1367 | PMID: 33706879
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Abstract

Ambulatory Electrocardiogram Monitoring in Patients Undergoing Transcatheter Aortic Valve Replacement: JACC State-of-the-Art Review.

Muntané-Carol G, Philippon F, Nault I, Faroux L, ... Mittal S, Rodés-Cabau J
Transcatheter aortic valve replacement (TAVR) has changed the treatment of patients with severe aortic stenosis. However, the occurrence of conduction disturbances has not decreased significantly over time and remains the main drawback of the procedure. In addition, new-onset atrial fibrillation is the most frequent tachyarrhythmia during the hospitalization period and is associated with worse clinical outcomes. However, little is known regarding the incidence and clinical impact of arrhythmic events beyond the periprocedural TAVR period. Ambulatory electrocardiogram (AECG) monitoring has recently emerged as a tool to unravel the complex issue of arrhythmic disorders (bradyarrhythmias and tachyarrhythmias) before and after TAVR. To date, the preliminary results from the initial experience using AECG monitoring systems showed the safety, usefulness, and potential clinical implications of this diagnostic tool in TAVR recipients. This review provides an overview of the current status, clinical implications, and future perspectives of AECG monitoring in the TAVR setting.

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

J Am Coll Cardiol: 15 Mar 2021; 77:1344-1356
Muntané-Carol G, Philippon F, Nault I, Faroux L, ... Mittal S, Rodés-Cabau J
J Am Coll Cardiol: 15 Mar 2021; 77:1344-1356 | PMID: 33706878
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Abstract

Heart-After-Liver Transplantation Attenuates Rejection of Cardiac Allografts in Sensitized Patients.

Daly RC, Rosenbaum AN, Dearani JA, Clavell AL, ... Edwards BS, Kushwaha SS
Background
In patients undergoing heart transplantation, significant allosensitization limits access to organs, resulting in longer wait times and high waitlist mortality. Current desensitization strategies are limited in enabling successful transplantation.
Objectives
The purpose of this study was to describe the cumulative experience of combined heart-liver transplantation using a novel heart-after-liver transplant (HALT) protocol resulting in profound immunologic protection.
Methods
Reported are the results of a clinical protocol that was instituted to transplant highly sensitized patients requiring combined heart and liver transplantation at a single institution. Patients were dual-organ listed with perceived elevated risk of rejection or markedly prolonged waitlist time due to high levels of allo-antibodies. Detailed immunological data and long-term patient and graft outcomes were obtained.
Results
A total of 7 patients (age 43 ± 7 years, 86% women) with high allosensitization (median calculated panel reactive antibody = 77%) underwent HALT. All had significant, unacceptable donor specific antibodies (DSA) (>4,000 mean fluorescence antibody). Prospective pre-operative flow cytometric T-cell crossmatch was positive in all, and B-cell crossmatch was positive in 5 of 7. After HALT, retrospective crossmatch (B- and T-cell) became negative in all. DSA fell dramatically; at last follow-up, all pre-formed or de novo DSA levels were insignificant at <2,000 mean fluorescence antibody. No patients experienced >1R rejection over a median follow-up of 48 months (interquartile range: 25 to 68 months). There was 1 death due to metastatic cancer and no significant graft dysfunction.
Conclusions
A heart-after-liver transplantation protocol enables successful transplantation via near-elimination of DSA and is effective in preventing adverse immunological outcomes in highly sensitized patients listed for combined heart-liver transplantation.

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

J Am Coll Cardiol: 15 Mar 2021; 77:1331-1340
Daly RC, Rosenbaum AN, Dearani JA, Clavell AL, ... Edwards BS, Kushwaha SS
J Am Coll Cardiol: 15 Mar 2021; 77:1331-1340 | PMID: 33706876
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Abstract

Impact of Obesity on Outcomes of Pregnancy in Women With Heart Disease.

Pfaller B, Siu SC, D\'Souza R, Wichert-Schmitt B, ... Maxwell C, Silversides CK
Background
Women with heart disease are at risk for complications during pregnancy. This study sought to examine the effect of maternal obesity on pregnancy complications in women with heart disease.
Objectives
The objective was to determine the incidence of adverse cardiac events (CE) in pregnant women with heart disease and obesity.
Methods
Adverse CE during pregnancy were examined in a prospective cohort of women with heart disease. CE were a composite of the following: cardiac death/arrest, arrhythmias, heart failure, myocardial infarction, stroke, aortic dissection, and thromboembolic events. Pre-eclampsia and post-partum hemorrhage were also studied. Outcomes were examined according to body mass index (BMI). To identify additional predictors of CE, a baseline risk score (CARPREG [Canadian Cardiac Disease in Pregnancy Study] II score) for predicting cardiac complications was calculated for all pregnancies and included in a multivariable logistic regression model.
Results
Of 790 pregnancies, 19% occurred in women with BMI ≥30 kg/m2 (obesity), 25% in women with BMI 25 to 29.9 kg/m2 (overweight), 53% in women with BMI 18.5 to 24.9 kg/m2 (normal weight), and 3% in women with BMI <18.5 kg/m2 (underweight). Women with obesity were at higher risk of CE when compared with women with normal weight (23% vs. 14%; p = 0.006). In a multivariable model, obesity (odds ratio: 1.7; 95% confidence interval: 1.0 to 2.7) and higher CARPREG II risk scores (odds ratio: 1.7; 95% confidence interval: 1.5 to 1.9) predicted CE. Pre-eclampsia was more frequent in women with obesity compared with those with normal weight (8% vs. 2%; p = 0.001).
Conclusions
Obesity increases the risk of maternal cardiovascular complications in pregnant women with heart disease. This modifiable risk factor should be addressed at the time of preconception counseling.

Copyright © 2021. Published by Elsevier Inc.

J Am Coll Cardiol: 15 Mar 2021; 77:1317-1326
Pfaller B, Siu SC, D'Souza R, Wichert-Schmitt B, ... Maxwell C, Silversides CK
J Am Coll Cardiol: 15 Mar 2021; 77:1317-1326 | PMID: 33706874
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Abstract

Hypertensive Disorders of Pregnancy and Subsequent Risk of Premature Mortality.

Wang YX, Arvizu M, Rich-Edwards JW, Wang L, ... Rexrode KM, Chavarro JE
Background
Hypertensive disorders of pregnancy (HDPs) are leading causes of maternal and perinatal morbidity and mortality. However, it is uncertain whether HDPs are associated with long-term risk of premature mortality (before age 70 years).
Objectives
The objective of this study was to evaluate whether HDPs were associated with premature mortality.
Methods
Between 1989 and 2017, the authors followed 88,395 parous female nurses participating in the Nurses\' Health Study II. The study focused on gestational hypertension and pre-eclampsia within the term HDPs. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between HDPs and premature mortality were estimated by using Cox proportional hazards models, with adjustment for relevant confounders.
Results
The authors documented that 2,387 women died before age 70 years, including 1,141 cancer deaths and 212 CVD deaths. The occurrence of HDPs, either gestational hypertension or pre-eclampsia, was associated with an HR of 1.31 (95% CI: 1.18 to 1.46) for premature death during follow-up. When specific causes of death were examined, these relations were strongest for CVD-related mortality (HR: 2.26; 95% CI: 1.67 to 3.07). The association between HDPs and all-cause premature death persisted, regardless of the subsequent development of chronic hypertension (HR: 1.20 [95% CI: 1.02 to 1.40] for HDPs only and HR: 2.02 [95% CI: 1.75 to 2.33] for both HDPs and subsequent chronic hypertension).
Conclusions
An occurrence of HDPs, either gestational hypertension or pre-eclampsia, was associated with an increased risk of premature mortality, particularly CVD mortality, even in the absence of chronic hypertension.

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

J Am Coll Cardiol: 15 Mar 2021; 77:1302-1312
Wang YX, Arvizu M, Rich-Edwards JW, Wang L, ... Rexrode KM, Chavarro JE
J Am Coll Cardiol: 15 Mar 2021; 77:1302-1312 | PMID: 33706872
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Abstract

Systolic Blood Pressure Time in Target Range and Cardiovascular Outcomes in Patients With Hypertension.

Fatani N, Dixon DL, Van Tassell BW, Fanikos J, Buckley LF
Background
Standard blood pressure control metrics may not account for fluctuations in blood pressure over time.
Objectives
This study sought to estimate the independent association between time in systolic blood pressure target range and major adverse cardiovascular events among adults with hypertension.
Methods
This study was a post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial), a randomized clinical trial that compared intensive (<120 mm Hg) and standard (<140 mm Hg) systolic blood pressure treatment interventions in adults with hypertension and high cardiovascular risk. Target range was defined as 110 to 130 mm Hg and 120 to 140 mm Hg for the intensive and standard arms, respectively. Time in target range was estimated over the first 3 months of follow-up using linear interpolation. The association between time in target range with major adverse cardiovascular events was estimated using adjusted Cox proportional hazards regression models.
Results
Participants with greater time in target range were younger, had lower 10-year cardiovascular risk and lower baseline systolic blood pressure, and were more likely women and statin users. Each 1-SD increase in time in target range was significantly associated with a decreased risk of first major adverse cardiovascular event in fully adjusted models. Time in target range remained significantly associated with major adverse cardiovascular events despite adjustment for mean systolic blood pressure or systolic blood pressure variability. Among participants with mean systolic blood pressure at or below target, time in target range remained associated with major adverse cardiovascular events.
Conclusions
Time in systolic blood pressure target range independently predicts major adverse cardiovascular event risk.

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

J Am Coll Cardiol: 15 Mar 2021; 77:1290-1299
Fatani N, Dixon DL, Van Tassell BW, Fanikos J, Buckley LF
J Am Coll Cardiol: 15 Mar 2021; 77:1290-1299 | PMID: 33706870
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Abstract

Platelet Reactivity in Patients With Acute Coronary Syndromes Awaiting Surgical Revascularization.

Nakashima CAK, Dallan LAO, Lisboa LAF, Jatene FB, ... Gurbel PA, Nicolau JC
Background
Dual antiplatelet therapy is recommended for patients with acute coronary syndromes (ACS). Approximately 10% to 15% of these patients will undergo coronary artery bypass graft (CABG) surgery for index events, and current guidelines recommend stopping clopidogrel at least 5 days before CABG. This waiting time has clinical and economic implications.
Objectives
This study aimed to evaluate if a platelet reactivity-based strategy is noninferior to standard of care for 24-h post-CABG bleeding.
Methods
In this randomized, open label noninferiority trial, 190 patients admitted with ACS with indications for CABG and on aspirin and P2Y12 receptor inhibitors, were assigned to either control group, P2Y12 receptor inhibitor withdrawn 5 to 7 days before CABG, or intervention group, daily measurements of platelet reactivity by Multiplate analyzer (Roche Diagnostics GmbH, Vienna, Austria) with CABG planned the next working day after platelet reactivity normalization (pre-defined as ≥46 aggregation units).
Results
Within the first 24 h of CABG, the median chest tube drainage was 350 ml (interquartile range [IQR]: 250 to 475 ml) and 350 ml (IQR: 255 to 500 ml) in the intervention and control groups, respectively (p for noninferiority <0.001). The median waiting period between the decision to undergo CABG and the procedure was 112 h (IQR: 66 to 142 h) and 136 h (IQR: 112 to 161 h) (p < 0.001), respectively. In the intention-to-treat analysis, a 6.4% decrease in the median in-hospital expenses was observed in the intervention group (p = 0.014), with 11.2% decrease in the analysis per protocol (p = 0.003).
Conclusions
A strategy based on platelet reactivity-guided is noninferior to the standard of care in patients with ACS awaiting CABG regarding peri-operative bleeding, significantly shortens the waiting time to CABG, and decreases hospital expenses. (Evaluation of Platelet Aggregability in the Release of CABG in Patients With ACS With DAPT; NCT02516267).

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

J Am Coll Cardiol: 15 Mar 2021; 77:1277-1286
Nakashima CAK, Dallan LAO, Lisboa LAF, Jatene FB, ... Gurbel PA, Nicolau JC
J Am Coll Cardiol: 15 Mar 2021; 77:1277-1286 | PMID: 33706868
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Abstract

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review.

Talasaz AH, Sadeghipour P, Kakavand H, Aghakouchakzadeh M, ... Goldhaber SZ, Bikdeli B
Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

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

J Am Coll Cardiol: 10 Mar 2021; epub ahead of print
Talasaz AH, Sadeghipour P, Kakavand H, Aghakouchakzadeh M, ... Goldhaber SZ, Bikdeli B
J Am Coll Cardiol: 10 Mar 2021; epub ahead of print | PMID: 33741176
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Abstract

Managing Patients With Short-Term Mechanical Circulatory Support: JACC Review Topic of the Week.

Balthazar T, Vandenbriele C, Verbrugge FH, Den Uil C, ... Price S, Adriaenssens T
The use of mechanical circulatory support for patients presenting with cardiogenic shock is rapidly increasing. Currently, there is only limited and conflicting evidence available regarding the role of the Impella (a microaxial, continuous-flow, short-term, left or right ventricular assist device) in cardiogenic shock; further randomized trials are needed. Patient selection, timing of implantation, and post-implantation management in the cardiac intensive care unit are crucial elements for success. Particular challenges at the bedside include the practical management of anticoagulation, evaluation of correct device position, and the approach to use in a patient with signs of insufficient hemodynamic support. Profound knowledge of these issues is required to enable the maximal potential of the device. This review provides a comprehensive overview of the short-term assist device and describes a practical approach to optimize care for patients supported with the device.

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 08 Mar 2021; 77:1243-1256
Balthazar T, Vandenbriele C, Verbrugge FH, Den Uil C, ... Price S, Adriaenssens T
J Am Coll Cardiol: 08 Mar 2021; 77:1243-1256 | PMID: 33663742
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Abstract

Advanced Therapies for Ventricular Arrhythmias in Patients With Chagasic Cardiomyopathy: JACC State-of-the-Art Review.

Romero J, Velasco A, Pisani CF, Alviz I, ... Scanavacca M, Di Biase L
Chagas disease is caused by infection from the protozoan parasite Trypanosoma cruzi. Although it is endemic to Latin America, global migration has led to an increased incidence of Chagas in Europe, Asia, Australia, and North America. Following acute infection, up to 30% of patients will develop chronic Chagas disease, with most patients developing Chagasic cardiomyopathy. Chronic Chagas cardiomyopathy is highly arrhythmogenic, with estimated annual rates of appropriate implantable cardioverter-defibrillator therapies and electrical storm of 25% and 9.1%, respectively. Managing arrhythmias in patients with Chagasic cardiomyopathy is a major challenge for the clinical electrophysiologist, requiring intimate knowledge of cardiac anatomy, advanced training, and expertise. Endocardial-epicardial mapping and ablation strategy is needed to treat arrhythmias in this patient population, owing to the suboptimal long-term success rate of endocardial mapping and ablation alone. We also describe innovative approaches to improve acute and long-term clinical outcomes in patients with refractory ventricular arrhythmias following catheter ablation, such as bilateral cervicothoracic sympathectomy and bilateral renal denervation, among others.

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

J Am Coll Cardiol: 08 Mar 2021; 77:1225-1242
Romero J, Velasco A, Pisani CF, Alviz I, ... Scanavacca M, Di Biase L
J Am Coll Cardiol: 08 Mar 2021; 77:1225-1242 | PMID: 33663741
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Abstract

Spironolactone in Patients With Heart Failure, Preserved Ejection Fraction, and Worsening Renal Function.

Beldhuis IE, Myhre PL, Bristow M, Claggett B, ... Solomon SD, Desai AS
Background
Treatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood.
Objectives
The purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF.
Methods
In 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term.
Results
WRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF.
Conclusions
Among HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF.

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 08 Mar 2021; 77:1211-1221
Beldhuis IE, Myhre PL, Bristow M, Claggett B, ... Solomon SD, Desai AS
J Am Coll Cardiol: 08 Mar 2021; 77:1211-1221 | PMID: 33663739
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Impact:
Abstract

Randomized, Double-Blind Comparison of Half-Dose Versus Full-Dose Edoxaban in 14,014 Patients With Atrial Fibrillation.

Steffel J, Ruff CT, Yin O, Braunwald E, ... Antman EM, Giugliano RP
Background
In the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, the lower dose edoxaban regimen (LDER) and the higher dose edoxaban regimen (HDER) were noninferior to well-managed warfarin for stroke prevention in atrial fibrillation.
Objectives
The objective of the present analysis of the ENGAGE AF TIMI-48 trial was to comprehensively compare the net clinical outcome (NCO) of LDER (30 mg once daily, dose reduced to 15 mg in selective patients) versus HDER (60 mg once daily, dose reduced to 30 mg in selective patients).
Methods
This study performed a pre-specified analysis of the ENGAGE AF-TIMI 48 trial, comparing patients on LDER versus HDER.
Results
The pre-defined primary NCO (stroke/systemic embolism [SEE], major bleeding, death) was less frequent with LDER (7.26% vs. 8.01%; hazard ratio: 0.90; 95% confidence interval: 0.84 to 0.98; p = 0.014). The secondary (disabling stroke, life-threatening bleeding, or all-cause mortality) and tertiary pre-defined NCOs (stroke, SEE, life-threatening bleeding, or all-cause mortality) were similar between the 2 dosing regimens. Patients randomized to LDER versus HDER had a significantly higher risk of stroke/SEE (2.04% vs. 1.56%; hazard ratio: 1.31; 95% confidence interval: 1.12 to 1.52; p < 0.001). Conversely, major bleeding, intracranial hemorrhage, major gastrointestinal bleeding, and life-threatening bleeding occurred significantly less frequently with LDER compared with those of HDER. These findings were supported by multiple pharmacokinetic findings.
Conclusions
In the ENGAGE AF-TIMI 48 trial, the primary NCO was reduced with LDER versus HDER, whereas the secondary and tertiary NCOs were similar between the 2 dosing regimens. These results may aid physicians in evidence-based individualization of edoxaban dosing. However, the approved HDER remains the standard therapy among the available edoxaban dosing regimens for stroke prevention in atrial fibrillation. (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48 [ENGAGE AF-TIMI 48]; NCT00781391).

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

J Am Coll Cardiol: 08 Mar 2021; 77:1197-1207
Steffel J, Ruff CT, Yin O, Braunwald E, ... Antman EM, Giugliano RP
J Am Coll Cardiol: 08 Mar 2021; 77:1197-1207 | PMID: 33663737
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Impact:
Abstract

Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis.

Wright RS, Ray KK, Raal FJ, Kallend DG, ... Kastelein JJP, ORION Phase III Investigators
Background
Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin-kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing.
Objectives
The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran.
Methods
Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C-lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed.
Results
A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was -50.7% (95% confidence interval: -52.9% to -48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was -50.5% (95% confidence interval: -52.1% to -48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups.
Conclusions
These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents.

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 08 Mar 2021; 77:1182-1193
Wright RS, Ray KK, Raal FJ, Kallend DG, ... Kastelein JJP, ORION Phase III Investigators
J Am Coll Cardiol: 08 Mar 2021; 77:1182-1193 | PMID: 33663735
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Impact:
Abstract

10-Year Follow-Up of Patients With Everolimus-Eluting Versus Bare-Metal Stents After ST-Segment Elevation Myocardial Infarction.

Brugaletta S, Gomez-Lara J, Ortega-Paz L, Jimenez-Diaz V, ... Serruys PW, Sabaté M
Background
Outcomes data for a durable-polymer everolimus-eluting stent (EES) at extended long-term follow-up in patients with ST-segment elevation myocardial infarction (STEMI) are unknown.
Objectives
The aim of this study was to assess the 10-year outcomes of patients enrolled in the EXAMINATION (A Clinical Evaluation of Everolimus Eluting Coronary Stents in the Treatment of Patients With ST-Segment Elevation Myocardial Infarction) trial.
Methods
The EXAMINATION-EXTEND (10-Years Follow-Up of the EXAMINATION Trial) study is an investigator-driven 10-year follow-up of the EXAMINATION trial, which randomly assigned 1,498 patients with STEMI in a 1:1 ratio to receive either EES (n = 751) or bare-metal stents (n = 747). The primary endpoint was a patient-oriented composite endpoint of all-cause death, any myocardial infarction, or any revascularization. Secondary endpoints included a device-oriented composite endpoint of cardiac death, target vessel myocardial infarction, or target lesion revascularization; the individual components of the combined endpoints; and stent thrombosis.
Results
Complete 10-year clinical follow-up was obtained in 94.5% of the EES group and 95.9% of the bare-metal stent group. Rates of the patient-oriented composite endpoint and device-oriented composite endpoint were significantly reduced in the EES group (32.4% vs. 38.0% [hazard ratio: 0.81; 95% confidence interval: 0.68 to 0.96; p = 0.013] and 13.6% vs. 18.4% [hazard ratio: 0.72; 95% confidence interval: 0.55 to 0.93; p = 0.012], respectively), driven mainly by target lesion revascularization (5.7% vs. 8.8%; p = 0.018). The rate of definite stent thrombosis was similar in both groups (2.2% vs. 2.5%; p = 0.590). No differences were found between the groups in terms of target lesion revascularization (1.4% vs. 1.3%; p = 0.963) and definite or probable stent thrombosis (0.6% vs. 0.4%; p = 0.703) between 5 and 10 years.
Conclusions
At 10-year follow-up, EES demonstrated confirmed superiority in combined patient- and device-oriented composite endpoints compared with bare-metal stents in patients with STEMI requiring primary percutaneous coronary intervention. Between 5- and 10-year follow-up, a low incidence of adverse cardiovascular events related to device failure was found in both groups. (10-Years Follow-Up of the EXAMINATION Trial; NCT04462315).

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

J Am Coll Cardiol: 08 Mar 2021; 77:1165-1178
Brugaletta S, Gomez-Lara J, Ortega-Paz L, Jimenez-Diaz V, ... Serruys PW, Sabaté M
J Am Coll Cardiol: 08 Mar 2021; 77:1165-1178 | PMID: 33663733
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Impact:
Abstract

Outcomes 2 Years After Transcatheter Aortic Valve Replacement in Patients at Low Surgical Risk.

Leon MB, Mack MJ, Hahn RT, Thourani VH, ... Pibarot P, PARTNER 3 Investigators
Background
In low surgical risk patients with symptomatic severe aortic stenosis, the PARTNER 3 (Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis) trial demonstrated superiority of transcatheter aortic valve replacement (TAVR) versus surgery for the primary endpoint of death, stroke, or re-hospitalization at 1 year.
Objectives
This study determined both clinical and echocardiographic outcomes between 1 and 2 years in the PARTNER 3 trial.
Methods
This study randomly assigned 1,000 patients (1:1) to transfemoral TAVR with the SAPIEN 3 valve versus surgery (mean Society of Thoracic Surgeons score: 1.9%; mean age: 73 years) with clinical and echocardiography follow-up at 30 days and at 1 and 2 years. This study assessed 2-year rates of the primary endpoint and several secondary endpoints (clinical, echocardiography, and quality-of-life measures) in this as-treated analysis.
Results
Primary endpoint follow-up at 2 years was available in 96.5% of patients. The 2-year primary endpoint was significantly reduced after TAVR versus surgery (11.5% vs. 17.4%; hazard ratio: 0.63; 95% confidence interval: 0.45 to 0.88; p = 0.007). Differences in death and stroke favoring TAVR at 1 year were not statistically significant at 2 years (death: TAVR 2.4% vs. surgery 3.2%; p = 0.47; stroke: TAVR 2.4% vs. surgery 3.6%; p = 0.28). Valve thrombosis at 2 years was increased after TAVR (2.6%; 13 events) compared with surgery (0.7%; 3 events; p = 0.02). Disease-specific health status continued to be better after TAVR versus surgery through 2 years. Echocardiographic findings, including hemodynamic valve deterioration and bioprosthetic valve failure, were similar for TAVR and surgery at 2 years.
Conclusions
At 2 years, the primary endpoint remained significantly lower with TAVR versus surgery, but initial differences in death and stroke favoring TAVR were diminished and patients who underwent TAVR had increased valve thrombosis. (Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis [PARTNER 3]; NCT02675114).

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

J Am Coll Cardiol: 08 Mar 2021; 77:1149-1161
Leon MB, Mack MJ, Hahn RT, Thourani VH, ... Pibarot P, PARTNER 3 Investigators
J Am Coll Cardiol: 08 Mar 2021; 77:1149-1161 | PMID: 33663731
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Abstract

Management of Patients With Giant Cell Myocarditis: JACC Review Topic of the Week.

Bang V, Ganatra S, Shah SP, Dani SS, ... Nohria A, Cooper LT
Giant cell myocarditis is a rare, often rapidly progressive and potentially fatal, disease due to T-cell lymphocyte-mediated inflammation of the myocardium that typically affects young and middle-aged adults. Frequently, the disease course is marked by acute heart failure, cardiogenic shock, intractable ventricular arrhythmias, and/or heart block. Diagnosis is often difficult due to its varied clinical presentation and overlap with other cardiovascular conditions. Although cardiac biomarkers and multimodality imaging are often used as initial diagnostic tests, endomyocardial biopsy is required for definitive diagnosis. Combination immunosuppressive therapy, along with guideline-directed medical therapy, has led to a paradigm shift in the management of giant cell myocarditis resulting in an improvement in overall and transplant-free survival. Early diagnosis and prompt management can decrease the risk of transplantation or death, which remain common in patients who present with cardiogenic shock.

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

J Am Coll Cardiol: 01 Mar 2021; 77:1122-1134
Bang V, Ganatra S, Shah SP, Dani SS, ... Nohria A, Cooper LT
J Am Coll Cardiol: 01 Mar 2021; 77:1122-1134 | PMID: 33632487
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Impact:
Abstract

Malaria and the Heart: JACC State-of-the-Art Review.

Gupta S, Gazendam N, Farina JM, Saldarriaga C, ... Martínez-Sellés M, Baranchuk A
As one of the tropical diseases, malaria is endemic in developing countries. Severe malaria, mainly caused by the Plasmodium falciparum parasite, can result in life-threatening complications. Traditionally, cardiac involvement has not been included as a frequent cause of morbidity and mortality. This could be due to under-reporting or underdiagnosing. Specific cardiovascular (CV) complications include electrocardiogram abnormalities, myocarditis, pericarditis, pericardial effusion, ischemic disease, and heart failure. According to the data analyzed, CV manifestations can lead to severe consequences. Possible theories related to the pathophysiological mechanisms related to CV compromise include an imbalanced pro-inflammatory cytokine response and/or erythrocyte sequestration by increased cytoadherence to endothelium. Although there is a paucity of data regarding cardiac manifestations of malaria, an algorithm for appropriate use of diagnostic tools to assess cardiac involvement has been developed in this paper. Furthermore, it is important to note that typical antimalarial treatment regimens can have fatal cardiac side-effects.

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

J Am Coll Cardiol: 01 Mar 2021; 77:1110-1121
Gupta S, Gazendam N, Farina JM, Saldarriaga C, ... Martínez-Sellés M, Baranchuk A
J Am Coll Cardiol: 01 Mar 2021; 77:1110-1121 | PMID: 33632486
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Impact:
Abstract

Comparison of Management Strategies for Neonates With Symptomatic Tetralogy of Fallot.

Goldstein BH, Petit CJ, Qureshi AM, McCracken CE, ... Bauser-Heaton H, Glatz AC
Background
Neonates with tetralogy of Fallot and symptomatic cyanosis (sTOF) require early intervention.
Objectives
This study sought to perform a balanced multicenter comparison of staged repair (SR) (initial palliation [IP] and subsequent complete repair [CR]) versus primary repair (PR) treatment strategies.
Methods
Consecutive neonates with sTOF who underwent IP or PR at ≤30 days of age from 2005 to 2017 were retrospectively reviewed from the Congenital Cardiac Research Collaborative. The primary outcome was death. Secondary outcomes included component (IP, CR, PR) and cumulative (SR): hospital and intensive care unit lengths of stay; durations of cardiopulmonary bypass, anesthesia, ventilation, and inotrope use; and complication and reintervention rates. Outcomes were compared using propensity score adjustment.
Results
The cohort consisted of 342 patients who underwent SR (IP: surgical, n = 256; transcatheter, n = 86) and 230 patients who underwent PR. Pre-procedural ventilation, prematurity, DiGeorge syndrome, and pulmonary atresia were more common in the SR group (p ≤0.01). The observed risk of death was not different between the groups (10.2% vs 7.4%; p = 0.25) at median 4.3 years. After adjustment, the hazard of death remained similar between groups (hazard ratio: 0.82; 95% confidence interval: 0.49 to 1.38; p = 0.456), but it favored SR during early follow-up (<4 months; p = 0.041). Secondary outcomes favored the SR group in component analysis, whereas they largely favored PR in cumulative analysis. Reintervention risk was higher in the SR group (p = 0.002).
Conclusions
In this multicenter comparison of SR or PR for management of neonates with sTOF, adjusted for patient-related factors, early mortality and neonatal morbidity were lower in the SR group, but cumulative morbidity and reinterventions favored the PR group, findings suggesting potential benefits to each strategy.

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

J Am Coll Cardiol: 01 Mar 2021; 77:1093-1106
Goldstein BH, Petit CJ, Qureshi AM, McCracken CE, ... Bauser-Heaton H, Glatz AC
J Am Coll Cardiol: 01 Mar 2021; 77:1093-1106 | PMID: 33632484
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Impact:
Abstract

Mitochondria-Rich Extracellular Vesicles From Autologous Stem Cell-Derived Cardiomyocytes Restore Energetics of Ischemic Myocardium.

Ikeda G, Santoso MR, Tada Y, Li AM, ... Ye J, Yang PC
Background
Mitochondrial dysfunction results in an imbalance between energy supply and demand in a failing heart. An innovative therapy that targets the intracellular bioenergetics directly through mitochondria transfer may be necessary.
Objectives
The purpose of this study was to establish a preclinical proof-of-concept that extracellular vesicle (EV)-mediated transfer of autologous mitochondria and their related energy source enhance cardiac function through restoration of myocardial bioenergetics.
Methods
Human-induced pluripotent stem cell-derived cardiomyocytes (iCMs) were employed. iCM-conditioned medium was ultracentrifuged to collect mitochondria-rich EVs (M-EVs). Therapeutic effects of M-EVs were investigated using in vivo murine myocardial infarction (MI) model.
Results
Electron microscopy revealed healthy-shaped mitochondria inside M-EVs. Confocal microscopy showed that M-EV-derived mitochondria were transferred into the recipient iCMs and fused with their endogenous mitochondrial networks. Treatment with 1.0 × 108/ml M-EVs significantly restored the intracellular adenosine triphosphate production and improved contractile profiles of hypoxia-injured iCMs as early as 3 h after treatment. In contrast, isolated mitochondria that contained 300× more mitochondrial proteins than 1.0 × 108/ml M-EVs showed no effect after 24 h. M-EVs contained mitochondrial biogenesis-related messenger ribonucleic acids, including proliferator-activated receptor γ coactivator-1α, which on transfer activated mitochondrial biogenesis in the recipient iCMs at 24 h after treatment. Finally, intramyocardial injection of 1.0 × 108 M-EVs demonstrated significantly improved post-MI cardiac function through restoration of bioenergetics and mitochondrial biogenesis.
Conclusions
M-EVs facilitated immediate transfer of their mitochondrial and nonmitochondrial cargos, contributing to improved intracellular energetics in vitro. Intramyocardial injection of M-EVs enhanced post-MI cardiac function in vivo. This therapy can be developed as a novel, precision therapeutic for mitochondria-related diseases including heart failure.

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

J Am Coll Cardiol: 01 Mar 2021; 77:1073-1088
Ikeda G, Santoso MR, Tada Y, Li AM, ... Ye J, Yang PC
J Am Coll Cardiol: 01 Mar 2021; 77:1073-1088 | PMID: 33632482
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Impact:
Abstract

Association of Hypertensive Disorders of Pregnancy With Left Ventricular Remodeling Later in Life.

Countouris ME, Villanueva FS, Berlacher KL, Cavalcante JL, Parks WT, Catov JM
Background
Hypertensive disorders of pregnancy (HDP) are associated with short-term cardiac structure and function abnormalities, but later life changes are not well studied.
Objectives
This study aimed to determine if HDP history is associated with echocardiographic differences 8 to 10 years after delivery, and if subgroups with placental maternal vascular malperfusion (MVM) lesions or current hypertension may be particularly affected.
Methods
Women with pregnancies delivered from 2008 to 2009 were selected from a clinical cohort with abstracted pregnancy and placental pathology data to undergo transthoracic echocardiography (2017 to 2020). Medical history, blood pressure, and weight were measured at the study visit.
Results
The authors enrolled 132 women (10 ± 1 years post-delivery, age 38 ± 6 years): 102 with normotensive pregnancies and 30 with HDP: pre-eclampsia (n = 21) or gestational hypertension (n = 9). Compared with women with normotensive pregnancies, those with HDP history were more likely to have current hypertension (63% vs. 26%; p < 0.001). After adjusting for age, race, MVM lesions, body mass index, current hypertension, and hemoglobin A1c, women with HDP history had higher interventricular septal thickness (β = 0.08; p = 0.04) and relative wall thickness (β = 0.04; p = 0.04). In subgroup analyses, those with both HDP history and current hypertension had a higher proportion of left ventricular remodeling (79.0%) compared with all other groups (only HDP [36.4%; p = 0.01], only current hypertension [46.2%; p = 0.02], and neither HDP nor hypertension [38.2%; p < 0.001]), and lower mitral inflow E/A and annular e\'. Accounting for placental MVM lesions did not impact results.
Conclusions
Women with both HDP history and current hypertension have pronounced differences in left ventricular structure and function a decade after pregnancy, warranting continued surveillance and targeted therapies for cardiovascular disease prevention.

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

J Am Coll Cardiol: 01 Mar 2021; 77:1057-1068
Countouris ME, Villanueva FS, Berlacher KL, Cavalcante JL, Parks WT, Catov JM
J Am Coll Cardiol: 01 Mar 2021; 77:1057-1068 | PMID: 33632480
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Impact:
Abstract

Prognostic Value of Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes.

Kofoed KF, Engstrøm T, Sigvardsen PE, Linde JJ, ... Kelbæk H, Køber LV
Background
Severity and extent of coronary artery disease (CAD) assessed by invasive coronary angiography (ICA) guide treatment and may predict clinical outcome in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS).
Objectives
This study tested the hypothesis that coronary computed tomography angiography (CTA) is equivalent to ICA for risk assessment in patients with NSTEACS.
Methods
The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial evaluated timing of treatment in relation to outcome in patients with NSTEACS and included a clinically blinded coronary CTA conducted prior to ICA. Severity of CAD was defined as obstructive (coronary stenosis ≥50%) or nonobstructive. Extent of CAD was defined as high risk (obstructive left main or proximal left anterior descending artery stenosis and/or multivessel disease) or non-high risk. The primary endpoint was a composite of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or heart failure.
Results
Coronary CTA and ICA were conducted in 978 patients. During a median follow-up time of 4.2 years (interquartile range: 2.7 to 5.5 years), the primary endpoint occurred in 208 patients (21.3%). The rate of the primary endpoint was up to 1.7-fold higher in patients with obstructive CAD compared with in patients with nonobstructive CAD as defined by coronary CTA (hazard ratio [HR]: 1.74; 95% confidence interval [CI]: 1.22 to 2.49; p = 0.002) or ICA (HR: 1.54; 95% CI: 1.13 to 2.11; p = 0.007). In patients with high-risk CAD, the rate of the primary endpoint was 1.5-fold higher compared with the rate in those with non-high-risk CAD as defined by coronary CTA (HR: 1.56; 95% CI: 1.18 to 2.07; p = 0.002). A similar trend was noted for ICA (HR: 1.28; 95% CI: 0.98 to 1.69; p = 0.07).
Conclusions
Coronary CTA is equivalent to ICA for the assessment of long-term risk in patients with NSTEACS. (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes [VERDICT]; NCT02061891).

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

J Am Coll Cardiol: 01 Mar 2021; 77:1044-1052
Kofoed KF, Engstrøm T, Sigvardsen PE, Linde JJ, ... Kelbæk H, Køber LV
J Am Coll Cardiol: 01 Mar 2021; 77:1044-1052 | PMID: 33632478
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Impact:
Abstract

3-Year Outcomes of Transcatheter Mitral Valve Repair in Patients With Heart Failure.

Mack MJ, Lindenfeld J, Abraham WT, Kar S, ... Stone GW, COAPT Investigators
Background
In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, transcatheter mitral valve repair (TMVr) resulted in fewer heart failure hospitalizations (HFHs) and lower mortality at 24 months in patients with heart failure (HF) with mitral regurgitation (MR) secondary to left ventricular dysfunction compared with guideline-directed medical therapy (GDMT) alone.
Objectives
This study determined if these benefits persisted to 36 months and if control subjects who were allowed to cross over at 24 months derived similar benefit.
Methods
This study randomized 614 patients with HF with moderate-to-severe or severe secondary MR, who remained symptomatic despite maximally tolerated GDMT, to TMVr plus GDMT versus GDMT alone. The primary effectiveness endpoint was all HFHs through 24-month follow-up. Patients have now been followed for 36 months.
Results
The annualized rates of HFHs per patient-year were 35.5% with TMVr and 68.8% with GDMT alone (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.37 to 0.63; p < 0.001; number needed to treat (NNT) = 3.0; 95% CI: 2.4 to 4.0). Mortality occurred in 42.8% of the device group versus 55.5% of control group (HR: 0.67; 95% CI: 0.52 to 0.85; p = 0.001; NNT = 7.9; 95% CI: 4.6 to 26.1). Patients who underwent TMVr also had sustained 3-year improvements in MR severity, quality-of-life measures, and functional capacity. Among 58 patients assigned to GDMT alone who crossed over and were treated with TMVr, the subsequent composite rate of mortality or HFH was reduced compared with those who continued on GDMT alone (adjusted HR: 0.43; 95% CI: 0.24 to 0.78; p = 0.006).
Conclusions
Among patients with HF and moderate-to-severe or severe secondary MR who remained symptomatic despite GDMT, TMVr was safe, provided a durable reduction in MR, reduced the rate of HFH, and improved survival, quality of life, and functional capacity compared with GDMT alone through 36 months. Surviving patients who crossed over to device treatment had a prognosis comparable to those originally assigned to transcatheter therapy. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation [COAPT]; NCT01626079).

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

J Am Coll Cardiol: 01 Mar 2021; 77:1029-1040
Mack MJ, Lindenfeld J, Abraham WT, Kar S, ... Stone GW, COAPT Investigators
J Am Coll Cardiol: 01 Mar 2021; 77:1029-1040 | PMID: 33632476
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Impact:
Abstract

Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week.

Pieroni M, Moon JC, Arbustini E, Barriales-Villa R, ... Pietilä-Effati P, Namdar M
Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by deficient α-galactosidase A activity that leads to an accumulation of globotriasylceramide (Gb3) in affected tissues, including the heart. Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death. Following the introduction of enzyme replacement therapy, early diagnosis and treatment have become essential to slow disease progression and prevent major cardiac complications. Recent advances in the understanding of FD pathophysiology suggest that in addition to Gb3 accumulation, other mechanisms contribute to the development of Fabry cardiomyopathy. Progress in imaging techniques have improved diagnosis and staging of FD-related cardiac disease, suggesting a central role for myocardial inflammation and setting the stage for further research. In addition, with the recent approval of oral chaperone therapy and new treatment developments, the FD-specific treatment landscape is rapidly evolving.

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

J Am Coll Cardiol: 22 Feb 2021; 77:922-936
Pieroni M, Moon JC, Arbustini E, Barriales-Villa R, ... Pietilä-Effati P, Namdar M
J Am Coll Cardiol: 22 Feb 2021; 77:922-936 | PMID: 33602475
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Impact:
Abstract

Pathophysiology of Takotsubo Syndrome: JACC State-of-the-Art Review.

Lyon AR, Citro R, Schneider B, Morel O, ... Templin C, Omerovic E
Takotsubo syndrome (TTS) has been a recognized clinical entity for 31 years, since its first description in 1990. TTS is now routinely diagnosed in patients who present with acute chest pain, electrocardiographic changes, troponin elevation, unobstructed coronary arteries, and a typical pattern of circumferential left ventricular wall motion abnormalities that usually involve the apical and midventricular myocardium. Increasing understanding of this intriguing syndrome stems from wider recognition, possible increasing frequency, and a rising number of publications focused on the pathophysiology in clinical and laboratory studies. A comprehensive understanding of TTS pathophysiology and evidence-based treatments are lacking, and specific and effective treatments are urgently required. This paper reviews the pathophysiology of this fascinating syndrome; what is known from both clinical and preclinical studies, including review of the evidence for microvascular dysfunction, myocardial beta-adrenergic signaling, inflammation, and electrophysiology; and where focused research needs to fill gaps in understanding TTS.

Copyright © 2021. Published by Elsevier Inc.

J Am Coll Cardiol: 22 Feb 2021; 77:902-921
Lyon AR, Citro R, Schneider B, Morel O, ... Templin C, Omerovic E
J Am Coll Cardiol: 22 Feb 2021; 77:902-921 | PMID: 33602474
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Impact:
Abstract

Subclinical Atherosclerosis and Brain Metabolism in Middle-Aged Individuals: The PESA Study.

Cortes-Canteli M, Gispert JD, Salvadó G, Toribio-Fernandez R, ... Molinuevo JL, Fuster V
Background
Atherosclerosis has been linked to cognitive decline in late life; however, the impact of cardiovascular risk factors (CVRFs) and subclinical atherosclerosis on brain metabolism at earlier stages remains unexplored.
Objectives
This study sought to determine the association between brain metabolism, subclinical atherosclerosis, and CVRFs in middle-aged asymptomatic individuals.
Methods
This study included 547 asymptomatic middle-aged participants (50 ± 4 years, 82% men) from the PESA (Progression of Early Subclinical Atherosclerosis) study with evidence of subclinical atherosclerosis. Participants underwent 18F-fluorodeoxyglucose (FDG)-positron emission tomography. Global brain FDG uptake and voxel-wise analyses were used to evaluate the associations of cerebral metabolism with CVRFs and atherosclerotic plaque burden in carotids and femorals assessed by 3-dimensional vascular ultrasound.
Results
Global FDG uptake showed an inverse correlation with 30-year Framingham Risk Score (FRS) (β = -0.15, p < 0.001). This association was mainly driven by the presence of hypertension (d = 0.36, p < 0.001). Carotid plaque burden was inversely associated with global brain FDG uptake (β = -0.16, p < 0.001), even after adjusting for 30-year FRS. Voxel-wise approaches revealed that the brain areas most strongly affected by hypometabolism in association with 30-year FRS, hypertension, and carotid plaque burden were parietotemporal regions (angular, supramarginal, and inferior/middle temporal gyri) and the cingulate gyrus.
Conclusions
In asymptomatic middle-aged individuals, cardiovascular risk is associated with brain hypometabolism, with hypertension being the modifiable CVRF showing the strongest association. Subclinical carotid plaque burden is also linked to reduced brain metabolism independently of CVRFs. Cerebral areas showing hypometabolism include those known to be affected in dementia. These data reinforce the need to control CVRFs early in life in order to potentially reduce the brain\'s midlife vulnerability to future cognitive dysfunction.

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

J Am Coll Cardiol: 22 Feb 2021; 77:888-898
Cortes-Canteli M, Gispert JD, Salvadó G, Toribio-Fernandez R, ... Molinuevo JL, Fuster V
J Am Coll Cardiol: 22 Feb 2021; 77:888-898 | PMID: 33602472
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Abstract

Pre-Diabetes Increases Stroke Risk in Patients With Nonvalvular Atrial Fibrillation.

Kezerle L, Tsadok MA, Akriv A, Senderey AB, ... Leventer-Roberts M, Haim M
Background
Diabetes mellitus (DM) increases the risk of embolism in nonvalvular atrial fibrillation (NVAF). The association between pre-diabetes and risk of ischemic stroke has not been studied separately in this population.
Objectives
The purpose of this study was to evaluate whether pre-diabetes is associated with increased risk of stroke and death in patients with NVAF.
Methods
We conducted a historical cohort study using the Clalit Health Services electronic medical records. The study population included all members aged ≥25 years, with a first diagnosis of NVAF between January 1, 2010, and December 31, 2016. We compared 3 groups of individuals: those with pre-diabetes, those with diabetes, and normoglycemic patients.
Results
A total of 44,451 cases were identified. The median age was 75 years, and 52.5% were women. During a mean follow-up of 38 months, the incidence rates of stroke (per 100 person-years) were: 1.14 in normoglycemic individuals, 1.40 in those with pre-diabetes, and 2.15 in those with diabetes. In both univariate and multivariate analyses, pre-diabetes was associated with an increased risk of stroke compared with normoglycemic persons (adjusted hazard ratio [adjHR]: 1.19; 95% confidence interval [CI]: 1.01 to 1.4) even after adjustment for CHA2DS2-Vasc risk factors and use of anticoagulants, while diabetes conferred an even higher risk (vs. normoglycemia (adjHR: 1.56; 95% CI: 1.37 to 1.79). The risk for mortality was higher for individuals with diabetes (adjHR: 1.47; 95% CI: 1.41 to 1.54) but not for those with pre-diabetes (adjHR: 0.98; 95% CI: 0.92 to 1.03).
Conclusions
In this cohort of patients with incident NVAF, pre-diabetes was associated with an increased risk of stroke even after accounting for other recognized risk factors.

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

J Am Coll Cardiol: 22 Feb 2021; 77:875-884
Kezerle L, Tsadok MA, Akriv A, Senderey AB, ... Leventer-Roberts M, Haim M
J Am Coll Cardiol: 22 Feb 2021; 77:875-884 | PMID: 33602470
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Abstract

Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome.

Taub PR, Zadourian A, Lo HC, Ormiston CK, Golshan S, Hsu JC
Background
Postural orthostatic tachycardia syndrome (POTS) is a complex, multifaceted disorder that impairs functional status and quality of life. Current pharmacological treatments are limited.
Objectives
This study investigated the effect of ivabradine (selective blocker of the Ifunny channel in the sinoatrial node) on heart rate, quality of life (QOL), and plasma norepinephrine (NE) levels in patients with hyperadrenergic POTS defined by plasma NE >600 pg/ml and abnormal tilt table test.
Methods
In total, 22 patients with hyperadrenergic POTS as the predominant subtype completed a randomized, double-blinded, placebo-controlled, crossover trial with ivabradine. Patients were randomized to start either ivabradine or placebo for 1 month, and then were crossed over to the other treatment for 1 month. Heart rate, QOL, and plasma NE levels were measured at baseline and at the end of each treatment month.
Results
The average age was 33.9 ± 11.7 years, 95.5% were women (n = 21), and 86.4% were White (n = 23). There was a significant reduction in heart rate between placebo and ivabradine (p < 0.001). Patients reported significant improvements in QOL with RAND 36-Item Health Survey 1.0 for physical functioning (p = 0.008) and social functioning (p = 0.021). There was a strong trend in reduction of NE levels upon standing with ivabradine (p = 0.056). Patients did not experience any significant side-effects, such as bradycardia or hypotension, with ivabradine.
Conclusion
Ivabradine is safe and effective in significantly improving heart rate and QOL in patients with hyperadrenergic POTS as the predominant subtype.

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

J Am Coll Cardiol: 22 Feb 2021; 77:861-871
Taub PR, Zadourian A, Lo HC, Ormiston CK, Golshan S, Hsu JC
J Am Coll Cardiol: 22 Feb 2021; 77:861-871 | PMID: 33602468
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Abstract

Patient Characteristics and Clinical Outcomes of Type 1 Versus Type 2 Myocardial Infarction.

McCarthy CP, Kolte D, Kennedy KF, Vaduganathan M, Wasfy JH, Januzzi JL
Background
Type 2 myocardial infarction (MI) patients may have different characteristics and outcomes when compared with type 1 MI.
Objectives
The purpose of this study was to compare patients with type 1 MI to those with type 2 MI in the United States.
Methods
Using the Nationwide Readmissions Database, MI patients were categorized over the 3 months following the introduction of an International Classification of Diseases-10th Revision code specific for type 2 MI. Baseline characteristics and inpatient and post-discharge outcomes among both cohorts were compared.
Results
There were 216,657 patients with type 1 MI, 37,765 patients with type 2 MI, and 1,525 patients with both type 1 and 2 MI. Patients with type 2 MI were older (71 years vs. 69 years; p < 0.001), were more likely to be women (47.3% vs. 40%; p < 0.001), and had higher prevalence of heart failure (27.9% vs. 10.9%; p < 0.001), kidney disease (35.7% vs. 25.7%; p < 0.001), and atrial fibrillation (31% vs. 21%; p < 0.001). Rates of coronary angiography (10.9% vs. 57.3%; p < 0.001), percutaneous coronary intervention (1.7% vs. 38.5%; p < 0.001), and coronary artery bypass grafting (0.4% vs. 7.8%; p < 0.001) were lower among type 2 MI patients. Patients with type 2 MI had lower risk of in-hospital mortality (adjusted odds ratio: 0.57 [95% confidence interval: 0.54 to 0.60]) and 30-day MI readmission (adjusted odds ratio: 0.46 [95% confidence interval: 0.35 to 0.59]). There was no difference in risk of 30-day all-cause or heart failure readmission.
Conclusions
Patients with type 2 MI have a unique cardiovascular phenotype when compared with type 1 MI, and are managed in a heterogenous manner. Validated management strategies for type 2 MI are needed.

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

J Am Coll Cardiol: 22 Feb 2021; 77:848-857
McCarthy CP, Kolte D, Kennedy KF, Vaduganathan M, Wasfy JH, Januzzi JL
J Am Coll Cardiol: 22 Feb 2021; 77:848-857 | PMID: 33602466
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Impact:
Abstract

Clinical Impact of Contralateral Carotid Occlusion in Patients Undergoing Carotid Artery Revascularization.

Krawisz AK, Rosenfield K, White CJ, Jaff MR, ... Jones S, Secemsky EA
Background
The presence of a contralateral carotid occlusion (CCO) is an established high-risk feature for patients undergoing carotid endarterectomy (CEA) and is traditionally an indication for carotid artery stenting (CAS). Recent observational data have called into question whether CCO remains a high-risk feature for CEA.
Objectives
The purpose of this study was to determine the clinical impact of CCO among patients undergoing CEA and CAS in a contemporary nationwide registry.
Methods
All patients undergoing CEA or CAS from 2007 to 2019 in the NCDR CARE (National Cardiovascular Data Registry Carotid Artery Revascularization and Endarterectomy) and PVI (Peripheral Vascular Intervention) registries were included. The primary exposure was the presence of CCO. The outcome was a composite of in-hospital death, stroke, and myocardial infarction. Multivariable logistic regression and inverse-probability of treatment weighting were used to compare outcomes.
Results
Among 58,423 patients who underwent carotid revascularization, 4,624 (7.9%) had a CCO. Of those, 68.9% (n = 3,185) underwent CAS and 31.1% (n = 1,439) underwent CEA. The average age of patients with CCO was 69.5 ± 9.7 years, 32.6% were women, 92.8% were Caucasian, 51.7% had a prior transient ischemic attack or stroke, and 45.4% presented with symptomatic disease. Over the study period, there was a 41.7% decrease in the prevalence of CCO among patients who underwent carotid revascularization (p < 0.001), but CAS remained the primary revascularization strategy. Unadjusted composite outcome rates were lower in patients with CCO after CAS (2.1%) than CEA (3.6%). Following adjustment, CCO was associated with a 71% increase in the odds of an adverse outcome after CEA (95% confidence interval: 1.27 to 2.30; p < 0.001) compared with no increase after CAS (adjusted odds ratio: 0.94; 95% confidence interval: 0.72 to 1.22; p = 0.64).
Conclusions
CCO remains an important predictor of increased risk among patients undergoing CEA, but not CAS.

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

J Am Coll Cardiol: 22 Feb 2021; 77:835-844
Krawisz AK, Rosenfield K, White CJ, Jaff MR, ... Jones S, Secemsky EA
J Am Coll Cardiol: 22 Feb 2021; 77:835-844 | PMID: 33602464
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Abstract

Preventing Arrhythmic Death in Patients With Tetralogy of Fallot: JACC Review Topic of the Week.

Cohen MI, Khairy P, Zeppenfeld K, Van Hare GF, Lakkireddy DR, Triedman JK
Patients with tetralogy of Fallot are at risk for ventricular arrhythmias and sudden cardiac death. These abnormalities are associated with pulmonary regurgitation, right ventricular enlargement, and a substrate of discrete, slowly-conducting isthmuses. Although these arrhythmic events are rare, their prediction is challenging. This review will address contemporary risk assessment and prevention strategies. Numerous variables have been proposed to predict who would benefit from an implantable cardioverter-defibrillator. Current risk stratification models combine independently associated factors into risk scores. Cardiac magnetic resonance imaging, QRS fragmentation assessment, and electrophysiology testing in selected patients may refine some of these models. Interaction between right and left ventricular function is emerging as a critical factor in our understanding of disease progression and risk assessment. Multicenter studies evaluating risk factors and risk mitigating strategies such as pulmonary valve replacement, ablative strategies, and use of implantable cardiac-defibrillators are needed moving forward.

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

J Am Coll Cardiol: 15 Feb 2021; 77:761-771
Cohen MI, Khairy P, Zeppenfeld K, Van Hare GF, Lakkireddy DR, Triedman JK
J Am Coll Cardiol: 15 Feb 2021; 77:761-771 | PMID: 33573746
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Abstract

Leptin in Leanness and Obesity: JACC State-of-the-Art Review.

Perakakis N, Farr OM, Mantzoros CS
Leptin has emerged over the past 2 decades as a key hormone secreted by adipose tissue that conveys information on energy stores. Leptin is considered an important regulator of both neuroendocrine function and energy homeostasis. Numerous studies (mainly preclinical and much less in humans) have investigated the mechanisms of leptin\'s actions both in the healthy state as well as in a wide range of metabolic diseases. In this review, the authors present leptin physiology and review the main findings from animal studies, observational and interventional studies, and clinical trials in humans that have investigated the role of leptin in metabolism and cardiometabolic diseases (energy deficiency, obesity, diabetes, cardiovascular diseases, nonalcoholic fatty liver disease). The authors discuss the similarities and discrepancies between animal and human biology and present clinical applications of leptin, directions for future research, and current approaches for the development of the next-generation leptin analogs.

Published by Elsevier Inc.

J Am Coll Cardiol: 15 Feb 2021; 77:745-760
Perakakis N, Farr OM, Mantzoros CS
J Am Coll Cardiol: 15 Feb 2021; 77:745-760 | PMID: 33573745
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Abstract

Absolute Coronary Blood Flow Measured by Continuous Thermodilution in Patients With Ischemia and Nonobstructive Disease.

Konst RE, Elias-Smale SE, Pellegrini D, Hartzema-Meijer M, ... van Royen N, Damman P
Background
Intracoronary continuous thermodilution is a novel technique to quantify absolute coronary flow (Q) and resistance (R) and has potential advantages over current methods such as coronary flow reserve (CFR) and index of microvascular resistance (IMR). However, no data are available in patients with ischemia and nonobstructive coronary artery disease (INOCA).
Objectives
This study aimed to assess the relationship of Q and R with the established CFR/IMR in INOCA patients, to explore the potential of absolute Q, and to predict self-reported angina.
Methods
Consecutive INOCA patients (n = 84; 87% women; mean age 56 ± 8 years) underwent coronary function testing, including acetylcholine (ACH) provocation testing, adenosine (ADE) testing (CFR/IMR), and continuous thermodilution (absolute Q and R) with saline-induced hyperemia.
Results
ACH testing was abnormal (ACH+) in 87%, and ADE testing (ADE+) in 38%. The median absolute Q was 198 ml/min, and the median absolute R was 416 WU. The absolute R was higher in patients with ADE+ versus ADE- (495 WU vs. 375 WU; p = 0.04) but did not differ between patients with ACH+ versus ACH- (421 WU vs. 409 WU; p = 0.74). Low Q and high R were associated with severe angina (odds ratio: 3.09; 95% confidence interval: 1.16 to 8.28; p = 0.03; and odds ratio: 2.60; 95% confidence interval: 0.99 to 6.81; p = 0.05), respectively.
Conclusions
In this study, absolute R was higher in patients with abnormal CFR/IMR, whereas both Q and R were unrelated to coronary vasospasm. Q and R were associated with angina, although their exact predictive value should be determined in larger studies.

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

J Am Coll Cardiol: 15 Feb 2021; 77:728-741
Konst RE, Elias-Smale SE, Pellegrini D, Hartzema-Meijer M, ... van Royen N, Damman P
J Am Coll Cardiol: 15 Feb 2021; 77:728-741 | PMID: 33573743
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Abstract

Progression of Tricuspid Regurgitation After Surgery for Ischemic Mitral Regurgitation.

Bertrand PB, Overbey JR, Zeng X, Levine RA, ... Hung J, Cardiothoracic Surgical Trials Network (CTSN)
Background
Whether to repair nonsevere tricuspid regurgitation (TR) during surgery for ischemic mitral valve regurgitation (IMR) remains uncertain.
Objectives
The goal of this study was to investigate the incidence, predictors, and clinical significance of TR progression and presence of ≥moderate TR after IMR surgery.
Methods
Patients (n = 492) with untreated nonsevere TR within 2 prospectively randomized IMR trials were included. Key outcomes were TR progression (either progression by ≥2 grades, surgery for TR, or severe TR at 2 years) and presence of ≥moderate TR at 2 years.
Results
Patients\' mean age was 66 ± 10 years (67% male), and TR distribution was 60% ≤trace, 31% mild, and 9% moderate. Among 2-year survivors, TR progression occurred in 20 (6%) of 325 patients. Baseline tricuspid annular diameter (TAD) was not predictive of TR progression. At 2 years, 37 (11%) of 323 patients had ≥moderate TR. Baseline TR grade, indexed TAD, and surgical ablation for atrial fibrillation were independent predictors of ≥moderate TR. However, TAD alone had poor discrimination (area under the curve, ≤0.65). Presence of ≥moderate TR at 2 years was higher in patients with MR recurrence (20% vs. 9%; p = 0.02) and a permanent pacemaker/defibrillator (19% vs. 9%; p = 0.01). Clinical event rates (composite of ≥1 New York Heart Association functional class increase, heart failure hospitalization, mitral valve surgery, and stroke) were higher in patients with TR progression (55% vs. 23%; p = 0.003) and ≥moderate TR at 2 years (38% vs. 22%; p = 0.04).
Conclusions
After IMR surgery, progression of unrepaired nonsevere TR is uncommon. Baseline TAD is not predictive of TR progression and is poorly discriminative of ≥moderate TR at 2 years. TR progression and presence of ≥moderate TR are associated with clinical events. (Comparing the Effectiveness of a Mitral Valve Repair Procedure in Combination With Coronary Artery Bypass Grafting [CABG] Versus CABG Alone in People With Moderate Ischemic Mitral Regurgitation, NCT00806988; Comparing the Effectiveness of Repairing Versus Replacing the Heart\'s Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation, NCT00807040).

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

J Am Coll Cardiol: 15 Feb 2021; 77:713-724
Bertrand PB, Overbey JR, Zeng X, Levine RA, ... Hung J, Cardiothoracic Surgical Trials Network (CTSN)
J Am Coll Cardiol: 15 Feb 2021; 77:713-724 | PMID: 33573741
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Abstract

Natriuretic Equation to Predict Loop Diuretic Response in Patients With Heart Failure.

Rao VS, Ivey-Miranda JB, Cox ZL, Riello R, ... Collins SP, Testani JM
Background
Most acute decompensated heart failure admissions are driven by congestion. However, residual congestion is common and often driven by the lack of reliable tools to titrate diuretic therapy. The authors previously developed a natriuretic response prediction equation (NRPE), which predicts sodium output using a spot urine sample collected 2 h after loop diuretic administration.
Objectives
The purpose of this study was to validate the NRPE and describe proof-of-concept that the NRPE can be used to guide diuretic therapy.
Methods
Two cohorts were assembled: 1) the Diagnosing and Targeting Mechanisms of Diuretic Resistance (MDR) cohort was used to validate the NRPE to predict 6-h sodium output after a loop diuretic, which was defined as poor (<50 mmol), suboptimal (<100 mmol), or excellent (>150 mmol); and 2) the Yale Diuretic Pathway (YDP) cohort, which used the NRPE to guide loop diuretic titration via a nurse-driven automated protocol.
Results
Evaluating 638 loop diuretic administrations, the NRPE showed excellent discrimination with areas under the curve ≥0.90 to predict poor, suboptimal, and excellent natriuretic response, and outperformed clinically obtained net fluid loss (p < 0.05 for all cutpoints). In the YDP cohort (n = 161) using the NRPE to direct therapy mean daily urine output (1.8 ± 0.9 l vs. 3.0 ± 0.8 l), net fluid output (-1.1 ± 0.9 l vs. -2.1 ± 0.9 l), and weight loss (-0.3 ± 0.3 kg vs. -2.5 ± 0.3 kg) improved substantially following initiation of the YDP (p < 0.001 for all pre-post comparisons).
Conclusions
Natriuretic response can be rapidly and accurately predicted by the NRPE, and this information can be used to guide diuretic therapy during acute decompensated heart failure. Additional study of diuresis guided by the NRPE is warranted.

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

J Am Coll Cardiol: 15 Feb 2021; 77:695-708
Rao VS, Ivey-Miranda JB, Cox ZL, Riello R, ... Collins SP, Testani JM
J Am Coll Cardiol: 15 Feb 2021; 77:695-708 | PMID: 33573739
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Abstract

Intracranial Atherosclerotic Plaque as a Potential Cause of Embolic Stroke of Undetermined Source.

Tao L, Li XQ, Hou XW, Yang BQ, ... Ntaios G, Chen HS
Background
Previous studies investigated the potential mechanism of embolic stroke of undetermined source (ESUS) from extracranial artery plaque, but there has been no study other than a case report on high-risk intracranial plaque in ESUS.
Objectives
The aim of this study was to investigate the issue by evaluating the morphology and composition of intracranial plaque in patients with ESUS and small-vessel disease (SVD) using 3.0-T high-resolution magnetic resonance imaging.
Methods
Two hundred forty-three consecutive patients with ESUS and 160 patients with SVD-associated stroke between January 2015 and December 2019 were retrospectively enrolled. Multidimensional parameters involving the presence of plaque on both sides, including remodeling index (RI), plaque burden, presence of discontinuity of plaque surface, thick fibrous cap, intraplaque hemorrhage, and complicated American Heart Association type VI plaque at the maximal luminal narrowing site, were evaluated using intracranial high-resolution magnetic resonance imaging.
Results
Among 243 patients with ESUS, the prevalence of intracranial plaque was much higher in the ipsilateral than the contralateral side (63.8% vs. 42.8%; odds ratio [OR]: 5.25; 95% confidence interval [CI]: 2.83 to 9.73), a finding that was not evident in patients with SVD (35.6% vs. 30.6%; OR: 2.14; 95% CI: 0.87 to 5.26; p = 0.134). Logistic analysis showed that RI was independently associated with ESUS in model 1 (OR: 2.329; 95% CI: 1.686 to 3.217; p < 0.001) and model 2 (OR: 2.295; 95% CI: 1.661 to 3.172; p < 0.001). RI alone with an optimal cutoff of 1.162, corresponding to an area under the curve of 0.740, had good diagnostic efficiency for ESUS.
Conclusions
The present study supports an etiologic role of high-risk nonstenotic intracranial plaque in ESUS.

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

J Am Coll Cardiol: 15 Feb 2021; 77:680-691
Tao L, Li XQ, Hou XW, Yang BQ, ... Ntaios G, Chen HS
J Am Coll Cardiol: 15 Feb 2021; 77:680-691 | PMID: 33573737
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Impact:
Abstract

Pooled Analysis of PFO Occluder Device Trials in Patients With PFO and Migraine.

Mojadidi MK, Kumar P, Mahmoud AN, Elgendy IY, ... Silberstein SD, Tobis JM
Background
Although observational studies have shown percutaneous patent foramen ovale (PFO) closure to be a safe means of reducing the frequency and duration of migraine, randomized clinical trials have not met their primary efficacy endpoints.
Objectives
The authors report the results of a pooled analysis of individual participant data from the 2 randomized trials using the Amplatzer PFO Occluder to assess the efficacy and safety of percutaneous device closure as a therapy for episodic migraine with or without aura.
Methods
The authors analyzed individual patient-level data from 2 randomized migraine trials (the PRIMA [Percutaneous Closure of Patent Foramen Ovale in Migraine With Aura] and PREMIUM [Prospective Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects with Migraine and PFO Using the Amplatzer PFO Occluder Compared to Medical Management] studies). Efficacy endpoints were mean reduction in monthly migraine days, responder rate (defined as ≥50% reduction in monthly migraine attacks), mean reduction in monthly migraine attacks, and percentage of patients who experienced complete cessation of migraine. The safety endpoint was major procedure- and device-related adverse events.
Results
Among 337 subjects, 176 were randomized by blocks to device closure and 161 to medical treatment only. At 12-month follow-up, the analysis met 3 of the 4 efficacy endpoints: mean reduction of monthly migraine days (-3.1 days vs. -1.9 days; p = 0.02), mean reduction of monthly migraine attacks (-2.0 vs. -1.4; p = 0.01), and number of subjects who experienced complete cessation of migraine (14 [9%] vs. 1 [0.7%]; p < 0.001). For the safety analysis, 9 procedure-related and 4 device-related adverse events occurred in 245 subjects who eventually received devices. All events were transient and resolved.
Conclusions
This pooled analysis of patient-level data demonstrates that PFO closure was safe and significantly reduced the mean number of monthly migraine days and monthly migraine attacks, and resulted in a greater number of subjects who experienced complete migraine cessation.

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

J Am Coll Cardiol: 15 Feb 2021; 77:667-676
Mojadidi MK, Kumar P, Mahmoud AN, Elgendy IY, ... Silberstein SD, Tobis JM
J Am Coll Cardiol: 15 Feb 2021; 77:667-676 | PMID: 33573735
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Abstract

Red Yeast Rice for Hypercholesterolemia: JACC Focus Seminar.

Cicero AFG, Fogacci F, Zambon A
The extracts of red yeast rice (RYR) are currently the most effective cholesterol-lowering nutraceuticals. This activity is mainly due to monacolin K, a weak reversible inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, whose daily consumption causes a reduction in low-density lipoprotein (LDL)-cholesterol plasma levels up to 15% to 25% within 6 to 8 weeks. The decrease in LDL-cholesterol is accompanied by a proportional decrease in total and non-high-density lipoprotein cholesterol, plasma apolipoprotein B, and high-sensitivity C-reactive protein. Some trials suggest that RYR use is associated with improvement in endothelial function and arterial stiffness, whereas a long-term study supports its role in the prevention of cardiovascular events. Despite the statin-like mechanism of action, the risk related to 3 to 10 mg monacolin K taken per day is minimal (mild myalgia in previously severely statin-intolerant subjects). RYR could represent a therapeutic tool to support lifestyle improvement in managing mild to moderate hypercholesterolemia in low-risk patients, including those who cannot be treated with statins or other LDL-cholesterol-lowering therapies.

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

J Am Coll Cardiol: 08 Feb 2021; 77:620-628
Cicero AFG, Fogacci F, Zambon A
J Am Coll Cardiol: 08 Feb 2021; 77:620-628 | PMID: 33538260
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Abstract

Coenzyme Q for Patients With Cardiovascular Disease: JACC Focus Seminar.

Raizner AE, Quiñones MA
Coenzyme Q10 (CoQ10) is a naturally occurring compound that is found in animals and all humans. It has a fundamental role in cellular energy production. Although it is produced in the body, tissue deficiency can occur due to medications such as statins, which inhibit the mevalonate pathway. The clinical syndromes of statin-associated muscle symptoms (SAMS) and some of the features observed in patients with heart failure (HF) may be related to blood and tissue deficiency of CoQ10. Numerous clinical trials of CoQ10 in SAMS have yielded conflicting results. Yet, the weight of evidence as reflected in meta-analyses supports the use of exogenous CoQ10 in SAMS. In patients with HF, large-scale randomized clinical trials are lacking, although one relatively contemporary trial, Q-SYMBIO, suggests an adjunctive role for CoQ10. The possibility that statin-related CoQ10 deficiency may play a role in patients with diastolic HF is an intriguing hypothesis that warrants further exploration.

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

J Am Coll Cardiol: 08 Feb 2021; 77:609-619
Raizner AE, Quiñones MA
J Am Coll Cardiol: 08 Feb 2021; 77:609-619 | PMID: 33538259
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Impact:
Abstract

Cardiovascular Impact of Nutritional Supplementation With Omega-3 Fatty Acids: JACC Focus Seminar.

Weinberg RL, Brook RD, Rubenfire M, Eagle KA
Omega-3 polyunsaturated fatty acids (PUFAs) are a key component of a heart-healthy diet. For patients without clinical atherosclerotic cardiovascular disease, 2 or more servings of fatty fish per week is recommended to obtain adequate intake of omega-3 PUFAs. If this not possible, dietary supplementation with an appropriate fish oil may be reasonable. Supplementation with omega-3 PUFA capsules serves 2 distinct but overlapping roles: treatment of hypertriglyceridemia and prevention of cardiovascular events. Marine-derived omega-3 PUFAs reduce triglycerides and have pleiotropic effects including decreasing inflammation, improving plaque composition and stability, and altering cellular membranes. Clinical trial data have shown inconsistent results with omega-3 PUFAs improving cardiovascular outcomes. In this paper, the authors provide an overview of PUFAs and a summary of key clinical trial data. Recent trial data suggest the use of prescription eicosapentaenoic acid ethyl ester for atherosclerotic cardiovascular disease event reduction in selected populations.

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

J Am Coll Cardiol: 08 Feb 2021; 77:593-608
Weinberg RL, Brook RD, Rubenfire M, Eagle KA
J Am Coll Cardiol: 08 Feb 2021; 77:593-608 | PMID: 33538258
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Impact:
Abstract

Local Pressure Drives Low-Density Lipoprotein Accumulation and Coronary Atherosclerosis in Hypertensive Minipigs.

Al-Mashhadi RH, Al-Mashhadi AL, Nasr ZP, Mortensen MB, ... Vázquez J, Bentzon JF
Background
The mechanisms by which hypertension accelerates coronary artery disease are poorly understood. Patients with hypertension often have confounding humoral changes, and to date, no experimental models have allowed analysis of the isolated effect of pressure on atherosclerosis in a setting that recapitulates the dimensions and biomechanics of human coronary arteries.
Objectives
This study sought to analyze the effect of pressure on coronary atherosclerosis and explore the underlying mechanisms.
Methods
Using inflatable suprarenal aortic cuffs, we increased mean arterial pressure by >30 mm Hg in the cephalad body part of wild-type and hypercholesterolemic proprotein convertase subtilisin kexin type 9 (PCSK9)D374Y Yucatan minipigs for >1 year. Caudal pressures remained normal.
Results
Under hypercholesterolemic conditions in PCSK9D374Y transgenic minipigs, cephalad hypertension accelerated coronary atherosclerosis to almost 5-fold with consistent development of fibroatheromas that were sufficiently large to cause stenosis on computed tomography angiography. This was caused by local pressure forces, because vascular beds shielded from hypertension, but exposed to the same humoral factors, showed no changes in lesion formation. The same experiment was conducted under normocholesterolemic conditions in wild-type minipigs to examine the underlying mechanisms. Hypertension produced clear changes in the arterial proteome with increased abundance of mechanical strength proteins and reduced levels of infiltrating plasma macromolecules. This was paralleled by increased smooth muscle cells and increased intimal accumulation of low-density lipoproteins in the coronary arteries.
Conclusions
Increased pressure per se facilitates coronary atherosclerosis. Our data indicate that restructuring of the artery to match increased tensile forces in hypertension alters the passage of macromolecules and leads to increased intimal accumulation of low-density lipoproteins.

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

J Am Coll Cardiol: 08 Feb 2021; 77:575-589
Al-Mashhadi RH, Al-Mashhadi AL, Nasr ZP, Mortensen MB, ... Vázquez J, Bentzon JF
J Am Coll Cardiol: 08 Feb 2021; 77:575-589 | PMID: 33538256
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Impact:
Abstract

Association of NT-ProBNP, Blood Pressure, and Cardiovascular Events: The ARIC Study.

Hussain A, Sun W, Deswal A, de Lemos JA, ... Ballantyne CM, Nambi V
Background
Although intensive blood pressure reduction has cardiovascular benefits, the absolute benefit is greater in those at higher cardiovascular disease (CVD) risk.
Objectives
This study examined whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) helps identify subjects at higher risk for CVD events across systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse pressure (PP) categories.
Methods
Participants from the ARIC (Atherosclerosis Risk In Communities) study visit 4 (1996 to 98) were grouped according to SBP, DBP, or PP categories and further stratified by NT-proBNP categories. Cox regression models were used to estimate hazard ratios for incident CVD (coronary heart disease, ischemic stroke, or heart failure hospitalization) and mortality across combined NT-proBNP and/or BP categories, adjusting for CVD risk factors.
Results
There were 9,309 participants (age: 62.6 ± 5.6 years; 58.3% women) with 2,416 CVD events over a median follow-up of 16.7 years. Within each SBP, DBP, or PP category, a higher category of NT-proBNP (100 to <300 or 300 pg/ml, compared with NT-proBNP <100 pg/ml) was associated with a graded increased risk for CVD events and mortality. Participants with SBP 130 to 139 mm Hg but NT-proBNP ≥300 pg/ml had a hazards ratio of 3.4 for CVD (95% confidence interval: 2.44 to 4.77) compared with a NT-proBNP of <100 pg/ml and SBP of 140 to 149 mm Hg.
Conclusions
Elevated NT-proBNP is independently associated with CVD and mortality across SBP, DBP, and PP categories and helps identify subjects at the highest risk. Participants with stage 1 hypertension but elevated NT-proBNP had greater cardiovascular risk compared with those with stage 2 SBP but lower NT-proBNP. Future studies are needed to evaluate use of biomarker-based strategies for CVD risk assessment to assist with initiation or intensification of BP treatment.

Published by Elsevier Inc.

J Am Coll Cardiol: 08 Feb 2021; 77:559-571
Hussain A, Sun W, Deswal A, de Lemos JA, ... Ballantyne CM, Nambi V
J Am Coll Cardiol: 08 Feb 2021; 77:559-571 | PMID: 33538254
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Impact:
Abstract

Prospective Cohort Study of Infective Endocarditis in People Who Inject Drugs.

Pericàs JM, Llopis J, Athan E, Hernández-Meneses M, ... Miró JM, International Collaboration on Endocarditis (ICE) Investigators
Background
Infective endocarditis (IE) in people who inject drugs (PWID) is an emergent public health problem.
Objectives
The purpose of this study was to investigate IE in PWID and compare it with IE in non-PWID patients.
Methods
Two prospective cohort studies (ICE-PCS and ICE-Plus databases, encompassing 8,112 IE episodes from 2000 to 2006 and 2008 to 2012, with 64 and 34 sites and 28 and 18 countries, respectively). Outcomes were compared between PWID and non-PWID patients with IE. Logistic regression analyses were performed to investigate risk factors for 6-month mortality and relapses amongst PWID.
Results
A total of 7,616 patients (591 PWID and 7,025 non-PWID) were included. PWID patients were significantly younger (median 37.0 years [interquartile range: 29.5 to 44.2 years] vs. 63.3 years [interquartile range: 49.3 to 74.0 years]; p < 0.001), male (72.5% vs. 67.4%; p = 0.007), and presented lower rates of comorbidities except for human immunodeficiency virus, liver disease, and higher rates of prior IE. Amongst IE cases in PWID, 313 (53%) episodes involved left-side valves and 204 (34.5%) were purely left-sided IE. PWID presented a larger proportion of native IE (90.2% vs. 64.4%; p < 0.001), whereas prosthetic-IE and cardiovascular implantable electronic device-IE were more frequent in non-PWID (9.3% vs. 27.0% and 0.5% vs. 8.6%; both p < 0.001). Staphylococcus aureus caused 65.9% and 26.8% of cases in PWID and non-PWID, respectively (p < 0.001). PWID presented higher rates of systemic emboli (51.1% vs. 22.5%; p < 0.001) and persistent bacteremia (14.7% vs. 9.3%; p < 0.001). Cardiac surgery was less frequently performed (39.5% vs. 47.8%; p < 0.001), and in-hospital and 6-month mortality were lower in PWID (10.8% vs. 18.2% and 14.4% vs. 22.2%; both p < 0.001), whereas relapses were more frequent in PWID (9.5% vs. 2.8%; p < 0.001). Prior IE, left-sided IE, polymicrobial etiology, intracardiac complications, and stroke were risk factors for 6-month mortality, whereas cardiac surgery was associated with lower mortality in the PWID population.
Conclusions
A notable proportion of cases in PWID involve left-sided valves, prosthetic valves, or are caused by microorganisms other than S. aureus.

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

J Am Coll Cardiol: 08 Feb 2021; 77:544-555
Pericàs JM, Llopis J, Athan E, Hernández-Meneses M, ... Miró JM, International Collaboration on Endocarditis (ICE) Investigators
J Am Coll Cardiol: 08 Feb 2021; 77:544-555 | PMID: 33538252
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Abstract

Mortality 10 Years After Percutaneous or Surgical Revascularization in Patients With Total Coronary Artery Occlusions.

Kawashima H, Takahashi K, Ono M, Hara H, ... Onuma Y, SYNTAX Extended Survival Investigators
Background
The long-term clinical benefit after percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with total occlusions (TOs) and complex coronary artery disease has not yet been clarified.
Objectives
The objective of this analysis was to assess 10-year all-cause mortality in patients with TOs undergoing PCI or CABG.
Methods
This is a subanalysis of patients with at least 1 TO in the SYNTAXES (Synergy Between PCI With Taxus and Cardiac Surgery Extended Survival) study, which investigated 10-year all-cause mortality in the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) trial, beyond its original 5-year follow-up. Patients with TOs were further stratified according to the status of TO recanalization or revascularization.
Results
Of 1,800 randomized patients to the PCI or CABG arm, 460 patients had at least 1 lesion of TO. In patients with TOs, the status of TO recanalization or revascularization was not associated with 10-year all-cause mortality, irrespective of the assigned treatment (PCI arm: 29.9% vs. 29.4%; adjusted hazard ratio [HR]: 0.992; 95% confidence interval [CI]: 0.474 to 2.075; p = 0.982; and CABG arm: 28.0% vs. 21.4%; adjusted HR: 0.656; 95% CI: 0.281 to 1.533; p = 0.330). When TOs existed in left main and/or left anterior descending artery, the status of TO recanalization or revascularization did not have an impact on the mortality (34.5% vs. 26.9%; adjusted HR: 0.896; 95% CI: 0.314 to 2.555; p = 0.837).
Conclusions
At 10-year follow-up, the status of TO recanalization or revascularization did not affect mortality, irrespective of the assigned treatment and location of TOs. The present study might support contemporary practice among high-volume chronic TO-PCI centers where recanalization is primarily offered to patients for the management of angina refractory to medical therapy when myocardial viability is confirmed. (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES]; NCT03417050; SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX]; NCT00114972).

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 08 Feb 2021; 77:529-540
Kawashima H, Takahashi K, Ono M, Hara H, ... Onuma Y, SYNTAX Extended Survival Investigators
J Am Coll Cardiol: 08 Feb 2021; 77:529-540 | PMID: 33538250
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Abstract

Rivaroxaban Plus Aspirin in Obese and Overweight Patients With Vascular Disease in the COMPASS Trial.

Guzik TJ, Ramasundarahettige C, Pogosova N, Lopez-Jaramillo P, ... Yusuf S, Eikelboom JW
Background
Direct oral anticoagulants are administered in fixed doses irrespective of body weight, but guidelines recommend against their use in patients with extremes of body weight.
Objectives
This study determined the effects of dual-pathway inhibition antithrombotic regimen (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg/day) compared with aspirin Halone across a range of patient body mass indexes (BMIs) and body weights.
Methods
This was a secondary analysis of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial, which included patients with chronic coronary artery disease or peripheral artery disease. Efficacy and safety outcomes were studied in relation to BMI: (normal 18.5 ≤BMI <25 kg/m2, overweight 25 ≤BMI <30 kg/m2, obese ≥30 kg/m2) and body weight (≤70 kg, 70 < weight ≤90 kg, and >90 kg; as well as ≤120 kg vs. >120 kg).
Results
Among 27,395 randomized patients, 6,459 (24%) had normal BMI, 12,047 (44%) were overweight, and 8,701 (32%) were obese. The combination of rivaroxaban and aspirin compared with aspirin produced a consistent reduction in the primary outcome of cardiovascular death, stroke, or myocardial infarction, irrespective of BMI or body weight. For 18.5 ≤BMI <25 kg/m2: 3.5% vs. 5.0%; hazard ratio (HR): 0.73 (95% credible interval [CrI]: 0.58 to 0.90); 25 ≤ BMI <30 kg/m2: 4.3% vs. 5.1%; HR: 0.80 (95% CrI: 0.66 to 0.96); BMI ≥30 kg/m2: 4.2% vs. 6.1%; HR: 0.71 (95% CrI: 0.57 to 0.86). For body weight ≤70 kg: 4.1% vs. 5.3%; HR: 0.75 (95% CrI: 0.62 to 0.91); 70 < weight ≤90 kg: 4.1% vs. 5.3%; HR: 0.76 (95% CrI: 0.65 to 0.89); >90 kg: 4.2% vs. 5.7%; HR: 0.74 (95% CrI: 0.61 to 0.90). Effects on bleeding, mortality, and net clinical benefit were consistent irrespective of BMI or bodyweight.
Conclusions
The effects of dual-pathway antithrombotic therapy are consistent irrespective of BMI or body weight, suggesting no need for dose adjustments in the ranges of weights and BMI of patients enrolled in the COMPASS trial. Further studies need to address this problem in relation to greater extremes of body weight. (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease [COMPASS]; NCT01776424).

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

J Am Coll Cardiol: 08 Feb 2021; 77:511-525
Guzik TJ, Ramasundarahettige C, Pogosova N, Lopez-Jaramillo P, ... Yusuf S, Eikelboom JW
J Am Coll Cardiol: 08 Feb 2021; 77:511-525 | PMID: 33538248
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Impact:
Abstract

Strain-Guided Management of Potentially Cardiotoxic Cancer Therapy.

Thavendiranathan P, Negishi T, Somerset E, Negishi K, ... Marwick TH, SUCCOUR Investigators
Background
In patients at risk of cancer therapy-related cardiac dysfunction (CTRCD), initiation of cardioprotective therapy (CPT) is constrained by the low sensitivity of ejection fraction (EF) for minor changes in left ventricular (LV) function. Global longitudinal strain (GLS) is a robust and sensitive marker of LV dysfunction, but existing observational data have been insufficient to support a routine GLS-guided strategy for CPT.
Objectives
This study sought to identify whether GLS-guided CPT prevents reduction in LVEF and development of CTRCD in high-risk patients undergoing potentially cardiotoxic chemotherapy, compared with usual care.
Methods
In this international, multicenter, prospective, randomized controlled trial, 331 anthracycline-treated patients with another heart failure risk factor were randomly allocated to CPT initiation guided by either ≥12% relative reduction in GLS (n = 166) or >10% absolute reduction of LVEF (n = 165). Patients were followed for EF and development of CTRCD (symptomatic EF reduction of >5% or >10% asymptomatic to <55%) over 1 year.
Results
Of 331 randomized patients, 2 died, and 22 withdrew consent or were lost to follow-up. Among 307 patients (age: 54 ± 12 years; 94% women; baseline LVEF: 59 ± 6%; GLS: -20.6 ± 2.4%) with a median (interquartile range) follow-up of 1.02 years (0.98 to 1.07 years), most (n = 278) had breast cancer. Heart failure risk factors were prevalent: 29% had hypertension, and 13% had diabetes mellitus. At the 1-year follow-up, although the primary outcome of change in LVEF was not significantly different between the 2 arms, there was significantly greater use of CPT, and fewer patients met CTRCD criteria in the GLS-guided than the EF-guided arm (5.8% vs. 13.7%; p = 0.02), and the 1-year EF was 57 ± 6% versus 55 ± 7% (p = 0.05). Patients who received CPT in the EF-guided arm had a larger reduction in LVEF at follow-up than in the GLS-guided arm (9.1 ± 10.9% vs. 2.9 ± 7.4%; p = 0.03).
Conclusions
Although the change in LVEF was not different between the 2 arms as a whole, when patients who received CPT were compared, those in the GLS-guided arm had a significantly lower reduction in LVEF at 1 year follow-up. Furthermore, GLS-guided CPT significantly reduced a meaningful fall of LVEF to the abnormal range. The results support the use of GLS in surveillance for CTRCD. (Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes [SUCCOUR]; ACTRN12614000341628).

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

J Am Coll Cardiol: 01 Feb 2021; 77:392-401
Thavendiranathan P, Negishi T, Somerset E, Negishi K, ... Marwick TH, SUCCOUR Investigators
J Am Coll Cardiol: 01 Feb 2021; 77:392-401 | PMID: 33220426
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Impact:
Abstract

2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

Writing Committee Members, Otto CM, Nishimura RA, Bonow RO, ... Thompson A, Toly C
Aim
This executive summary of the valvular heart disease guideline provides recommendations for clinicians to diagnose and manage valvular heart disease as well as supporting documentation to encourage their use.
Methods
A comprehensive literature search was conducted from January 1, 2010, to March 1, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, Cochrane, Agency for Healthcare Research and Quality Reports, and other selected database relevant to this guideline.
Structure
Many recommendations from the earlier valvular heart disease guidelines have been updated with new evidence and provides newer options for diagnosis and treatment of valvular heart disease. This summary includes only the recommendations from the full guideline which focus on diagnostic work-up, the timing and choice of surgical and catheter interventions, and recommendations for medical therapy. The reader is referred to the full guideline for graphical flow charts, text, and tables with additional details about the rationale for and implementation of each recommendation, and the evidence tables detailing the data considered in developing these guidelines.

Copyright © 2021 American College of Cardiology Foundation and the American Heart Association, Inc. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 01 Feb 2021; 77:450-500
Writing Committee Members, Otto CM, Nishimura RA, Bonow RO, ... Thompson A, Toly C
J Am Coll Cardiol: 01 Feb 2021; 77:450-500 | PMID: 33342587
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Abstract

Vitamin D, Calcium Supplements, and Implications for Cardiovascular Health: JACC Focus Seminar.

Michos ED, Cainzos-Achirica M, Heravi AS, Appel LJ
Vitamin D and calcium supplements are commonly used, often together, to optimize bone health. Multiple observational studies have linked low serum 25-hydroxyvitamin D concentrations with increased cardiovascular risk. However, subsequent randomized controlled trials (RCTs) failed to demonstrate cardiovascular benefit with vitamin D supplementation. Although vitamin D supplements do not appear to be harmful for cardiovascular health, the lack of benefit in RCTs should discourage their use for this purpose, favoring optimizing vitamin D status through healthy lifestyles such as specific foods and modest sunlight exposure. Furthermore, some (but not all) observational and RCT studies of calcium supplementation have suggested potential for cardiovascular harm. Therefore, calcium supplementation should be used cautiously, striving for recommended intake of calcium predominantly from food sources. In this review, the authors examine the currently available evidence investigating whether vitamin D and calcium supplements are helpful, harmful, or neutral for cardiovascular health.

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

J Am Coll Cardiol: 01 Feb 2021; 77:437-449
Michos ED, Cainzos-Achirica M, Heravi AS, Appel LJ
J Am Coll Cardiol: 01 Feb 2021; 77:437-449 | PMID: 33509400
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Impact:
Abstract

Supplemental Vitamins and Minerals for Cardiovascular Disease Prevention and Treatment: JACC Focus Seminar.

Jenkins DJA, Spence JD, Giovannucci EL, Kim YI, ... Pichika SC, Sievenpiper JL
This is an update of the previous 2018 systematic review and meta-analysis of vitamin and mineral supplementation on cardiovascular disease outcomes and all-cause mortality. New randomized controlled trials and meta-analyses were identified by searching the Cochrane library, Medline, and Embase, and data were analyzed using random effects models and classified by the Grading of Recommendations Assessment Development and Evaluation approach. This updated review shows similar findings to the previous report for preventive benefits from both folic acid and B vitamins for stroke and has been graded with moderate quality. No effect was seen for the commonly used multivitamins, vitamin D, calcium, and vitamin C, and an increased risk was seen with niacin (with statin) for all-cause mortality. Conclusive evidence for the benefit of supplements across different dietary backgrounds, when the nutrient is sufficient, has not been demonstrated.

Copyright © 2021. Published by Elsevier Inc.

J Am Coll Cardiol: 01 Feb 2021; 77:423-436
Jenkins DJA, Spence JD, Giovannucci EL, Kim YI, ... Pichika SC, Sievenpiper JL
J Am Coll Cardiol: 01 Feb 2021; 77:423-436 | PMID: 33509399
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Abstract

Etiology-Dependent Impairment of Diastolic Cardiomyocyte Calcium Homeostasis in Heart Failure With Preserved Ejection Fraction.

Frisk M, Le C, Shen X, Røe ÅT, ... Altara R, Louch WE
Background
Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF.
Objectives
This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF.
Methods
T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions.
Results
HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models.
Conclusions
Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.

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

J Am Coll Cardiol: 01 Feb 2021; 77:405-419
Frisk M, Le C, Shen X, Røe ÅT, ... Altara R, Louch WE
J Am Coll Cardiol: 01 Feb 2021; 77:405-419 | PMID: 33509397
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Impact:
Abstract

Prognostic Implications of Declining Hemoglobin Content in Patients Hospitalized With Acute Coronary Syndromes.

Leonardi S, Gragnano F, Carrara G, Gargiulo G, ... Windecker S, Valgimigli M
Background
Contemporary definitions of bleeding endpoints are restricted mostly to clinically overt events. Whether hemoglobin drop per se, with or without overt bleeding, adversely affects the prognosis of patients with acute coronary syndrome (ACS) remains unclear.
Objectives
The aim of this study was to examine in the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial the incidence, predictors, and prognostic implications of in-hospital hemoglobin drop in patients with ACS managed invasively stratified by the presence of in-hospital bleeding.
Methods
Patients were categorized by the presence and amount of in-hospital hemoglobin drop on the basis of baseline and nadir hemoglobin values and further stratified by the occurrence of adjudicated in-hospital bleeding. Hemoglobin drop was defined as minimal (<3 g/dl), minor (≥3 and <5 g/dl), or major (≥5 g/dl). Using multivariate Cox regression, we modeled the association between hemoglobin drop and mortality in patients with and without overt bleeding.
Results
Among 7,781 patients alive 24 h after randomization with available hemoglobin data, 6,504 patients (83.6%) had hemoglobin drop, of whom 5,756 (88.5%) did not have overt bleeding and 748 (11.5%) had overt bleeding. Among patients without overt bleeding, minor (hazard ratio [HR]: 2.37; 95% confidence interval [CI]: 1.32 to 4.24; p = 0.004) and major (HR: 2.58; 95% CI: 0.98 to 6.78; p = 0.054) hemoglobin drop were independently associated with higher 1-year mortality. Among patients with overt bleeding, the association of minor and major hemoglobin drop with 1-year mortality was directionally similar but had wider CIs (minor: HR: 3.53 [95% CI: 1.06 to 11.79]; major: HR: 13.32 [95% CI: 3.01 to 58.98]).
Conclusions
Among patients with ACS managed invasively, in-hospital hemoglobin drop ≥3 g/dl, even in the absence of overt bleeding, is common and is independently associated with increased risk for 1-year mortality. (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox; NCT01433627).

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

J Am Coll Cardiol: 01 Feb 2021; 77:375-388
Leonardi S, Gragnano F, Carrara G, Gargiulo G, ... Windecker S, Valgimigli M
J Am Coll Cardiol: 01 Feb 2021; 77:375-388 | PMID: 33509394
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Impact:
Abstract

Risk Stratification Among Survivors of Cardiac Arrest Considered for Coronary Angiography.

Harhash AA, May TL, Hsu CH, Agarwal S, ... Rab T, Kern KB
Background
The American College of Cardiology Interventional Council published consensus-based recommendations to help identify resuscitated cardiac arrest patients with unfavorable clinical features in whom invasive procedures are unlikely to improve survival.
Objectives
This study sought to identify how many unfavorable features are required before prognosis is significantly worsened and which features are most impactful in predicting prognosis.
Methods
Using the INTCAR (International Cardiac Arrest Registry), the impact of each proposed \"unfavorable feature\" on survival to hospital discharge was individually analyzed. Logistic regression was performed to assess the association of such unfavorable features with poor outcomes.
Results
Seven unfavorable features (of 10 total) were captured in 2,508 patients successfully resuscitated after cardiac arrest (ongoing cardiopulmonary resuscitation and noncardiac etiology were exclusion criteria in our registry). Chronic kidney disease was used in lieu of end-stage renal disease. In total, 39% survived to hospital discharge. The odds ratio (OR) of survival to hospital discharge for each unfavorable feature was as follows: age >85 years OR: 0.30 (95% CI: 0.15 to 0.61), time-to-ROSC >30 min OR: 0.30 (95% CI: 0.23 to 0.39), nonshockable rhythm OR: 0.39 (95% CI: 0.29 to 0.54), no bystander cardiopulmonary resuscitation OR: 0.49 (95% CI: 0.38 to 0.64), lactate >7 mmol/l OR: 0.50 (95% CI: 0.40 to 0.63), unwitnessed arrest OR: 0.58 (95% CI: 0.44 to 0.78), pH <7.2 OR: 0.78 (95% CI: 0.63 to 0.98), and chronic kidney disease OR: 0.96 (95% CI: 0.70 to 1.33). The presence of any 3 or more unfavorable features predicted <40% survival. Presence of the 3 strongest risk factors (age >85 years, time-to-ROSC >30 min, and non-ventricular tachycardia/ventricular fibrillation) together or ≥6 unfavorable features predicted a ≤10% chance of survival to discharge.
Conclusions
Patients successfully resuscitated from cardiac arrest with 6 or more unfavorable features have a poor long-term prognosis. Delaying or even forgoing invasive procedures in such patients is reasonable.

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

J Am Coll Cardiol: 01 Feb 2021; 77:360-371
Harhash AA, May TL, Hsu CH, Agarwal S, ... Rab T, Kern KB
J Am Coll Cardiol: 01 Feb 2021; 77:360-371 | PMID: 33509392
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Impact:
Abstract

Feasibility Study of the Transcatheter Valve Repair System for Severe Tricuspid Regurgitation.

Kodali S, Hahn RT, Eleid MF, Kipperman R, ... Davidson CJ, CLASP TR EFS Investigators
Background
Tricuspid regurgitation (TR) is a prevalent disease with limited treatment options.
Objectives
This is the first 30-day report of the U.S. single-arm, multicenter, prospective CLASP TR early feasibility study of the PASCAL transcatheter valve repair system in the treatment of TR.
Methods
Patients with symptomatic TR despite optimal medical therapy, reviewed by the local heart team and central screening committee, were eligible for the study. Data were collected at baseline, discharge, and the 30-day follow-up and were reviewed by an independent clinical events committee and echocardiographic core laboratory. Feasibility endpoints included safety (composite major adverse event [MAE] rate), echocardiographic, clinical, and functional endpoints.
Results
Of the 34 patients enrolled in the study, the mean age was 76 years, 53% were women, the mean Society of Thoracic Surgeons score was 7.3%, 88% had atrial fibrillation/flutter, 97% had severe or greater TR, and 79% had New York Heart Association (NYHA) functional class III/IV symptoms. Twenty-nine patients (85%) received implants; at 30 days, 85% of them achieved a TR severity reduction of at least 1 grade, with 52% with moderate or less TR (p < 0.001). The MAE rate was 5.9%, and none of the patients experienced cardiovascular mortality, stroke, myocardial infarction, renal complication, or reintervention. Eighty-nine percent of the patients improved to NYHA functional class I/II (p < 0.001), the mean 6-min walk distance improved by 71 m (p < 0.001), and the mean Kansas City Cardiomyopathy Questionnaire score improved by 15 points (p < 0.001).
Conclusions
In this early experience, the repair system performed as intended, with substantial TR reduction, favorable safety results with a low MAE rate, no mortality or reintervention, and significant improvements in functional status, exercise capacity, and quality of life. (Edwards CLASP TR EFS [CLASP TR EFS]; NCT03745313).

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

J Am Coll Cardiol: 01 Feb 2021; 77:345-356
Kodali S, Hahn RT, Eleid MF, Kipperman R, ... Davidson CJ, CLASP TR EFS Investigators
J Am Coll Cardiol: 01 Feb 2021; 77:345-356 | PMID: 33509390
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Impact:
Abstract

Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization.

Oyama K, Furtado RHM, Fagundes A, Zelniker TA, ... Sabatine MS, Bergmark BA
Objectives
This study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization.
Background
PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall.
Methods
FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length >60 mm) or coronary artery bypass grafting surgery (CABG).
Results
In this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p < 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p < 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p < 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p < 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years).
Conclusions
Adding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.).

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

J Am Coll Cardiol: 25 Jan 2021; 77:259-267
Oyama K, Furtado RHM, Fagundes A, Zelniker TA, ... Sabatine MS, Bergmark BA
J Am Coll Cardiol: 25 Jan 2021; 77:259-267 | PMID: 33197560
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Abstract

Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction.

Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, Garcia-Ropero A, ... Badimon JJ, EMPA-TROPISM (ATRU-4) Investigators
Background
Large clinical trials established the benefits of sodium-glucose cotransporter 2 inhibitors in patients with diabetes and with heart failure with reduced ejection fraction (HFrEF). The early and significant improvement in clinical outcomes is likely explained by effects beyond a reduction in hyperglycemia.
Objectives
The purpose of this study was to assess the effect of empagliflozin on left ventricular (LV) function and volumes, functional capacity, and quality of life (QoL) in nondiabetic HFrEF patients.
Methods
In this double-blind, placebo-controlled trial, nondiabetic HFrEF patients (n = 84) were randomized to empagliflozin 10 mg daily or placebo for 6 months. The primary endpoint was change in LV end-diastolic and -systolic volume assessed by cardiac magnetic resonance. Secondary endpoints included changes in LV mass, LV ejection fraction, peak oxygen consumption in the cardiopulmonary exercise test, 6-min walk test, and quality of life.
Results
Empagliflozin was associated with a significant reduction of LV end-diastolic volume (-25.1 ± 26.0 ml vs. -1.5 ± 25.4 ml for empagliflozin vs. placebo, respectively; p < 0.001) and LV end-systolic volume (-26.6 ± 20.5 ml vs. -0.5 ± 21.9 ml for empagliflozin vs. placebo; p < 0.001). Empagliflozin was associated with reductions in LV mass (-17.8 ± 31.9 g vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively; p < 0.001) and LV sphericity, and improvements in LV ejection fraction (6.0 ± 4.2 vs. -0.1 ± 3.9; p < 0.001). Patients who received empagliflozin had significant improvements in peak O2 consumption (1.1 ± 2.6 ml/min/kg vs. -0.5 ± 1.9 ml/min/kg for empagliflozin vs. placebo, respectively; p = 0.017), oxygen uptake efficiency slope (111 ± 267 vs. -145 ± 318; p < 0.001), as well as in 6-min walk test (81 ± 64 m vs. -35 ± 68 m; p < 0.001) and quality of life (Kansas City Cardiomyopathy Questionnaire-12: 21 ± 18 vs. 2 ± 15; p < 0.001).
Conclusions
Empagliflozin administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality of life when compared with placebo. Our observations strongly support a role for sodium-glucose cotransporter 2 inhibitors in the treatment of HFrEF patients independently of their glycemic status. (Are the \"Cardiac Benefits\" of Empagliflozin Independent of Its Hypoglycemic Activity? [ATRU-4] [EMPA-TROPISM]; NCT03485222).

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

J Am Coll Cardiol: 25 Jan 2021; 77:243-255
Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, Garcia-Ropero A, ... Badimon JJ, EMPA-TROPISM (ATRU-4) Investigators
J Am Coll Cardiol: 25 Jan 2021; 77:243-255 | PMID: 33197559
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Abstract

Pathological Evidence for SARS-CoV-2 as a Cause of Myocarditis: JACC Review Topic of the Week.

Kawakami R, Sakamoto A, Kawai K, Gianatti A, ... Virmani R, Finn AV
To investigate whether severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-induced myocarditis constitutes an important mechanism of cardiac injury, a review was conducted of the published data and the authors\' experience was added from autopsy examination of 16 patients dying of SARS-CoV-2 infection. Myocarditis is an uncommon pathologic diagnosis occurring in 4.5% of highly selected cases undergoing autopsy or endomyocardial biopsy. Although polymerase chain reaction-detectable virus could be found in the lungs of most coronavirus disease-2019 (COVID-19)-infected subjects in our own autopsy registry, in only 2 cases was the virus detected in the heart. It should be appreciated that myocardial inflammation alone by macrophages and T cells can be seen in noninfectious deaths and COVID-19 cases, but the extent of each is different, and in neither case do such findings represent clinically relevant myocarditis. Given its extremely low frequency and unclear therapeutic implications, the authors do not advocate use of endomyocardial biopsy to diagnose myocarditis in the setting of COVID-19.

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

J Am Coll Cardiol: 25 Jan 2021; 77:314-325
Kawakami R, Sakamoto A, Kawai K, Gianatti A, ... Virmani R, Finn AV
J Am Coll Cardiol: 25 Jan 2021; 77:314-325 | PMID: 33478655
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Abstract

Machine Learning and the Future of Cardiovascular Care: JACC State-of-the-Art Review.

Quer G, Arnaout R, Henne M, Arnaout R
The role of physicians has always been to synthesize the data available to them to identify diagnostic patterns that guide treatment and follow response. Today, increasingly sophisticated machine learning algorithms may grow to support clinical experts in some of these tasks. Machine learning has the potential to benefit patients and cardiologists, but only if clinicians take an active role in bringing these new algorithms into practice. The aim of this review is to introduce clinicians who are not data science experts to key concepts in machine learning that will allow them to better understand the field and evaluate new literature and developments. The current published data in machine learning for cardiovascular disease is then summarized, using both a bibliometric survey, with code publicly available to enable similar analysis for any research topic of interest, and select case studies. Finally, several ways that clinicians can and must be involved in this emerging field are presented.

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

J Am Coll Cardiol: 25 Jan 2021; 77:300-313
Quer G, Arnaout R, Henne M, Arnaout R
J Am Coll Cardiol: 25 Jan 2021; 77:300-313 | PMID: 33478654
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