Journal: JAMA Cardiol

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Abstract

Exercise Capacity in Young Adults Born Small for Gestational Age.

Crispi F, Rodríguez-López M, Bernardino G, Sepúlveda-Martínez Á, ... Bijnens B, Gratacós E
Importance
Being born small for gestational age (SGA), approximately 10% of all births, is associated with increased risk of cardiovascular mortality in adulthood, but mechanistic pathways are unclear. Cardiac remodeling and dysfunction occur in fetuses SGA and children born SGA, but it is uncertain whether and how these changes persist into adulthood.
Objective
To evaluate baseline cardiac function and structure and exercise capacity in young adults born SGA.
Design, setting, and participants
This cohort study conducted from January 2015 to January 2018 assessed a perinatal cohort born at a tertiary university hospital in Spain between 1975 and 1995. Participants included 158 randomly selected young adults aged 20 to 40 years born SGA (birth weight below the 10th centile) or with intrauterine growth within standard reference ranges (controls). Participants provided their medical history, filled out questionnaires regarding smoking and physical activity habits, and underwent incremental cardiopulmonary exercise stress testing, cardiac magnetic resonance imaging, and a physical examination, with blood pressure, glucose level, and lipid profile data collected.
Exposure
Being born SGA.
Main outcomes and measures
Cardiac structure and function assessed by cardiac magnetic resonance imaging, including biventricular end-diastolic shape analysis. Exercise capacity assessed by incremental exercise stress testing.
Results
This cohort study included 81 adults born SGA (median age at study, 34.4 years [IQR, 30.8-36.7 years]; 43 women [53%]) and 77 control participants (median age at study, 33.7 years [interquartile range (IQR), 31.0-37.1 years]; 33 women [43%]). All participants were of White race/ethnicity and underwent imaging, whereas 127 participants (80% of the cohort; 66 control participants and 61 adults born SGA) completed the exercise test. Cardiac shape analysis showed minor changes at rest in right ventricular geometry (DeLong test z, 2.2098; P = .02) with preserved cardiac function in individuals born SGA. However, compared with controls, adults born SGA had lower exercise capacity, with decreased maximal workload (mean [SD], 180 [62] W vs 214 [60] W; P = .006) and oxygen consumption (median, 26.0 mL/min/kg [IQR, 21.5-33.5 mL/min/kg vs 29.5 mL/min/kg [IQR, 24.0-36.0 mL/min/kg]; P = .02). Exercise capacity was significantly correlated with left ventricular mass (ρ = 0.7934; P < .001).

Conclusions:
and relevance
This cohort of young adults born SGA had markedly reduced exercise capacity. These results support further research to clarify the causes of impaired exercise capacity and the potential association with increased cardiovascular mortality among adults born SGA.



JAMA Cardiol: 20 Jul 2021; epub ahead of print
Crispi F, Rodríguez-López M, Bernardino G, Sepúlveda-Martínez Á, ... Bijnens B, Gratacós E
JAMA Cardiol: 20 Jul 2021; epub ahead of print | PMID: 34287644
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Impact:
Abstract

Posttraumatic Stress Disorder and Cardiovascular Disease: State of the Science, Knowledge Gaps, and Research Opportunities.

O\'Donnell CJ, Schwartz Longacre L, Cohen BE, Fayad ZA, ... Sopko G, Stein MB
Posttraumatic stress disorder (PTSD) is characterized by a persistent maladaptive reaction after exposure to severe psychological trauma. Traumatic events that may precipitate PTSD include violent personal assaults, natural and human-made disasters, and exposure to military combat or warfare. There is a growing body of evidence for associations of PTSD with major risk factors for cardiovascular disease (CVD), such as hypertension and diabetes, as well as with major CVD outcomes, such as myocardial infarction and heart failure. However, it is unclear whether these associations are causal or confounded. Furthermore, the biological and behavioral mechanisms underlying these associations are poorly understood. Here, the available evidence on the association of PTSD with CVD from population, basic, and genomic research as well as from clinical and translational research are reviewed, seeking to identify major research gaps, barriers, and opportunities in knowledge acquisition and technology as well as research tools to support and accelerate critical research for near-term and longer-term translational research directions. Large-scale, well-designed prospective studies, capturing diverse and high-risk populations, are warranted that include uniform phenotyping of PTSD as well as broad assessment of biological and behavioral risk factors and CVD outcomes. Available evidence from functional brain imaging studies demonstrates that PTSD pathophysiology includes changes in specific anatomical brain regions and circuits, and studies of immune system function in individuals with PTSD suggest its association with enhanced immune inflammatory activity. However, establishment of animal models and human tissue biobanks is also warranted to elucidate the potential causal connection of PTSD-induced brain changes and/or inflammation with CVD pathophysiology. Emerging large-scale genome-wide association studies of PTSD will provide an opportunity to conduct mendelian randomization studies that test hypotheses regarding the presence, magnitude, and direction of causal associations between PTSD and CVD outcomes. By identifying research gaps in epidemiology and genomics, animal, and human translational research, opportunities to better justify and design future interventional trials are highlighted that may test whether treatment of PTSD or underlying neurobiological or immune dysregulation may improve or prevent CVD risk or outcomes.



JAMA Cardiol: 13 Jul 2021; epub ahead of print
O'Donnell CJ, Schwartz Longacre L, Cohen BE, Fayad ZA, ... Sopko G, Stein MB
JAMA Cardiol: 13 Jul 2021; epub ahead of print | PMID: 34259831
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Abstract

Effect of Paroxetine-Mediated G-Protein Receptor Kinase 2 Inhibition vs Placebo in Patients With Anterior Myocardial Infarction: A Randomized Clinical Trial.

Pilgrim T, Vollenbroich R, Deckarm S, Gräni C, ... Windecker S, Lanz J
Importance
Left ventricular remodeling following acute myocardial infarction results in progressive myocardial dysfunction and adversely affects prognosis.
Objective
To investigate the efficacy of paroxetine-mediated G-protein-coupled receptor kinase 2 inhibition to mitigate adverse left ventricular remodeling in patients presenting with acute myocardial infarction.
Design, setting, and participants
This double-blind, placebo-controlled randomized clinical trial was conducted at Bern University Hospital, Bern, Switzerland. Patients with acute anterior ST-segment elevation myocardial infarction with left ventricular ejection fraction (LVEF) of 45% or less were randomly allocated to 2 study arms between October 26, 2017, and September 21, 2020.
Interventions
Patients in the experimental arm received 20 mg of paroxetine daily; patients in the control group received a placebo daily. Both treatments were provided for 12 weeks.
Main outcomes and measures
The primary end point was the difference in patient-level improvement of LVEF between baseline and 12 weeks as assessed by cardiac magnetic resonance tomography. Secondary end points were changes in left ventricular dimensions and late gadolinium enhancement between baseline and follow-up.
Results
Fifty patients (mean [SD] age, 62 [13] years; 41 men [82%]) with acute anterior myocardial infarction were randomly allocated to paroxetine or placebo, of whom 38 patients underwent cardiac magnetic resonance imaging both at baseline and 12 weeks. There was no difference in recovery of LVEF between the experimental group (mean [SD] change, 4.0% [7.0%]) and the control group (mean [SD] change, 6.3% [6.3%]; mean difference, -2.4% [95% CI, -6.8% to 2.1%]; P = .29) or changes in left ventricular end-diastolic volume (mean difference, 13.4 [95% CI, -12.3 to 39.0] mL; P = .30) and end-systolic volume (mean difference, 11.4 [95% CI, -3.6 to 26.4] mL; P = .13). Late gadolinium enhancement as a percentage of the total left ventricular mass decreased to a larger extent in the experimental group (mean [SD], -13.6% [12.9%]) compared with the control group (mean [SD], -4.5% [9.5%]; mean difference, -9.1% [95% CI, -16.6% to -1.6%]; P = .02).

Conclusions:
and relevance
In this trial, treatment with paroxetine did not improve LVEF after myocardial infarction compared with placebo.
Trial registration
ClinicalTrials.gov Identifier: NCT03274752.



JAMA Cardiol: 13 Jul 2021; epub ahead of print
Pilgrim T, Vollenbroich R, Deckarm S, Gräni C, ... Windecker S, Lanz J
JAMA Cardiol: 13 Jul 2021; epub ahead of print | PMID: 34259826
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Abstract

Assessment of Coronary Artery Calcium Scoring to Guide Statin Therapy Allocation According to Risk-Enhancing Factors: The Multi-Ethnic Study of Atherosclerosis.

Patel J, Pallazola VA, Dudum R, Greenland P, ... Martin SS, Al Rifai M
Importance
The 2018 American Heart Association/American College of Cardiology Guideline on the Management of Blood Cholesterol recommends the use of risk-enhancing factor assessment and the selective use of coronary artery calcium (CAC) scoring to guide the allocation of statin therapy among individuals with an intermediate risk of atherosclerotic cardiovascular disease (ASCVD).
Objective
To examine the association between risk-enhancing factors and incident ASCVD by CAC burden among those at intermediate risk of ASCVD.
Design, setting, and participants
The Multi-Ethnic Study of Atherosclerosis is a multicenter population-based prospective cross-sectional study conducted in the US. Baseline data for the present study were collected between July 15, 2000, and July 14, 2002, and follow-up for incident ASCVD events was ascertained through August 20, 2015. Participants were aged 45 to 75 years with no clinical ASCVD or diabetes at baseline, were at intermediate risk of ASCVD (≥7.5% to <20.0%), and had a low-density lipoprotein cholesterol level of 70 to 189 mg/dL.
Exposures
Family history of premature ASCVD, premature menopause, metabolic syndrome, chronic kidney disease, lipid and inflammatory biomarkers, and low ankle-brachial index.
Main outcomes and measures
Incident ASCVD over a median follow-up of 12.0 years.
Results
A total of 1688 participants (mean [SD] age, 65 [6] years; 976 men [57.8%]). Of those, 648 individuals (38.4%) were White, 562 (33.3%) were Black, 305 (18.1%) were Hispanic, and 173 (10.2%) were Chinese American. A total of 722 participants (42.8%) had a CAC score of 0. Among those with 1 to 2 risk-enhancing factors vs those with 3 or more risk-enhancing factors, the prevalence of a CAC score of 0 was 45.7% vs 40.3%, respectively. Over a median follow-up of 12.0 years (interquartile range [IQR], 11.5-12.6 years), the unadjusted incidence rate of ASCVD among those with a CAC score of 0 was less than 7.5 events per 1000 person-years for all individual risk-enhancing factors (with the exception of ankle-brachial index, for which the incidence rate was 10.4 events per 1000 person-years [95% CI, 1.5-73.5]) and combinations of risk-enhancing factors, including participants with 3 or more risk-enhancing factors. Although the individual and composite addition of risk-enhancing factors to the traditional risk factors was associated with improvement in the area under the receiver operating curve, the use of CAC scoring was associated with the greatest improvement in the C statistic (0.633 vs 0.678) for ASCVD events. For incident ASCVD, the net reclassification improvement for CAC was 0.067.

Conclusions:
and relevance
In this cross-sectional study, among participants with CAC scores of 0, the presence of risk-enhancing factors was generally not associated with an overall ASCVD risk that was higher than the recommended treatment threshold for the initiation of statin therapy. The use of CAC scoring was associated with significant improvements in the reclassification and discrimination of incident ASCVD. The results of this study support the utility of CAC scoring as an adjunct to risk-enhancing factor assessment to more accurately classify individuals with an intermediate risk of ASCVD who might benefit from statin therapy.



JAMA Cardiol: 13 Jul 2021; epub ahead of print
Patel J, Pallazola VA, Dudum R, Greenland P, ... Martin SS, Al Rifai M
JAMA Cardiol: 13 Jul 2021; epub ahead of print | PMID: 34259820
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Impact:
Abstract

Association of Mitral Annular Disjunction With Cardiovascular Outcomes Among Patients With Marfan Syndrome.

Demolder A, Timmermans F, Duytschaever M, Muiño-Mosquera L, De Backer J
Importance
Mitral annular disjunction (MAD) has received particular interest in patients with mitral valve prolapse, ventricular tachycardia, and sudden cardiac death. The clinical significance of MAD for patients with Marfan syndrome (MFS) remains largely unexplored.
Objective
To define the prevalence of MAD and examine its association with cardiovascular outcomes and arrhythmia among patients with MFS.
Design, setting, and participants
This retrospective, single-center cohort study included 142 patients with a diagnosis of MFS based on the revised Ghent criteria and a confirmed (likely) pathogenic variant in the FBN1 gene who underwent regular follow-up between January 1, 2004, and December 31, 2019.
Main outcomes and measures
The presence of MAD was assessed by echocardiography, and the extent of MAD was categorized in tertiles. Patients also underwent resting electrocardiography and 24-hour Holter monitoring. Outcomes included aortic events (aortic dissection or prophylactic aortic surgery), arrhythmic events (defined as sustained ventricular tachycardia or sudden cardiac death), and mitral valve surgery.
Results
A total of 142 patients (72 female patients [51%]; median age at first examination, 25 years [range, 2-64 years]) were evaluated. Forty-eight patients (34%) had MAD. Patients with MAD had larger aortic root z scores than patients without MAD (4.1 [interquartile range, 2.8-5.7] vs 3.0 [interquartile range, 1.8-4.0]; P < .001) and more often had mitral valve prolapse (34 of 48 [71%] vs 14 of 94 [15%]; P < .001), ventricular ectopy (14 of 33 [42%] vs 15 of 70 [21%]; P = .03), and nonsustained ventricular tachycardia (13 of 33 [39%] vs 12 of 70 [17%]; P = .01). During follow-up, aortic events occurred at similar rates among patients with vs without MAD (15 of 43 [35%] vs 21 of 84 [25%]; P = .24), but patients in the upper MAD tertile (>10 mm) showed a higher occurrence of aortic events compared with patients with MAD of 10 mm or smaller (9 of 15 [60%] vs 6 of 28 [21%]; P = .01). Patients with arrhythmic events (n = 5) and patients requiring mitral valve surgery (n = 7) were observed exclusively in the group displaying MAD.

Conclusions:
and relevance
This study suggests that MAD among patients with MFS is associated with the occurrence of arrhythmic events, a higher need for mitral valve intervention, and, among patients with extensive MAD, more aortic events. Cardiac imaging for patients with MFS should consider the assessment of MAD as a potential marker for adverse outcomes.



JAMA Cardiol: 06 Jul 2021; epub ahead of print
Demolder A, Timmermans F, Duytschaever M, Muiño-Mosquera L, De Backer J
JAMA Cardiol: 06 Jul 2021; epub ahead of print | PMID: 34232254
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Abstract

Clinical Strategy for the Diagnosis and Treatment of Immune Checkpoint Inhibitor-Associated Myocarditis: A Narrative Review.

Lehmann LH, Cautela J, Palaskas N, Baik AH, ... Salem JE, Moslehi JJ
Importance
In the last decade, immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancer types. Immune checkpoint inhibitor-associated myocarditis has emerged as a significant and potentially fatal adverse effect. Recognizing, diagnosing, and treating ICI-associated myocarditis poses new challenges for the practicing clinician. Here, the current literature on ICI-associated myocarditis is reviewed.
Observations
Clinical presentation and cardiac pathological findings are highly variable in patients with ICI-associated myocarditis. Although endomyocardial biopsy is the criterion standard diagnostic test, a combination of clinical suspicion, cardiac biomarkers (specifically troponin), and cardiac imaging, in addition to biopsy, is often needed to support the diagnosis. Importantly, the combination of a cytotoxic T-lymphocyte-associated protein 4 inhibitor with a programmed cell death protein 1 or programmed death-ligand 1 inhibitor increases the risk of developing ICI-associated myocarditis.

Conclusion:
and relevance
This review aims to provide a standardized diagnostic and therapeutic approach for patients with suspected ICI-associated myocarditis. A complete history of recent cancer treatments and physical examination in combination with cardiac biomarkers, cardiac imaging, and endomyocardial biopsy represent a pragmatic diagnostic approach for most cases of ICI-associated myocarditis. The addition of novel biomarkers or imaging modalities is an area of active research and should be evaluated in larger cohorts.



JAMA Cardiol: 06 Jul 2021; epub ahead of print
Lehmann LH, Cautela J, Palaskas N, Baik AH, ... Salem JE, Moslehi JJ
JAMA Cardiol: 06 Jul 2021; epub ahead of print | PMID: 34232253
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Impact:
Abstract

Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction: A Substudy of the Empire HF Randomized Clinical Trial.

Omar M, Jensen J, Ali M, Frederiksen PH, ... Schou M, Møller JE
Importance
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve outcomes in patients with heart failure and a reduced ejection fraction (HFrEF). The association with cardiac remodeling has not been investigated.
Objective
To investigate the outcome of the SGLT2i empagliflozin, compared with placebo, on cardiac remodeling in patients with HFrEF.
Design, setting, and participants
This exploratory post hoc analysis included participants with stable HFrEF and ejection fractions of 40% or less, who were randomly enrolled in an investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trial in Denmark. Enrollment commenced on June 29, 2017, and continued through September 10, 2019, with the last participant follow-up on December 20, 2019.
Interventions
Randomization (1:1) to empagliflozin (10 mg once daily) or matching placebo in addition to recommended heart failure therapy for 12 weeks.
Main outcomes and measures
Efficacy measures were changes from baseline to week 12 in left ventricular end-systolic and end-diastolic volume indexes, left atrial volume index, and left ventricular ejection fraction adjusted for age, sex, type 2 diabetes, and atrial fibrillation. Secondary efficacy measures included changes in left ventricular mass index, global longitudinal strain, and relative wall thickness.
Results
A total of 190 patients were randomized (95 each receiving empagliflozin and placebo), with a mean (SD) age of 64 (11) years; 162 were men (85.3%), 97 (51.1%) had ischemic HFrEF, 24 (12.6%) had type 2 diabetes, and the mean (SD) latest recorded left ventricular ejection fraction was 29% (8%). Of the 190, 186 completed the study. Empagliflozin significantly reduced left ventricular end-systolic volume index (-4.3 [95% CI, -8.5 to -0.1] mL/m2; P = .04), left ventricular end-diastolic volume index (-5.5 [95% CI, -10.6 to -0.4] mL/m2; P = .03), and left atrial volume index (-2.5 [95% CI, -4.8 to -0.1] mL/m2; P = .04) compared with placebo at 12 weeks\' follow-up, with no change in left ventricular ejection fraction (1.2% [95% CI, -1.2% to 3.6%]; P = .32). These findings were consistent across subgroups. Of secondary efficacy measures, left ventricular mass index was significantly reduced by empagliflozin (-9.0 [95% CI, -17.2 to -0.8] g/m2; P = .03).

Conclusions:
and relevance
In this small, randomized, short-term study, empagliflozin was associated with modest reductions in left ventricular and left atrial volumes with no association with ejection fraction. Effects beyond 12 weeks of SGLT2i use require further study.
Trial registration
ClinicalTrials.gov Identifier: NCT03198585.



JAMA Cardiol: 30 Jun 2021; 6:836-840
Omar M, Jensen J, Ali M, Frederiksen PH, ... Schou M, Møller JE
JAMA Cardiol: 30 Jun 2021; 6:836-840 | PMID: 33404637
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Impact:
Abstract

Remote Postdischarge Treatment of Patients With Acute Myocardial Infarction by Allied Health Care Practitioners vs Standard Care: The IMMACULATE Randomized Clinical Trial.

Chan MY, Koh KWL, Poh SC, Marchesseau S, ... Richards AM, IMMACULATE Investigators
Importance
There are few data on remote postdischarge treatment of patients with acute myocardial infarction.
Objective
To compare the safety and efficacy of allied health care practitioner-led remote intensive management (RIM) with cardiologist-led standard care (SC).
Design, setting, and participants
This intention-to-treat feasibility trial randomized patients with acute myocardial infarction undergoing early revascularization and with N-terminal-pro-B-type natriuretic peptide concentration more than 300 pg/mL to RIM or SC across 3 hospitals in Singapore from July 8, 2015, to March 29, 2019. RIM participants underwent 6 months of remote consultations that included β-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACE-I/ARB) dose adjustment by a centralized nurse practitioner team while SC participants were treated face-to-face by their cardiologists.
Main outcomes and measures
The primary safety end point was a composite of hypotension, bradycardia, hyperkalemia, or acute kidney injury requiring hospitalization. To assess the efficacy of RIM in dose adjustment of β-blockers and ACE-I/ARBs compared with SC, dose intensity scores were derived by converting comparable doses of different β-blockers and ACE-I/ARBs to a scale from 0 to 5. The primary efficacy end point was the 6-month indexed left ventricular end-systolic volume (LVESV) adjusted for baseline LVESV.
Results
Of 301 participants, 149 (49.5%) were randomized to RIM and 152 (50.5%) to SC. RIM and SC participants had similar mean (SD) age (55.3 [8.5] vs 54.7 [9.1] years), median (interquartile range) N-terminal-pro-B-type natriuretic peptide concentration (807 [524-1360] vs 819 [485-1320] pg/mL), mean (SD) baseline left ventricular ejection fraction (57.4% [11.1%] vs 58.1% [10.3%]), and mean (SD) indexed LVESV (32.4 [14.1] vs 30.6 [11.7] mL/m2); 15 patients [5.9%] had a left ventricular ejection fraction <40%. The primary safety end point occurred in 0 RIM vs 2 SC participants (1.4%) (P = .50). The mean β-blocker and ACE-I/ARB dose intensity score at 6 months was 3.03 vs 2.91 (adjusted mean difference, 0.12 [95% CI, -0.02 to 0.26; P = .10]) and 2.96 vs 2.77 (adjusted mean difference, 0.19 [95% CI, -0.02 to 0.40; P = .07]), respectively. The 6-month indexed LVESV was 28.9 vs 29.7 mL/m2 (adjusted mean difference, -0.80 mL/m2 [95% CI, -3.20 to 1.60; P = .51]).

Conclusions:
and relevance
Among low-risk patients with revascularization after myocardial infarction, RIM by allied health care professionals was feasible and safe. There were no differences in achieved medication doses or indices of left ventricular remodeling. Further studies of RIM in higher-risk cohorts are warranted.
Trial registration
ClinicalTrials.gov Identifier: NCT02468349.



JAMA Cardiol: 30 Jun 2021; 6:830-835
Chan MY, Koh KWL, Poh SC, Marchesseau S, ... Richards AM, IMMACULATE Investigators
JAMA Cardiol: 30 Jun 2021; 6:830-835 | PMID: 33377898
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Impact:
Abstract

Efficacy and Safety of Revacept, a Novel Lesion-Directed Competitive Antagonist to Platelet Glycoprotein VI, in Patients Undergoing Elective Percutaneous Coronary Intervention for Stable Ischemic Heart Disease: The Randomized, Double-blind, Placebo-Controlled ISAR-PLASTER Phase 2 Trial.

Mayer K, Hein-Rothweiler R, Schüpke S, Janisch M, ... Kastrati A, Massberg S
Importance
The assessment of new antithrombotic agents with a favorable safety profile is clinically relevant.
Objective
To test the efficacy and safety of revacept, a novel, lesion-directed antithrombotic drug, acting as a competitive antagonist to platelet glycoprotein VI.
Design, setting, and participants
A phase 2 randomized clinical trial; patients were enrolled from 9 centers in Germany from November 20, 2017, to February 27, 2020; follow-up ended on March 27, 2020. The study included patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous coronary intervention (PCI).
Interventions
Single intravenous infusion of revacept, 160 mg, revacept, 80 mg, or placebo prior to the start of PCI on top of standard antithrombotic therapy.
Main outcomes and measures
The primary end point was the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin to at least 5 times the upper limit of normal within 48 hours from randomization. The safety end point was bleeding type 2 to 5 according to the Bleeding Academic Research Consortium criteria at 30 days.
Results
Of 334 participants (median age, 67.4 years; interquartile range, 60-75.1 years; 253 men [75.7%]; and 330 White participants [98.8%]), 120 were allocated to receive the 160-mg dose of revacept, 121 were allocated to receive the 80-mg dose, and 93 received placebo. The primary end point showed no significant differences between the revacept and placebo groups: 24.4%, 25.0%, and 23.3% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .98). The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, with a median 26.5 AU × min (interquartile range, 0.5-62.2 AU × min) in the revacept, 160 mg, group; 43.5 AU × min (interquartile range, 22.8-99.5 AU × min) in the revacept, 80 mg, group; and 41.0 AU × min (interquartile range, 31.2-101.0 AU × min) in the placebo group (P = .02), while adenosine 5\'-diphosphate-induced aggregation was not affected. Revacept did not increase Bleeding Academic Research Consortium type 2 or higher bleeding at 30 days compared with placebo: 5.0%, 5.9%, and 8.6% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .36).

Conclusions:
and relevance
Revacept did not reduce myocardial injury in patients with stable ischemic heart disease undergoing percutaneous coronary intervention. There were few bleeding events and no significant differences between treatment arms.
Trial registration
ClinicalTrials.gov Identifier: NCT03312855.



JAMA Cardiol: 30 Jun 2021; 6:753-761
Mayer K, Hein-Rothweiler R, Schüpke S, Janisch M, ... Kastrati A, Massberg S
JAMA Cardiol: 30 Jun 2021; 6:753-761 | PMID: 33787834
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Impact:
Abstract

Calcium/Calmodulin-Dependent Protein Kinase II Delta Inhibition and Ventricular Remodeling After Myocardial Infarction: A Randomized Clinical Trial.

Boyle AJ, Schultz C, Selvanayagam JB, Moir S, ... Collins N, McLachlan G
Importance
After anterior ST-segment elevation myocardial infarction (STEMI), left ventricular (LV) remodeling results in heart failure and death. Calcium/calmodulin-dependent protein kinase II delta (CaMKIId) is a key molecular mediator of adverse LV remodeling.
Objective
To determine whether NP202, an orally active inhibitor of CaMKIId, prevents LV remodeling in patients after anterior STEMI with early residual LV dysfunction.
Design, setting, and participants
A randomized, double-blind, placebo-controlled multicenter clinical trial of NP202 vs placebo in patients after primary percutaneous coronary intervention (PCI) for anterior STEMI was performed from November 19, 2015, to August 1, 2018. The study was performed at 32 sites across the US, Australia, and New Zealand. Patients presenting with anterior STEMI who underwent PCI within 12 hours of symptom onset and left ventricular ejection fraction (LVEF) less than 45% on screening echocardiogram 48 hours after primary PCI were included in the study. Baseline cardiovascular magnetic resonance (CMR) imaging was performed within 5 days of the STEMI and before administration of the study drug. Follow-up CMR was performed after 3 months. Data were analyzed from November 19, 2015, to August 1, 2018.
Interventions
Patients were randomly assigned to NP202, 1000 mg, daily for 3 months vs corresponding placebo.
Main outcomes and measures
The primary end point was change in LV end-systolic volume index (LVESVi) on CMR. Secondary end points were change in LV end-diastolic volume index, change in LVEF, change in infarct size, and change in diastolic function. Safety and tolerability were also assessed.
Results
A total of 147 patients (mean [SD] age, 58 [11] years; 129 men [88%]; 130 White patients [88%]) who experienced anterior STEMI treated with primary PCI were randomized to receive NP202 (73 [49.7%]) or placebo (74 [50.3%]). Baseline LVEF was similar between groups. At baseline, patients randomized to NP202 had greater LVESVi (48.2 mL/m2) than that in the placebo group (41.3 mL/m2; P = .03). However, the groups were otherwise well matched. For the primary end point of change in LVESVi from baseline to 3 months, there was no significant difference between the placebo (median [interquartile range] change, -0.60 [-9.28 to 5.99] mL/m2) and NP202 groups (-3.53 [-9.24 to 4.81] mL/m2) (P = .78). There was also no difference in the secondary efficacy end points assessed by CMR. NP202 was well tolerated and demonstrated an acceptable safety profile. Major adverse cardiac and cerebrovascular event rates were similar between groups. Two deaths occurred in each group during the follow-up period.

Conclusions:
and relevance
Three months of treatment with NP202 after primary PCI for anterior STEMI with residual LV dysfunction did not improve LV remodeling. The drug was safe and well tolerated.
Trial registration
ClinicalTrials.gov Identifier: NCT02557217.



JAMA Cardiol: 30 Jun 2021; 6:762-768
Boyle AJ, Schultz C, Selvanayagam JB, Moir S, ... Collins N, McLachlan G
JAMA Cardiol: 30 Jun 2021; 6:762-768 | PMID: 33851966
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Impact:
Abstract

Association of Dual Eligibility for Medicare and Medicaid With Heart Failure Quality and Outcomes Among Get With The Guidelines-Heart Failure Hospitals.

Bahiru E, Ziaeian B, Moucheraud C, Agarwal A, ... Yancy CW, Fonarow GC
Importance
The Centers for Medicare & Medicaid Services uses a new peer group-based payment system to compare hospital performance as part of its Hospital Readmissions Reduction Program, which classifies hospitals into quintiles based on their share of dual-eligible beneficiaries for Medicare and Medicaid. However, little is known about the association of a hospital\'s share of dual-eligible beneficiaries with the quality of care and outcomes for patients with heart failure (HF).
Objective
To evaluate the association between a hospital\'s proportion of patients with dual eligibility for Medicare and Medicaid and HF quality of care and outcomes.
Design, setting, and participants
This retrospective cohort study evaluated 436 196 patients hospitalized for HF using the Get With The Guidelines-Heart Failure registry from January 1, 2010, to December 31, 2017. The analysis included patients 65 years or older with available data on dual-eligibility status. Hospitals were divided into quintiles based on their share of dual-eligible patients. Quality and outcomes were analyzed using unadjusted and adjusted multivariable logistic regression models. Data analysis was performed from April 1, 2020, to January 1, 2021.
Main outcomes and measures
The primary outcome was 30-day all-cause readmission. The secondary outcomes included in-hospital mortality, 30-day HF readmissions, 30-day all-cause mortality, and HF process of care measures.
Results
A total of 436 196 hospitalized HF patients 65 years or older from 535 hospital sites were identified, with 258 995 hospitalized patients (median age, 81 years; interquartile range, 74-87 years) at 455 sites meeting the study criteria and included in the primary analysis. A total of 258 995 HF hospitalizations from 455 sites were included in the primary analysis of the study. Hospitals in the highest dual-eligibility quintile (quintile 5) tended to care for patients who were younger, were more likely to be female, belonged to racial minority groups, or were located in rural areas compared with quintile 1 sites. After multivariable adjustment, hospitals with the highest quintile of dual eligibility were associated with lower rates of key process measures, including evidence-based β-blocker prescription, measure of left ventricular function, and anticoagulation for atrial fibrillation or atrial flutter. Differences in clinical outcomes were seen with higher 30-day all-cause (adjusted odds ratio, 1.24; 95% CI, 1.14-1.35) and HF (adjusted odds ratio, 1.14; 95% CI, 1.03-1.27) readmissions in higher dual-eligible quintile 5 sites compared with quintile 1 sites. Risk-adjusted in-hospital and 30-day mortality did not significantly differ in quintile 1 vs quintile 5 hospitals.

Conclusions:
and relevance
In this cohort study, hospitals with a higher share of dual-eligible patients provided care with lower rates of some of the key HF quality of care process measures and with higher 30-day all-cause or HF readmissions compared with lower dual-eligibility quintile hospitals.



JAMA Cardiol: 30 Jun 2021; 6:791-800
Bahiru E, Ziaeian B, Moucheraud C, Agarwal A, ... Yancy CW, Fonarow GC
JAMA Cardiol: 30 Jun 2021; 6:791-800 | PMID: 33825802
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Impact:
Abstract

Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

Zelniker TA, Raz I, Mosenzon O, Dwyer JP, ... Sabatine MS, Wiviott SD
Importance
Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown.
Objective
To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR).
Design, setting, and participants
This secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018.
Interventions
Dapagliflozin vs placebo.
Main outcomes and measures
The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF.
Results
At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher.

Conclusions:
and relevance
The effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria.
Trial registration
ClinicalTrials.gov Identifier: NCT01730534.



JAMA Cardiol: 30 Jun 2021; 6:801-810
Zelniker TA, Raz I, Mosenzon O, Dwyer JP, ... Sabatine MS, Wiviott SD
JAMA Cardiol: 30 Jun 2021; 6:801-810 | PMID: 33851953
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Impact:
Abstract

Cardiovascular Biomarkers in the Early Discrimination of Type 2 Myocardial Infarction.

Nestelberger T, Boeddinghaus J, Lopez-Ayala P, Kaier TE, ... Mueller C, APACE Investigators
Importance
Rapid and accurate noninvasive discrimination of type 2 myocardial infarction (T2MI), which is because of a supply-demand mismatch, from type 1 myocardial infarction (T1MI), which arises via plaque rupture, is essential, because treatment differs substantially. Unfortunately, this is a major unmet clinical need, because even high-sensitivity cardiac troponin (hs-cTn) measurement provides only modest accuracy.
Objective
To test the hypothesis that novel cardiovascular biomarkers quantifying different pathophysiological pathways involved in T2MI and/or T1MI may aid physicians in the rapid discrimination of T2MI vs T1MI.
Design, setting, and participants
This international, multicenter prospective diagnostic study was conducted in 12 emergency departments in 5 countries (Switzerland, Spain, Italy, Poland, and the Czech Republic) with patients presenting with acute chest discomfort to the emergency departments. The study quantified the discrimination of hs-cTn T, hs-cTn I, and 17 novel cardiovascular biomarkers measured in subsets of consecutively enrolled patients against a reference standard (final diagnosis), centrally adjudicated by 2 independent cardiologists according to the fourth universal definition of MI, using all information, including cardiac imaging and serial measurements of hs-cTnT or hs-cTnI.
Results
Among 5887 patients, 1106 (18.8%) had an adjudicated final diagnosis of MI; of these, 860 patients (77.8%) had T1MI, and 246 patients (22.2%) had T2MI. Patients with T2MI vs those with T1MI had lower concentrations of biomarkers quantifying cardiomyocyte injury hs-cTnT (median [interquartile range (IQR)], 30 (17-55) ng/L vs 58 (28-150) ng/L), hs-cTnI (median [IQR], 23 [10-83] ng/L vs 115 [28-576] ng/L; P < .001), and cardiac myosin-binding protein C (at presentation: median [IQR], 76 [38-189] ng/L vs 257 [75-876] ng/L; P < .001) but higher concentrations of biomarkers quantifying endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress (median [IQR] values: C-terminal proendothelin 1, 97 [75-134] pmol/L vs 68 [55-91] pmol/L; midregional proadrenomedullin, 0.97 [0.67-1.51] pmol/L vs 0.72 [0.53-0.99] pmol/L; midregional pro-A-type natriuretic peptide, 378 [207-491] pmol/L vs 152 [90-247] pmol/L; and growth differentiation factor 15, 2.26 [1.44-4.35] vs 1.56 [1.02-2.19] ng/L; all P < .001). Discrimination for these biomarkers, as quantified by the area under the receiver operating characteristics curve, was modest (hs-cTnT, 0.67 [95% CI, 0.64-0.71]; hs-cTn I, 0.71 [95% CI, 0.67-0.74]; cardiac myosin-binding protein C, 0.67 [95% CI, 0.61-0.73]; C-terminal proendothelin 1, 0.73 [95% CI, 0.63-0.83]; midregional proadrenomedullin, 0.66 [95% CI, 0.60-0.73]; midregional pro-A-type natriuretic peptide, 0.77 [95% CI, 0.68-0.87]; and growth differentiation factor 15, 0.68 [95% CI, 0.58-0.79]).

Conclusions:
and relevance
In this study, biomarkers quantifying myocardial injury, endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress provided modest discrimination in early, noninvasive diagnosis of T2MI.



JAMA Cardiol: 30 Jun 2021; 6:771-780
Nestelberger T, Boeddinghaus J, Lopez-Ayala P, Kaier TE, ... Mueller C, APACE Investigators
JAMA Cardiol: 30 Jun 2021; 6:771-780 | PMID: 33881449
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Impact:
Abstract

Sex-Related Disparities in Cardiovascular Health Care Among Patients With Premature Atherosclerotic Cardiovascular Disease.

Lee MT, Mahtta D, Ramsey DJ, Liu J, ... Petersen LA, Virani SS
Importance
There is a paucity of data regarding secondary prevention care disparities in women with premature and extremely premature atherosclerotic cardiovascular disease (ASCVD), defined as an ASCVD event at 55 years or younger and 40 years or younger, respectively.
Objective
To evaluate sex-based differences in antiplatelet agents, any statin, high-intensity statin (HIS) therapy, and statin adherence in patients with premature and extremely premature ASCVD.
Design, setting, and participants
This was a cross-sectional, multicenter, nationwide VA health care system-based study with patients enrolled in the Veterans With Premature Atherosclerosis (VITAL) registry. The study assessed patients who had at least 1 primary care visit in the Veterans Affairs (VA) health care system from October 1, 2014, to September 30, 2015. Participants included 147 600 veteran patients with premature ASCVD, encompassing ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), and peripheral arterial disease (PAD).
Exposures
Women vs men with premature and extremely premature ASCVD.
Main outcomes and measures
Antiplatelet use, any statin use, HIS use, and statin adherence (proportion of days covered [PDC] ≥0.8).
Results
We identified 10 413 women and 137 187 men with premature ASCVD (age ≤55 years) and 1340 women and 8145 men with extremely premature (age ≤40 years) ASCVD. Among patients with premature and extremely premature ASCVD, women represented 7.1% and 14.1% of those groups, respectively. When compared with men, women with premature ASCVD had a higher proportion of African American patients (36.1% vs 23.8%) and lower proportions of Asian patients (0.5% vs 0.7%) and White patients (56.1% vs. 68.1%). In the extremely premature ASCVD group, women had a comparatively higher proportion of African American patients (36.8% vs 23.2%) and lower proportion of White patients (55.0% vs 67.8%) and Asian patients (1.3% vs 1.5%) than men. Among patients with premature IHD, women received less antiplatelet (adjusted odds ratio [AOR], 0.47, 95% CI, 0.45-0.50), any statin (AOR, 0.62; 95% CI, 0.59-0.66), and HIS (AOR, 0.63; 95% CI, 0.59-0.66) therapy and were less statin adherent (mean [SD] PDC, 0.68 [0.34] vs 0.73 [0.31]; β coefficient: -0.02; 95% CI, -0.03 to -0.01) compared with men. Similarly, women with premature ICVD and premature PAD received comparatively less antiplatelet agents, any statin, and HIS. Among patients with extremely premature ASCVD, women also received less antiplatelet therapy (AOR, 0.61; 95% CI, 0.53-0.70), any statin therapy (AOR,0.51; 95% CI, 0.44-0.58), and HIS therapy (AOR, 0.45; 95% CI, 0.37-0.54) than men. There were no sex-associated differences in statin adherence among patients with premature ICVD, premature PAD, or extremely premature ASCVD.

Conclusions:
and relevance
This cross-sectional study revealed that women veterans with premature ASCVD and extremely premature ASCVD receive less optimal secondary prevention cardiovascular care in comparison with men. Women with premature ASCVD, particularly those with IHD, were also less statin adherent. Multidisciplinary and patient-centered interventions are needed to improve these disparities in women.



JAMA Cardiol: 30 Jun 2021; 6:782-790
Lee MT, Mahtta D, Ramsey DJ, Liu J, ... Petersen LA, Virani SS
JAMA Cardiol: 30 Jun 2021; 6:782-790 | PMID: 33881448
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Impact:
Abstract

Association of Rare Genetic Variants and Early-Onset Atrial Fibrillation in Ethnic Minority Individuals.

Chalazan B, Mol D, Darbar FA, Ornelas-Loredo A, ... Ellinor P, Darbar D
Importance
Although rare variants in cardiac ion channels, transcription factors, and myocardial structural proteins are associated with early-onset atrial fibrillation (AF) in White individuals of European descent, it remains unclear whether genetic variation also contributes to the cause of AF in those of minority ethnicity.
Objectives
To assess the prevalence of rare and novel pathogenic variants in candidate genes in ethnic minority probands with early-onset AF and determine genotype-phenotype associations.
Design, setting, and participants
In this cohort, family-based study, probands of African and Hispanic descent with early-onset AF (defined as AF occurring in individuals aged ≤66 years) prospectively enrolled in a clinical and genetic biorepository underwent sequencing of 60 candidate genes. Recruitment took place from July 1, 2015, to June 30, 2019. Data were analyzed from February 1 to February 28, 2020.
Exposures
Rare and novel variants categorized as pathogenic or likely pathogenic.
Main outcomes and measures
The prevalence of rare and novel pathogenic variants in African American and Hispanic/Latinx probands with early-onset AF and genotype-phenotype associations.
Results
Among 227 probands with early-onset AF, mean (SD) age at onset of AF was 51.0 (9.9) years, 132 probands (58.1%) were men, 148 (65.2%) were African American, and 79 (34.8%) were Hispanic/Latinx. A family history of AF was verified in 24 probands with early-onset AF (10.6%). Sequencing 60 candidate genes identified 53 (23 rare and 30 novel) variants with 16 of the 227 (7.0%) probands harboring likely pathogenic (43.8%) or pathogenic (56.2%) variants, with most loss-of-function variants in TTN, the gene encoding the sarcomeric protein titin (46.7%). In 6 families with more than 2 affected members, variants of unknown significance in sodium channel (SCN10A), potassium channel (KCNE5), sarcomeric proteins (MYH6 and TTN), and atrial natriuretic peptide (NPPA) cosegregated with AF.

Conclusions:
and relevance
In this study, likely pathogenic and pathogenic variants were identified, with most loss-of-function variants in TTN, that increase susceptibility to early-onset AF in African American and Hispanic/Latinx individuals. These findings provide further understanding toward molecular phenotyping of AF and suggest novel mechanism-based therapeutic approaches for this common arrhythmia in ethnic minority groups.



JAMA Cardiol: 30 Jun 2021; 6:811-819
Chalazan B, Mol D, Darbar FA, Ornelas-Loredo A, ... Ellinor P, Darbar D
JAMA Cardiol: 30 Jun 2021; 6:811-819 | PMID: 33950154
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Impact:
Abstract

Association of Systolic Blood Pressure Elevation With Disproportionate Left Ventricular Remodeling in Very Preterm-Born Young Adults: The Preterm Heart and Elevated Blood Pressure.

Mohamed A, Marciniak M, Williamson W, Huckstep OJ, ... Leeson P, Lewandowski AJ
Importance
Preterm-born individuals have higher blood pressure with an increased risk of hypertension by young adulthood, as well as potentially adverse cardiac remodeling even when normotensive. To what extent blood pressure elevation affects left ventricular (LV) structure and function in adults born preterm is currently unknown.
Objective
To investigate whether changes observed in LV structure and function in preterm-born adults make them more susceptible to cardiac remodeling in association with blood pressure elevation.
Design, setting, and participants
This cross-sectional cohort study, conducted at the Oxford Cardiovascular Clinical Research Facility and Oxford Centre for Clinical Magnetic Resonance Research, included 468 adults aged 18 to 40 years. Of these, 200 were born preterm (<37 weeks\' gestation) and 268 were born at term (≥37 weeks\' gestation). Cardiac magnetic resonance imaging was used to characterize LV structure and function, with clinical blood pressure readings measured to assess hypertension status. Demographic and anthropometric data, as well as birth history and family medical history information, were collected. Data were analyzed between January 2012 and February 2021.
Main outcomes and measures
Cardiac magnetic resonance measures of LV structure and function in response to systolic blood pressure elevation.
Results
The cohort was primarily White (>95%) with a balanced sex distribution (51.5% women and 48.5% men). Preterm-born adults with and without hypertension had higher LV mass index, reduced LV function, and smaller LV volumes compared with term-born individuals both with and without hypertension. In regression analyses of systolic blood pressure with LV mass index and LV mass to end-diastolic volume ratio, there was a leftward shift in the slopes in preterm-born compared with term-born adults. Compared with term-born adults, there was a 2.5-fold greater LV mass index per 1-mm Hg elevation in systolic blood pressure in very and extremely preterm-born adults (<32 weeks\' gestation) (0.394 g/m2 vs 0.157 g/m2 per 1 mm Hg; P < .001) and a 1.6-fold greater LV mass index per 1-mm Hg elevation in systolic blood pressure in moderately preterm-born adults (32 to 36 weeks\' gestation) (0.250 g/m2 vs 0.157 g/m2 per 1 mm Hg; P < .001). The LV mass to end-diastolic volume ratio per 1-mm Hg elevation in systolic blood pressure in the very and extremely preterm-born adults was 3.4-fold greater compared with those born moderately preterm (3.56 × 10-3 vs 1.04 × 10-3 g/mL per 1 mm Hg; P < .001) and 3.3-fold greater compared with those born at term (3.56 × 10-3 vs 1.08 × 10-3 g/mL per 1 mm Hg; P < .001).

Conclusions:
and relevance
Preterm-born adults have a unique LV structure and function that worsens with systolic blood pressure elevation. Additional primary prevention strategies specifically targeting cardiovascular risk reduction in this population may be warranted.



JAMA Cardiol: 30 Jun 2021; 6:821-829
Mohamed A, Marciniak M, Williamson W, Huckstep OJ, ... Leeson P, Lewandowski AJ
JAMA Cardiol: 30 Jun 2021; 6:821-829 | PMID: 33978675
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Impact:
Abstract

Ticagrelor or Prasugrel for Patients With Acute Coronary Syndrome Treated With Percutaneous Coronary Intervention: A Prespecified Subgroup Analysis of a Randomized Clinical Trial.

Coughlan JJ, Aytekin A, Lahu S, Ndrepepa G, ... Schüpke S, Kastrati A
Importance
It is unclear whether ticagrelor or prasugrel hydrochloride is superior for patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI).
Objective
To assess the safety and efficacy of ticagrelor vs prasugrel for patients with ACS treated with PCI.
Design, setting, and participants
A prespecified analysis was performed of a postrandomization subgroup of 3377 patients who presented with ACS and were treated with PCI in the investigator-initiated, multicenter, phase 4, open-label Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 randomized clinical trial, conducted from September 1, 2013, to February 28, 2018. Statistical analysis was performed from September 1, 2020, to January 30, 2021. Analysis was performed according to the intention-to-treat principle.
Interventions
Patients were randomly assigned to a ticagrelor-based or prasugrel-based strategy. This analysis focuses on the subgroup of patients who underwent PCI that was formed after randomization.
Main outcomes and measures
The primary end point was a composite consisting of all-cause death, myocardial infarction, or stroke at 12 months. The safety end point was Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding.
Results
The ticagrelor group comprised 1676 patients (1323 men [78.9%]; mean [SD] age, 64.4 [12.0] years), and the prasugrel group comprised 1701 patients (1341 men [78.8%]; mean [SD] age, 64.7 [12.0] years). The primary end point occurred for 162 patients (9.8%) in the ticagrelor group and 120 patients (7.1%) in the prasugrel group (hazard ratio [HR], 1.41; 95% CI, 1.11-1.78; P = .005). Myocardial infarction occurred in 88 patients (5.3%) in the ticagrelor group compared with 55 patients (3.8%) in the prasugrel group (HR, 1.67; 95% CI, 1.19-2.34; P = .003). The safety end point, BARC type 3 to 5 bleeding, occurred in 84 of 1672 patients (5.3%) in the ticagrelor group and 78 of 1680 patients (4.9%) in the prasugrel group (HR; 1.10; 95% CI, 0.81-1.50; P = .54).

Conclusions:
and relevance
Among patients presenting with ACS who were treated with PCI, the incidence of the primary composite end point occurred less frequently for patients who received prasugrel compared with those who received ticagrelor. The incidence of bleeding events was comparable between the 2 groups. These results suggest that, for patients presenting with ACS who undergo PCI, a prasugrel-based strategy is superior to a ticagrelor-based strategy. However, because these observations are based on a postrandomization subgroup, these findings should be regarded as hypothesis generating and dedicated randomized clinical trials may be warranted to confirm these findings.
Trial registration
ClinicalTrials.gov Identifier: NCT01944800.



JAMA Cardiol: 29 Jun 2021; epub ahead of print
Coughlan JJ, Aytekin A, Lahu S, Ndrepepa G, ... Schüpke S, Kastrati A
JAMA Cardiol: 29 Jun 2021; epub ahead of print | PMID: 34190967
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Impact:
Abstract

Midlife Wealth Mobility and Long-term Cardiovascular Health.

Machado S, Sumarsono A, Vaduganathan M
Importance
The association of socioeconomic status and cardiovascular outcomes has been well described, but little is known about whether longitudinal changes in wealth are associated with cardiovascular health status.
Objective
To evaluate the association between midlife wealth mobility and risk of cardiovascular events.
Design, setting, and participants
This longitudinal, retrospective cohort study included US adults 50 years or older who participated in the Health and Retirement Study. Participants in the primary analysis had no history of cardiovascular disease and had observations in at least two of three 5-year age intervals (50-54, 55-59, and 60-64 years) and follow-up after 65 years of age. Data were collected from January 1, 1992, to December 31, 2016, and analyzed from November 10, 2020, to April 26, 2021.
Exposures
Quintiles of wealth (reflecting total nonhousing assets) were defined within each of 4 birth cohorts (1931-1935, 1936-1940, 1941-1945, and 1946-1950). Wealth mobility was defined as an increase or a decrease of 1 or more wealth quintiles and was compared with wealth stability (same quintile over time) using covariate-adjusted Cox proportional hazards regression models.
Main outcomes and measures
Composite outcome of nonfatal cardiovascular event (myocardial infarction, heart failure, cardiac arrhythmia, or stroke) or cardiovascular death.
Results
A total of 5579 participants were included in the primary analysis (mean [SD] age, 54.2 [2.6] years; 3078 women [55.2%]). During a mean (SD) follow-up of 16.9 (5.8) years, 1336 participants (24.0%) experienced a primary end point of nonfatal cardiovascular event or cardiovascular death (14.4 [95% CI, 13.6-15.2] per 1000 patient-years). Higher initial wealth (per quintile) was associated with lower cardiovascular risk (adjusted hazard ratio [aHR] per quintile, 0.89 [95% CI, 0.84-0.95]; P = .001). When compared with stable wealth, participants who experienced upward wealth mobility (by at least 1 quintile) had independently lower hazards of a subsequent nonfatal cardiovascular event or cardiovascular death (aHR, 0.84 [95% CI, 0.73-0.97]; P = .02), and participants who experienced downward wealth mobility had higher risks (aHR, 1.15 [95% CI, 1.00-1.32]; P = .046).

Conclusions:
and relevance
These findings suggest that upward wealth mobility relative to peers in late middle age is associated with lower risks of cardiovascular events or death after 65 years of age.



JAMA Cardiol: 29 Jun 2021; epub ahead of print
Machado S, Sumarsono A, Vaduganathan M
JAMA Cardiol: 29 Jun 2021; epub ahead of print | PMID: 34190965
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Impact:
Abstract

Patients With Acute Myocarditis Following mRNA COVID-19 Vaccination.

Kim HW, Jenista ER, Wendell DC, Azevedo CF, ... Parker MA, Kim RJ
Importance
Vaccine-associated myocarditis is an unusual entity that has been described for the smallpox vaccine, but only anecdotal case reports have been described for other vaccines. Whether COVID-19 vaccination may be linked to the occurrence of myocarditis is unknown.
Objective
To describe a group of 7 patients with acute myocarditis over 3 months, 4 of whom had recent messenger RNA (mRNA) COVID-19 vaccination.
Design, setting, and participants
All patients referred for cardiovascular magnetic resonance imaging at Duke University Medical Center were asked to participate in a prospective outcomes registry. Two searches of the registry database were performed: first, to identify patients with acute myocarditis for the 3-month period between February 1 and April 30 for 2017 through 2021, and second, to identify all patients with possible vaccine-associated myocarditis for the past 20 years. Once patients with possible vaccine-associated myocarditis were identified, data available in the registry were supplemented by additional data collection from the electronic health record and a telephone interview.
Exposures
mRNA COVID-19 vaccine.
Main outcomes and measures
Occurrence of acute myocarditis by cardiovascular magnetic resonance imaging.
Results
In the 3-month period between February 1 and April 30, 2021, 7 patients with acute myocarditis were identified, of which 4 occurred within 5 days of COVID-19 vaccination. Three were younger male individuals (age, 23-36 years) and 1 was a 70-year-old female individual. All 4 had received the second dose of an mRNA vaccine (2 received mRNA-1273 [Moderna], and 2 received BNT162b2 [Pfizer]). All presented with severe chest pain, had biomarker evidence of myocardial injury, and were hospitalized. Coincident testing for COVID-19 and respiratory viruses provided no alternative explanation. Cardiac magnetic resonance imaging findings were typical for myocarditis, including regional dysfunction, late gadolinium enhancement, and elevated native T1 and T2.

Conclusions:
and relevance
In this study, magnetic resonance imaging findings were found to be consistent with acute myocarditis in 7 patients; 4 of whom had preceding COVID-19 vaccination. Further investigation is needed to determine associations of COVID-19 vaccination and myocarditis.



JAMA Cardiol: 28 Jun 2021; epub ahead of print
Kim HW, Jenista ER, Wendell DC, Azevedo CF, ... Parker MA, Kim RJ
JAMA Cardiol: 28 Jun 2021; epub ahead of print | PMID: 34185046
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Impact:
Abstract

Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.

Montgomery J, Ryan M, Engler R, Hoffman D, ... Sanou A, Cooper LT
Importance
Myocarditis has been reported with COVID-19 but is not clearly recognized as a possible adverse event following COVID-19 vaccination.
Objective
To describe myocarditis presenting after COVID-19 vaccination within the Military Health System.
Design, setting, and participants
This retrospective case series studied patients within the US Military Health System who experienced myocarditis after COVID-19 vaccination between January and April 2021. Patients who sought care for chest pain following COVID-19 vaccination and were subsequently diagnosed with clinical myocarditis were included.
Exposure
Receipt of a messenger RNA (mRNA) COVID-19 vaccine between January 1 and April 30, 2021.
Main outcomes and measures
Clinical diagnosis of myocarditis after COVID-19 vaccination in the absence of other identified causes.
Results
A total of 23 male patients (22 currently serving in the military and 1 retiree; median [range] age, 25 [20-51] years) presented with acute onset of marked chest pain within 4 days after receipt of an mRNA COVID-19 vaccine. All military members were previously healthy with a high level of fitness. Seven received the BNT162b2-mRNA vaccine and 16 received the mRNA-1273 vaccine. A total of 20 patients had symptom onset following the second dose of an appropriately spaced 2-dose series. All patients had significantly elevated cardiac troponin levels. Among 8 patients who underwent cardiac magnetic resonance imaging within the acute phase of illness, all had findings consistent with the clinical diagnosis of myocarditis. Additional testing did not identify other etiologies for myocarditis, including acute COVID-19 and other infections, ischemic injury, or underlying autoimmune conditions. All patients received brief supportive care and were recovered or recovering at the time of this report. The military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period. While the observed number of myocarditis cases was small, the number was higher than expected among male military members after a second vaccine dose.

Conclusions:
and relevance
In this case series, myocarditis occurred in previously healthy military patients with similar clinical presentations following receipt of an mRNA COVID-19 vaccine. Further surveillance and evaluation of this adverse event following immunization is warranted. Potential for rare vaccine-related adverse events must be considered in the context of the well-established risk of morbidity, including cardiac injury, following COVID-19 infection.



JAMA Cardiol: 28 Jun 2021; epub ahead of print
Montgomery J, Ryan M, Engler R, Hoffman D, ... Sanou A, Cooper LT
JAMA Cardiol: 28 Jun 2021; epub ahead of print | PMID: 34185045
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Impact:
Abstract

Association of Pediatric Obstructive Sleep Apnea With Elevated Blood Pressure and Orthostatic Hypertension in Adolescence.

Fernandez-Mendoza J, He F, Calhoun SL, Vgontzas AN, Liao D, Bixler EO
Importance
Although pediatric guidelines have delineated updated thresholds for elevated blood pressure (eBP) in youth and adult guidelines have recognized obstructive sleep apnea (OSA) as an established risk factor for eBP, the relative association of pediatric OSA with adolescent eBP remains unexplored.
Objective
To assess the association of pediatric OSA with eBP and its orthostatic reactivity in adolescence.
Design, setting, and participants
At baseline of this population-based cohort study (Penn State Child Cohort) in 2000-2005, a random sample of 700 children aged 5 to 12 years from the general population was studied. A total of 421 participants (60.1%) were followed up in 2010-2013 after 7.4 years as adolescents (ages, 12-23 years). Data analyses were conducted from July 6 to October 29, 2020.
Main outcomes and measures
Outcomes were the apnea-hypopnea index (AHI) score, ascertained via polysomnography conducted in a laboratory; eBP measured in the seated position identified using guideline-recommended pediatric criteria; orthostatic hyperreactivity identified with BP assessed in the supine and standing positions; and visceral adipose tissue assessed via dual-energy x-ray absorptiometry.
Results
Among the 421 participants (mean [SD] age at follow-up, 16.5 [2.3] years), 227 (53.9%) were male and 92 (21.9%) were racial/ethnic minorities. A persistent AHI of 2 or more since childhood was longitudinally associated with adolescent eBP (odds ratio [OR], 2.9; 95% CI 1.1-7.5), while a remitted AHI of 2 or more was not (OR, 0.9; 95% CI 0.3-2.6). Adolescent OSA was associated with eBP in a dose-response manner; however, the association of an AHI of 2 to less than 5 among adolescents was nonsignificant (OR, 1.5; 95% CI, 0.9-2.6) and that of an AHI of 5 or more was approximately 2-fold (OR, 2.3; 95% CI, 1.1-4.9) after adjusting for visceral adipose tissue. An AHI of 5 or more (OR, 3.1; 95% CI, 1.2-8.5), but not between 2 and less than 5 (OR, 1.3; 95% CI, 0.6-3.0), was associated with orthostatic hyperreactivity among adolescents even after adjusting for visceral adipose tissue. Childhood OSA was not associated with adolescent eBP in female participants, while the risk of OSA and eBP was greater in male participants.

Conclusions:
and relevance
The results of this cohort study suggest that childhood OSA is associated with adolescent hypertension only if it persists during this developmental period. Visceral adiposity explains a large extent of, but not all, the risk of hypertension associated with adolescent OSA, which is greater in male individuals.



JAMA Cardiol: 22 Jun 2021; epub ahead of print
Fernandez-Mendoza J, He F, Calhoun SL, Vgontzas AN, Liao D, Bixler EO
JAMA Cardiol: 22 Jun 2021; epub ahead of print | PMID: 34160576
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Impact:
Abstract

Prevalence of Coronary Artery Disease and Coronary Microvascular Dysfunction in Patients With Heart Failure With Preserved Ejection Fraction.

Rush CJ, Berry C, Oldroyd KG, Rocchiccioli JP, ... McMurray JJV, Petrie MC
Importance
Coronary artery disease (CAD) and coronary microvascular dysfunction (CMD) may contribute to the pathophysiologic characteristics of heart failure with preserved ejection fraction (HFpEF). However, the prevalence of CAD and CMD have not been systematically studied.
Objective
To examine the prevalence of CAD and CMD in hospitalized patients with HFpEF.
Design, setting, and participants
A total of 106 consecutive patients hospitalized with HFpEF were evaluated in this prospective, multicenter, cohort study conducted between January 2, 2017, and August 1, 2018; data analysis was performed from March 4 to September 6, 2019. Participants underwent coronary angiography with guidewire-based assessment of coronary flow reserve, index of microvascular resistance, and fractional flow reserve, followed by coronary vasoreactivity testing. Cardiac magnetic resonance imaging was performed with late gadolinium enhancement and assessment of extracellular volume. Myocardial perfusion was assessed qualitatively and semiquantitatively using the myocardial-perfusion reserve index.
Main outcomes and measures
The prevalence of obstructive epicardial CAD, CMD, and myocardial ischemia, infarction, and fibrosis.
Results
Of 106 participants enrolled (53 [50%] women; mean [SD] age, 72 [9] years), 75 had coronary angiography, 62 had assessment of coronary microvascular function, 41 underwent coronary vasoreactivity testing, and 52 received cardiac magnetic resonance imaging. Obstructive epicardial CAD was present in 38 of 75 participants (51%, 95% CI, 39%-62%); 19 of 38 (50%; 95% CI, 34%-66%) had no history of CAD. Endothelium-independent CMD (ie, coronary flow reserve <2.0 and/or index of microvascular resistance ≥25) was identified in 41 of 62 participants (66%; 95% CI, 53%-77%). Endothelium-dependent CMD (ie, abnormal coronary vasoreactivity) was identified in 10 of 41 participants (24%; 95% CI, 13%-40%). Overall, 45 of 53 participants (85%; 95% CI, 72%-92%) had evidence of CMD and 29 of 36 (81%; 95% CI, 64%-91%) of those without obstructive epicardial CAD had CMD. Cardiac magnetic resonance imaging findings included myocardial-perfusion reserve index less than or equal to 1.84 (ie, impaired global myocardial perfusion) in 29 of 41 patients (71%; 95% CI, 54%-83%), visual perfusion defect in 14 of 46 patients (30%; 95% CI, 19%-46%), ischemic late gadolinium enhancement (ie, myocardial infarction) in 14 of 52 patients (27%; 95% CI, 16%-41%), and extracellular volume greater than 30% (ie, diffuse myocardial fibrosis) in 20 of 48 patients (42%; 95% CI, 28%-56%). Patients with obstructive CAD had more adverse events during follow-up (28 [74%]) than those without obstructive CAD (17 [46%]).

Conclusions:
and relevance
In this cohort study, 91% of patients with HFpEF had evidence of epicardial CAD, CMD, or both. Of those without obstructive CAD, 81% had CMD. Obstructive epicardial CAD and CMD appear to be common and often unrecognized in hospitalized patients with HFpEF and may be therapeutic targets.



JAMA Cardiol: 22 Jun 2021; epub ahead of print
Rush CJ, Berry C, Oldroyd KG, Rocchiccioli JP, ... McMurray JJV, Petrie MC
JAMA Cardiol: 22 Jun 2021; epub ahead of print | PMID: 34160566
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Impact:
Abstract

Skeletonized vs Pedicled Internal Mammary Artery Graft Harvesting in Coronary Artery Bypass Surgery: A Post Hoc Analysis From the COMPASS Trial.

Lamy A, Browne A, Sheth T, Zheng Z, ... Eikelboom J, COMPASS Investigators
Importance
The relative safety and patency of skeletonized vs pedicled internal mammary artery grafts in patients undergoing coronary artery bypass graft (CABG) surgery are unknown.
Objective
To investigate the association of skeletonized vs pedicled harvesting with internal mammary artery graft patency and clinical outcomes 1 year after CABG surgery.
Design, setting, and participants
This study was a post hoc analysis of the multicenter, randomized, double-blind, placebo-controlled Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) clinical trial, which enrolled 27 395 patients from 602 centers in 33 countries from March 2013 through May 2016. Eligibility criteria for the trial included CABG surgery for coronary artery disease with at least 2 grafts implanted and an estimated glomerular filtration rate of at least 30 mL/min. A total of 1002 of 1448 patients were randomized to the CABG arm of the COMPASS trial and underwent skeletonized (282 [28.1%]) or pedicled (720 [71.9%]) internal mammary artery harvesting. The patients had evaluable angiography results 1 year after surgery. Data were analyzed from October 11, 2019, to May 14, 2020.
Interventions
Patients underwent graft harvesting with either the pedicled technique or skeletonized technique.
Main outcomes and measures
The primary outcome was graft occlusion 1 year after CABG surgery, as assessed by computed tomography angiography.
Results
A total of 1002 patients underwent skeletonized (282 [28.1%]; mean [SD] age, 65.9 [8.1] years; 229 men [81.2%]; 194 White patients [68.8%]) or pedicled (720 [71.9%]; mean [SD] age, 64.8 [7.6] years; 603 men [83.8%]; 455 White patients [63.2%]) internal mammary artery harvesting. Rates of internal mammary artery graft occlusion 1 year after CABG surgery were higher in the skeletonized group than in the pedicled group (33 of 344 [9.6%] vs 30 of 764 [3.9%]; graft-level adjusted odds ratio, 2.41; 95% CI, 1.39-4.20; P = .002), including the left internal mammary artery to left anterior descending artery (21 of 289 [7.3%] vs 25 of 725 [3.4%]; graft-level adjusted odds ratio, 2.10; 95% CI, 1.14-3.88, P = .02). After a mean follow-up of 23 months, skeletonized graft harvesting was also associated with a higher rate of major adverse cardiovascular events (20 [7.1%] vs 15 [2.1%]; adjusted hazard ratio, 3.19; 95% CI, 1.53-6.67; P = .002) and repeated revascularization (14 [5.0%] vs 10 [1.4%]; adjusted hazard ratio, 2.75; 95% CI, 1.10-6.88; P = .03).

Conclusions:
and relevance
This post hoc analysis of the COMPASS randomized clinical trial found that harvesting of the internal mammary artery during CABG surgery using a skeletonized technique was associated with a higher rate of graft occlusion and worse clinical outcomes than the traditional pedicled technique. Future randomized clinical trials are needed to establish the safety and patency of the skeletonized technique.
Trial registration
ClinicalTrials.gov Identifier: NCT01776424.



JAMA Cardiol: 15 Jun 2021; epub ahead of print
Lamy A, Browne A, Sheth T, Zheng Z, ... Eikelboom J, COMPASS Investigators
JAMA Cardiol: 15 Jun 2021; epub ahead of print | PMID: 34132753
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Impact:
Abstract

Use of Lipid-Lowering Therapies Over 2 Years in GOULD, a Registry of Patients With Atherosclerotic Cardiovascular Disease in the US.

Cannon CP, de Lemos JA, Rosenson RS, Ballantyne CM, ... Kosiborod MN, GOULD Investigators
Importance
Guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) recommend intensive statin therapy and adding nonstatin therapy if low-density lipoprotein cholesterol (LDL-C) levels are 70 mg/dL or more. Compliance with guidelines is often low.
Objective
To track LDL-C treatment patterns in the US over 2 years.
Design, setting, and participants
GOULD is a prospective observational registry study involving multiple centers. Patients with ASCVD receiving any lipid-lowering therapy (LLT) were eligible. Between December 2016 and July 2018, patients were enrolled in 1 of 3 cohorts: (1) those currently receiving proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) and 2 groups not receiving PCSK9i drugs, with (2) LDL-C levels of 100 mg/dL or more or (3) LDL-C levels of 70 to 99 mg/dL. Patients had medical record reviews and telephone interviews every 6 months. Analysis was done on data collected as of October 5, 2020.
Main outcomes and measures
The primary outcome was the change in LLT use in 2 years. Secondary outcomes included the number of LDL-C measurements, LDL-C levels, and responses to structured physician and patient questionnaires over 2 years.
Results
A total of 5006 patients were enrolled (mean [SD] age, 67.8 [9.9] years; 1985 women [39.7%]; 4312 White individuals [86.1%]). At 2 years, 885 (17.1%) had LLT intensification. In the cohorts with LDL-C levels of 100 mg/dL or more and 70 to 99 mg/dL, LLT intensification occurred in 403 (22.4%) and 383 (14.4%), respectively; statins were intensified in 115 (6.4%) and 168 (6.3%), ezetimibe added in 123 (6.8%) and 118 (4.5%), and PCSK9i added in 114 (6.3%) and 58 (2.2%), respectively. In the PCSK9i cohort, 508 of 554 (91.7%) were still taking PCSK9i at 2 years. Lipid panels were measured at least once over 2 years in 3768 patients (88.5%; PCSK9i cohort, 492 [96.1%]; LDL-C levels ≥100 mg/dL or more, 1294 [85.9%]; 70-99 mg/dL, 1982 [88.6%]). Levels of LDL-C fell from medians (interquartile ranges) of 120 (108-141) mg/dL to 95 (73-118) mg/dL in the cohort with LDL-C levels of 100 mg/dL or more, 82 (75-89) to 77 (65-90) mg/dL in the cohort with LDL-C levels of 70 to 99 mg/dL, and 67 (42-104) mg/dL to 67 (42-96) mg/dL in the PCSK9i cohort. Levels of LDL-C less than 70 mg/dL at 2 years were achieved by 308 patients (21.0%) and 758 patients (33.9%) in the cohorts with LDL-C levels of 100 mg/dL or more and 70 to 99 mg/dL, respectively, and 272 patients (52.4%) in the PCSK9i cohort. At 2 years, practice characteristics were associated with more LLT intensification (teaching vs nonteaching hospitals, 148 of 589 [25.1%] vs 600 of 3607 [16.6%]; lipid protocols or none, 359 of 1612 [22.3%] vs 389 of 2584 [15.1%]; cardiology, 452 of 2087 [21.7%] vs internal or family medicine, 204 of 1745 [11.7%] and other, 92 of 364 [25.3%]; all P < .001) and achievement of LDL-C less than 70 mg/dL (teaching vs nonteaching hospitals, 173 of 488 [35.5%] vs 823 of 2986 [27.6%]; lipid protocols vs none, 451 of 1411 [32.0%] vs 545 of 2063 [26.4%]; both P < .001; cardiology, 523 of 1686 [30.1%] vs internal or family medicine, 377 of 1472 [25.6%] and other, 96 of 316 [30.4%]; P = .003).

Conclusions:
and relevance
Of patients with ASCVD, most with suboptimal LDL-C levels at baseline, only 17.1% had LLT intensification after 2 years, and two-thirds remained at an LDL-C level greater than 70 mg/dL. Further intensive efforts are needed to achieve optimal LDL-C management in patients with ASCVD.



JAMA Cardiol: 15 Jun 2021; epub ahead of print
Cannon CP, de Lemos JA, Rosenson RS, Ballantyne CM, ... Kosiborod MN, GOULD Investigators
JAMA Cardiol: 15 Jun 2021; epub ahead of print | PMID: 34132735
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Impact:
Abstract

Association of Diet Quality With Prevalence of Clonal Hematopoiesis and Adverse Cardiovascular Events.

Bhattacharya R, Zekavat SM, Uddin MM, Pirruccello J, ... Bick A, Natarajan P
Importance
Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of somatic leukemogenic variations in hematopoietic stem cells, has been associated with atherosclerotic cardiovascular disease. Because the inherited risk of developing CHIP is low, lifestyle elements such as dietary factors may be associated with the development and outcomes of CHIP.
Objective
To examine whether there is an association between diet quality and the prevalence of CHIP.
Design, setting, and participants
This retrospective cohort study used data from participants in the UK Biobank, an ongoing population-based study in the United Kingdom that examines whole-exome sequencing data and survey-based information on health-associated behaviors. Individuals from the UK Biobank were recruited between 2006 and 2010 and followed up prospectively with linkage to health data records through May 2020. The present study included 44 111 participants in the UK Biobank who were age 40 to 70 years, had data available from whole-exome sequencing of blood DNA, and were free of coronary artery disease (CAD) or hematologic cancer at baseline.
Exposures
Diet quality was categorized as unhealthy if the intake of healthy elements (fruits and vegetables) was lower than the median of all survey responses, and the intake of unhealthy elements (red meat, processed food, and added salt) was higher than the median. Diets were classified as healthy if the intake of healthy elements was higher than the median, and the intake of unhealthy elements was lower than the median. The presence of CHIP was detected by data from whole-exome sequencing of blood DNA.
Main outcomes and measures
The primary outcome was CHIP prevalence. Multivariable logistic regression analysis was used to examine the association between diet quality and the presence of CHIP. Multivariable Cox proportional hazards models were used to assess the association of incident events (acute coronary syndromes, coronary revascularization, or death) in each diet quality category stratified by the presence of CHIP.
Results
Among 44 111 participants (mean [SD] age at time of blood sample collection, 56.3 [8.0] years; 24 507 women [55.6%]), 2271 individuals (5.1%) had an unhealthy diet, 38 552 individuals (87.4%) had an intermediate diet, and 3288 individuals (7.5%) had a healthy diet. A total of 2507 individuals (5.7%) had CHIP, and the prevalence of CHIP decreased as diet quality improved from unhealthy (162 of 2271 participants [7.1%]) to intermediate (2177 of 38 552 participants [5.7%]) to healthy (168 of 3288 participants [5.1%]; P = .003 for trend). Compared with individuals without CHIP who had an intermediate diet, the rates of incident cardiovascular events progressively decreased among those with CHIP who had an unhealthy diet (hazard ratio [HR], 1.52; 95% CI, 1.04-2.22) and those with CHIP who had a healthy diet (HR, 0.99; 95% CI, 0.62-1.58) over a median of 10.0 years (interquartile range, 9.6-10.4 years) of follow-up.

Conclusions:
and relevance
This cohort study suggests that an unhealthy diet quality may be associated with a higher prevalence of CHIP and higher rates of adverse cardiovascular events and death independent of CHIP status.



JAMA Cardiol: 08 Jun 2021; epub ahead of print
Bhattacharya R, Zekavat SM, Uddin MM, Pirruccello J, ... Bick A, Natarajan P
JAMA Cardiol: 08 Jun 2021; epub ahead of print | PMID: 34106216
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Impact:
Abstract

Association of Novel Locus With Rheumatic Heart Disease in Black African Individuals: Findings From the RHDGen Study.

Machipisa T, Chong M, Muhamed B, Chishala C, ... Engel ME, Paré G
Importance
Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent heart valve damage, is the leading cause of cardiac surgery in Africa. However, its pathophysiologic characteristics and genetics are poorly understood. Understanding genetic susceptibility may aid in prevention, control, and interventions to eliminate RHD.
Objective
To identify common genetic loci associated with RHD susceptibility in Black African individuals.
Design, setting, and participants
This multicenter case-control genome-wide association study (GWAS), the Genetics of Rheumatic Heart Disease, examined more than 7 million genotyped and imputed single-nucleotide variations. The 4809 GWAS participants and 116 independent trio families were enrolled from 8 African countries between December 31, 2012, and March 31, 2018. All GWAS participants and trio probands were screened by use of echocardiography. Data analyses took place from May 15, 2017, until March 14, 2021.
Main outcomes and measures
Genetic associations with RHD.
Results
This study included 4809 African participants (2548 RHD cases and 2261 controls; 3301 women [69%]; mean [SD] age, 36.5 [16.3] years). The GWAS identified a single RHD risk locus, 11q24.1 (rs1219406 [odds ratio, 1.65; 95% CI, 1.48-1.82; P = 4.36 × 10-8]), which reached genome-wide significance in Black African individuals. Our meta-analysis of Black (n = 3179) and admixed (n = 1055) African individuals revealed several suggestive loci. The study also replicated a previously reported association in Pacific Islander individuals (rs11846409) at the immunoglobulin heavy chain locus, in the meta-analysis of Black and admixed African individuals (odds ratio, 1.16; 95% CI, 1.06-1.27; P = 1.19 × 10-3). The HLA (rs9272622) associations reported in Aboriginal Australian individuals could not be replicated. In support of the known polygenic architecture for RHD, overtransmission of a polygenic risk score from unaffected parents to affected probands was observed (polygenic transmission disequilibrium testing mean [SE], 0.27 [0.16] SDs; P = .04996), and the chip-based heritability was estimated to be high at 0.49 (SE = 0.12; P = 3.28 × 10-5) in Black African individuals.

Conclusions:
and relevance
This study revealed a novel candidate susceptibility locus exclusive to Black African individuals and an important heritable component to RHD susceptibility in African individuals.



JAMA Cardiol: 08 Jun 2021; epub ahead of print
Machipisa T, Chong M, Muhamed B, Chishala C, ... Engel ME, Paré G
JAMA Cardiol: 08 Jun 2021; epub ahead of print | PMID: 34106200
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Impact:
Abstract

Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals.

Guo L, Torii S, Fernandez R, Braumann RE, ... Virmani R, Finn AV
Importance
Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined.
Objective
To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes.
Design, setting, and participants
This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021.
Main outcomes and measures
The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD.
Results
The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants.

Conclusions:
and relevance
In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.



JAMA Cardiol: 01 Jun 2021; epub ahead of print
Guo L, Torii S, Fernandez R, Braumann RE, ... Virmani R, Finn AV
JAMA Cardiol: 01 Jun 2021; epub ahead of print | PMID: 34076677
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Impact:
Abstract

Effect of the Million Hearts Cardiovascular Disease Risk Reduction Model on Initiating and Intensifying Medications: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

Peterson GG, Pu J, Magid DJ, Barterian L, ... McCall N, Markovich P
Importance
The Million Hearts Cardiovascular Disease (CVD) Risk Reduction Model pays provider organizations for measuring and reducing Medicare patients\' cardiovascular risk.
Objective
To assess whether the model increases the initiation or intensification of antihypertensive medications or statins among patients with blood pressure or low-density lipoprotein (LDL) cholesterol levels above guideline thresholds for treatment intensification.
Design, setting, and participants
This prespecified secondary analysis of a cluster-randomized, pragmatic trial included primary care and cardiology practices, health care centers, and hospital-based outpatient departments across the US. Participants included Medicare patients who were enrolled into the model in 2017 by participating organizations and who were at high risk and at medium risk of a myocardial infarction or stroke in 10 years. Patient outcomes were analyzed for 1 year postenrollment (through December 2018) using an intent-to-treat design. Analysis began November 2019.
Interventions
US Centers for Medicare & Medicaid Services paid organizations for risk stratifying Medicare patients and reducing CVD risk among high-risk patients through discussing risk scores, developing individualized risk reduction plans, and following up with patients twice yearly.
Main outcomes and measures
Initiating or intensifying statin or antihypertensive therapy within 1 year of enrollment, measured in Medicare Part D claims, and LDL cholesterol and systolic blood pressure levels approximately 1 year after enrollment, measured in usual care and reported to Centers for Medicare & Medicaid Services via a data registry (data complete for 51% of high-risk enrollees). The study\'s primary outcome (incidence of first-time myocardial infarction and stroke) is not reported because the trial is ongoing.
Results
A total of 330 primary care and cardiology practices, health care centers, and hospital-based outpatient departments and 125 436 Medicare patients were included in this analysis. High-risk patients in the intervention group had a mean (SD) age of 74 (4.1), 15 213 (63%) were male, 21 657 (90%) were receiving antihypertensive medication at baseline, and 16 558 (69%) were receiving statins. Almost all (21 791 [91%]) high-risk intervention group patients had above-threshold systolic blood pressure level (>130 mm Hg), LDL cholesterol level (>70 mg/dL), or both. Patients in the intervention group with these risk factors were more likely than control patients (8127 [37.3%] vs 4753 [32.4%]; adjusted difference in percentage points, 4.8; 95% CI, 2.9-6.7; P < .001) to initiate or intensify statins or antihypertensive medication. Centers for Medicare & Medicaid Services did not pay for CVD risk reduction for medium-risk enrollees, but initiation or intensification rates for these enrollees were also higher in the intervention vs control groups (12 668 [27.9%] vs 7544 [24.8%]; adjusted difference in percentage points, 3.1; 95% CI, 1.9-4.3; P < .001). Among high-risk enrollees with clinical data approximately 1 year after enrollment, LDL cholesterol level was slightly lower in the intervention vs control groups (mean [SD], 89 [31.8] vs 91 [32.1] mg/dL; adjusted difference in percentage points, -1.8; 95% CI, -2.9 to -0.6; P = .002), as was systolic blood pressure (mean [SD], 133 [15.7] vs 135 [16.4] mm Hg; adjusted difference in percentage points, -1.7; 95% CI, -2.8 to -0.6; P = .003).

Conclusions:
and relevance
In this study, a pay-for-performance model led to modest increases in the use of CVD medications in a range of organizations, despite high medication use at baseline.



JAMA Cardiol: 01 Jun 2021; epub ahead of print
Peterson GG, Pu J, Magid DJ, Barterian L, ... McCall N, Markovich P
JAMA Cardiol: 01 Jun 2021; epub ahead of print | PMID: 34076665
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Impact:
Abstract

Clinical Outcomes and Response to Vericiguat According to Index Heart Failure Event: Insights From the VICTORIA Trial.

Lam CSP, Giczewska A, Sliwa K, Edelmann F, ... Armstrong PW, VICTORIA Study Group
Importance
The period following heart failure hospitalization (HFH) is a vulnerable time with high rates of death or recurrent HFH.
Objective
To evaluate clinical characteristics, outcomes, and treatment response to vericiguat according to prespecified index event subgroups and time from index HFH in the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial.
Design, setting, and participants
Analysis of an international, randomized, placebo-controlled trial. All VICTORIA patients had recent (<6 months) worsening HF (ejection fraction <45%). Index event subgroups were less than 3 months after HFH (n = 3378), 3 to 6 months after HFH (n = 871), and those requiring outpatient intravenous diuretic therapy only for worsening HF (without HFH) in the previous 3 months (n = 801). Data were analyzed between May 2, 2020, and May 9, 2020.
Intervention
Vericiguat titrated to 10 mg daily vs placebo.
Main outcomes and measures
The primary outcome was time to a composite of HFH or cardiovascular death; secondary outcomes were time to HFH, cardiovascular death, a composite of all-cause mortality or HFH, all-cause death, and total HFH.
Results
Among 5050 patients in the VICTORIA trial, mean age was 67 years, 24% were women, 64% were White, 22% were Asian, and 5% were Black. Baseline characteristics were balanced between treatment arms within each subgroup. Over a median follow-up of 10.8 months, the primary event rates were 40.9, 29.6, and 23.4 events per 100 patient-years in the HFH at less than 3 months, HFH 3 to 6 months, and outpatient worsening subgroups, respectively. Compared with the outpatient worsening subgroup, the multivariable-adjusted relative risk of the primary outcome was higher in HFH less than 3 months (adjusted hazard ratio, 1.48; 95% CI, 1.27-1.73), with a time-dependent gradient of risk demonstrating that patients closest to their index HFH had the highest risk. Vericiguat was associated with reduced risk of the primary outcome overall and in all subgroups, without evidence of treatment heterogeneity. Similar results were evident for all-cause death and HFH. Addtionally, a continuous association between time from HFH and vericiguat treatment showed a trend toward greater benefit with longer duration since HFH. Safety events (symptomatic hypotension and syncope) were infrequent in all subgroups, with no difference between treatment arms.

Conclusions:
and relevance
Among patients with worsening chronic HF, those in closest proximity to their index HFH had the highest risk of cardiovascular death or HFH, irrespective of age or clinical risk factors. The benefit of vericiguat did not differ significantly across the spectrum of risk in worsening HF.
Trial registration
ClinicalTrials.gov Identifier: NCT02861534.



JAMA Cardiol: 31 May 2021; 6:706-712
Lam CSP, Giczewska A, Sliwa K, Edelmann F, ... Armstrong PW, VICTORIA Study Group
JAMA Cardiol: 31 May 2021; 6:706-712 | PMID: 33185650
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Impact:
Abstract

Association of Financial Hardship Because of Medical Bills With Adverse Outcomes Among Families of Children With Congenital Heart Disease.

Ludomirsky AB, Bucholz EM, Newburger JW
Importance
Congenital heart disease (CHD) carries significant health care costs and out-of-pocket expenses for families. Little is known about how financial hardship because of medical bills affects families\' access to essential needs or medical care.
Objective
To assess the national prevalence of financial hardship because of medical bills among families of children with CHD in the US and the association of financial hardship with adverse outcomes.
Design, setting, and participants
This cross-sectional survey study used data on children 17 years and younger with self-reported CHD from the National Health Interview Survey of US households between 2011 and 2017. Data were analyzed from March 2019 to April 2020.
Exposures
Financial hardship because of medical bills was classified into 3 categories: no financial hardship, financial hardship but able to pay medical bills, and unable to pay medical bills.
Main outcomes and measures
Food insecurity, delayed care because of cost, and cost-related medication nonadherence.
Results
Of 188 families of children with CHD (weighted sample of 151 537 families), 48.9% reported some financial hardship because of medical bills, with 17.0% being unable to pay their medical bills at all. Compared with those who denied financial hardships because of medical bills, families who were unable to pay their medical bills reported significantly higher rates of food insecurity (61.8% [SE, 11.0] vs 13.6% [SE, 4.0]; P < .001) and delays in care because of cost (26.2% [SE, 10.4] vs 4.8% [SE, 2.5]; P = .002). Reported medication adherence did not differ across financial hardship groups. After adjusting for age, race/ethnicity, and maternal education, the differences between the groups persisted. The association of financial hardship with adverse outcomes was stronger among patients with private insurance than those with Medicaid.

Conclusions:
and relevance
In this study, financial hardship because of medical bills was common among families of children with CHD and was associated with high rates of food insecurity and delays in care because of cost, suggesting possible avenues for intervention.



JAMA Cardiol: 31 May 2021; 6:713-717
Ludomirsky AB, Bucholz EM, Newburger JW
JAMA Cardiol: 31 May 2021; 6:713-717 | PMID: 33325991
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Impact:
Abstract

Association of Non-High-Density Lipoprotein Cholesterol Measured in Adolescence, Young Adulthood, and Mid-Adulthood With Coronary Artery Calcification Measured in Mid-Adulthood.

Armstrong MK, Fraser BJ, Hartiala O, Buscot MJ, ... Raitakari OT, Magnussen CG
Importance
Elevated non-high-density lipoprotein cholesterol (non-HDL-C) is associated with the presence of coronary artery calcification (CAC), a marker of heart disease in adulthood. However, the relative importance of non-HDL-C levels at specific life stages for CAC remains unclear.
Objective
To identify the relative association of non-HDL-C measured at distinct life stages (adolescence, young adulthood, mid-adulthood) with the presence of CAC measured in mid-adulthood.
Design, setting, and participants
The Cardiovascular Risk in Young Finns Study is a population-based prospective cohort study that started in 1980 with follow-up over 28 years. Participants from 3 population centers (Kuopio, Tampere, and Turku in Finland) represent a convenience sample drawn from the 3 oldest cohorts at baseline (aged 12-18 years in 1980). Data were collected from September 1980 to August 2008. Analysis began February 2020.
Exposures
Non-HDL-C levels were measured at 3 life stages including adolescence (aged 12-18 years), young adulthood (aged 21-30 years), and mid-adulthood (aged 33-45 years).
Main outcomes and measures
In 2008, CAC was determined from computed tomography and dichotomized as 0 (no CAC, Agatston score = 0) and 1 (presence of CAC, Agatston score ≥1) for analysis. Using a bayesian relevant life course exposure model, the relative association was determined between non-HDL-C at each life stage and the presence of CAC in mid-adulthood.
Results
Of 589 participants, 327 (56%) were female. In a model adjusted for year of birth, sex, body mass index, systolic blood pressure, blood glucose level, smoking status, lipid-lowering and antihypertensive medication use, and family history of heart disease, cumulative exposure to non-HDL-C across all life stages was associated with CAC (odds ratio [OR], 1.50; 95% credible interval [CrI], 1.14-1.92). At each life stage, non-HDL-C was associated with CAC and exposure to non-HDL-C during adolescence had the strongest association (adolescence: OR, 1.16; 95% CrI, 1.01-1.46; young adulthood: OR, 1.14; 95% CrI, 1.01-1.43; mid-adulthood: OR, 1.12; 95% CrI, 1.01-1.34).

Conclusions:
and relevance
These data suggest that elevated non-HDL-C levels at all life stages are associated with coronary atherosclerosis in mid-adulthood. However, adolescent non-HDL-C levels showed the strongest association with the presence of CAC in mid-adulthood, and greater awareness of the importance of elevated non-HDL-C in adolescence is needed.



JAMA Cardiol: 31 May 2021; 6:661-668
Armstrong MK, Fraser BJ, Hartiala O, Buscot MJ, ... Raitakari OT, Magnussen CG
JAMA Cardiol: 31 May 2021; 6:661-668 | PMID: 33502454
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Impact:
Abstract

Utility of a Deep-Learning Algorithm to Guide Novices to Acquire Echocardiograms for Limited Diagnostic Use.

Narang A, Bae R, Hong H, Thomas Y, ... Weissman NJ, Thomas JD
Importance
Artificial intelligence (AI) has been applied to analysis of medical imaging in recent years, but AI to guide the acquisition of ultrasonography images is a novel area of investigation. A novel deep-learning (DL) algorithm, trained on more than 5 million examples of the outcome of ultrasonographic probe movement on image quality, can provide real-time prescriptive guidance for novice operators to obtain limited diagnostic transthoracic echocardiographic images.
Objective
To test whether novice users could obtain 10-view transthoracic echocardiographic studies of diagnostic quality using this DL-based software.
Design, setting, and participants
This prospective, multicenter diagnostic study was conducted in 2 academic hospitals. A cohort of 8 nurses who had not previously conducted echocardiograms was recruited and trained with AI. Each nurse scanned 30 patients aged at least 18 years who were scheduled to undergo a clinically indicated echocardiogram at Northwestern Memorial Hospital or Minneapolis Heart Institute between March and May 2019. These scans were compared with those of sonographers using the same echocardiographic hardware but without AI guidance.
Interventions
Each patient underwent paired limited echocardiograms: one from a nurse without prior echocardiography experience using the DL algorithm and the other from a sonographer without the DL algorithm. Five level 3-trained echocardiographers independently and blindly evaluated each acquisition.
Main outcomes and measures
Four primary end points were sequentially assessed: qualitative judgement about left ventricular size and function, right ventricular size, and the presence of a pericardial effusion. Secondary end points included 6 other clinical parameters and comparison of scans by nurses vs sonographers.
Results
A total of 240 patients (mean [SD] age, 61 [16] years old; 139 men [57.9%]; 79 [32.9%] with body mass indexes >30) completed the study. Eight nurses each scanned 30 patients using the DL algorithm, producing studies judged to be of diagnostic quality for left ventricular size, function, and pericardial effusion in 237 of 240 cases (98.8%) and right ventricular size in 222 of 240 cases (92.5%). For the secondary end points, nurse and sonographer scans were not significantly different for most parameters.

Conclusions:
and relevance
This DL algorithm allows novices without experience in ultrasonography to obtain diagnostic transthoracic echocardiographic studies for evaluation of left ventricular size and function, right ventricular size, and presence of a nontrivial pericardial effusion, expanding the reach of echocardiography to clinical settings in which immediate interrogation of anatomy and cardiac function is needed and settings with limited resources.



JAMA Cardiol: 31 May 2021; 6:624-632
Narang A, Bae R, Hong H, Thomas Y, ... Weissman NJ, Thomas JD
JAMA Cardiol: 31 May 2021; 6:624-632 | PMID: 33599681
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Impact:
Abstract

Derivation and Validation of a 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing.

Roy PM, Friou E, Germeau B, Douillet D, ... Moumneh T, Penaloza A
Importance
In patients with suspected pulmonary embolism (PE), overuse of diagnostic imaging is an important point of concern.
Objective
To derive and validate a 4-level pretest probability rule (4-Level Pulmonary Embolism Clinical Probability Score [4PEPS]) that makes it possible to rule out PE solely on clinical criteria and optimized D-dimer measurement to safely decrease imaging testing for suspected PE.
Design, setting, and participants
This study included consecutive outpatients suspected of having PE from US and European emergency departments. Individual data from 3 merged management studies (n = 11 114; overall prevalence of PE, 11%) were used for the derivation cohort and internal validation cohort. The external validation cohorts were taken from 2 independent studies, the first with a high PE prevalence (n = 1548; prevalence, 21.5%) and the second with a moderate PE prevalence (n = 1669; prevalence, 11.7%). A prior definition of pretest probability target values to achieve a posttest probability less than 2% was used on the basis of the negative likelihood ratios of D-dimer. Data were collected from January 2003 to April 2016, and data were analyzed from June 2018 to August 2019.
Main outcomes and measures
The rate of PE diagnosed during the initial workup or during follow-up and the rate of imaging testing.
Results
Of the 5588 patients in the derivation cohort, 3441 (61.8%) were female, and the mean (SD) age was 52 (18.5) years. The 4PEPS comprises 13 clinical variables scored from -2 to 5. It results in the following strategy: (1) very low probability of PE if 4PEPS is less than 0: PE ruled out without testing; (2) low probability of PE if 4PEPS is 0 to 5: PE ruled out if D-dimer level is less than 1.0 μg/mL; (3) moderate probability of PE if 4PEPS is 6 to 12: PE ruled out if D-dimer level is less than the age-adjusted cutoff value; (4) high probability of PE if 4PEPS is greater than 12: PE ruled out by imaging without preceding D-dimer test. In the first and the second external validation cohorts, the area under the receiver operator characteristic curves were 0.79 (95% CI, 0.76 to 0.82) and 0.78 (95% CI, 0.74 to 0.81), respectively. The false-negative testing rates if the 4PEPS strategy had been applied were 0.71% (95% CI, 0.37 to 1.23) and 0.89% (95% CI, 0.53 to 1.49), respectively. The absolute reductions in imaging testing were -22% (95% CI, -26 to -19) and -19% (95% CI, -22 to -16) in the first and second external validation cohorts, respectively. The 4PEPS strategy compared favorably with all recent strategies in terms of imaging testing.

Conclusions:
and relevance
The 4PEPS strategy may lead to a substantial and safe reduction in imaging testing for patients with suspected PE. It should now be tested in a formal outcome study.



JAMA Cardiol: 31 May 2021; 6:669-677
Roy PM, Friou E, Germeau B, Douillet D, ... Moumneh T, Penaloza A
JAMA Cardiol: 31 May 2021; 6:669-677 | PMID: 33656522
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Impact:
Abstract

Association of Posttraumatic Stress Disorder and Incident Ischemic Heart Disease in Women Veterans.

Ebrahimi R, Lynch KE, Beckham JC, Dennis PA, ... Shroyer ALW, Sumner JA
Importance
Posttraumatic stress disorder (PTSD) is associated with greater risk of ischemic heart disease (IHD) in predominantly male populations or limited community samples. Women veterans represent a growing, yet understudied, population with high levels of trauma exposure and unique cardiovascular risks, but research on PTSD and IHD in this group is lacking.
Objective
To determine whether PTSD is associated with incident IHD in women veterans.
Design, setting, and participants
In this retrospective, longitudinal cohort study of the national Veterans Health Administration (VHA) electronic medical records, the a priori hypothesis that PTSD would be associated with greater risk of IHD onset was tested. Women veterans 18 years or older with and without PTSD who were patients in the VHA from January 1, 2000, to December 31, 2017, were assessed for study eligibility. Exclusion criteria consisted of no VHA clinical encounters after the index visit, IHD diagnosis at or before the index visit, and IHD diagnosis within 90 days of the index visit. Propensity score matching on age at index visit, number of prior visits, and presence of traditional and female-specific cardiovascular risk factors and mental and physical health conditions was conducted to identify women veterans ever diagnosed with PTSD, who were matched in a 1:2 ratio to those never diagnosed with PTSD. Data were analyzed from October 1, 2018, to October 30, 2020.
Exposures
PTSD, defined by International Classification of Diseases, Ninth Revision (ICD-9), or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), diagnosis codes from inpatient or outpatient encounters.
Main outcomes and measures
Incident IHD, defined as new-onset coronary artery disease, angina, or myocardial infarction, based on ICD-9 and ICD-10 diagnosis codes from inpatient or outpatient encounters, and/or coronary interventions based on Current Procedural Terminology codes.
Results
A total of 398 769 women veterans, 132 923 with PTSD and 265 846 never diagnosed with PTSD, were included in the analysis. Baseline mean (SD) age was 40.1 (12.2) years. During median follow-up of 4.9 (interquartile range, 2.1-9.2) years, 4381 women with PTSD (3.3%) and 5559 control individuals (2.1%) developed incident IHD. In a Cox proportional hazards model, PTSD was significantly associated with greater risk of developing IHD (hazard ratio [HR], 1.44; 95% CI, 1.38-1.50). Secondary stratified analyses indicated that younger age identified women veterans with PTSD who were at greater risk of incident IHD. Effect sizes were largest for those younger than 40 years at baseline (HR, 1.72; 95% CI, 1.55-1.93) and decreased monotonically with increasing age (HR for ≥60 years, 1.24; 95% CI, 1.12-1.38).

Conclusions:
and relevance
This cohort study found that PTSD was associated with increased risk of IHD in women veterans and may have implications for IHD risk assessment in vulnerable individuals.



JAMA Cardiol: 31 May 2021; 6:642-651
Ebrahimi R, Lynch KE, Beckham JC, Dennis PA, ... Shroyer ALW, Sumner JA
JAMA Cardiol: 31 May 2021; 6:642-651 | PMID: 33729463
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Impact:
Abstract

Use of Machine Learning Models to Predict Death After Acute Myocardial Infarction.

Khera R, Haimovich J, Hurley NC, McNamara R, ... Mortazavi BJ, Krumholz HM
Importance
Accurate prediction of adverse outcomes after acute myocardial infarction (AMI) can guide the triage of care services and shared decision-making, and novel methods hold promise for using existing data to generate additional insights.
Objective
To evaluate whether contemporary machine learning methods can facilitate risk prediction by including a larger number of variables and identifying complex relationships between predictors and outcomes.
Design, setting, and participants
This cohort study used the American College of Cardiology Chest Pain-MI Registry to identify all AMI hospitalizations between January 1, 2011, and December 31, 2016. Data analysis was performed from February 1, 2018, to October 22, 2020.
Main outcomes and measures
Three machine learning models were developed and validated to predict in-hospital mortality based on patient comorbidities, medical history, presentation characteristics, and initial laboratory values. Models were developed based on extreme gradient descent boosting (XGBoost, an interpretable model), a neural network, and a meta-classifier model. Their accuracy was compared against the current standard developed using a logistic regression model in a validation sample.
Results
A total of 755 402 patients (mean [SD] age, 65 [13] years; 495 202 [65.5%] male) were identified during the study period. In independent validation, 2 machine learning models, gradient descent boosting and meta-classifier (combination including inputs from gradient descent boosting and a neural network), marginally improved discrimination compared with logistic regression (C statistic, 0.90 for best performing machine learning model vs 0.89 for logistic regression). Nearly perfect calibration in independent validation data was found in the XGBoost (slope of predicted to observed events, 1.01; 95% CI, 0.99-1.04) and the meta-classifier model (slope of predicted-to-observed events, 1.01; 95% CI, 0.99-1.02), with more precise classification across the risk spectrum. The XGBoost model reclassified 32 393 of 121 839 individuals (27%) and the meta-classifier model reclassified 30 836 of 121 839 individuals (25%) deemed at moderate to high risk for death in logistic regression as low risk, which were more consistent with the observed event rates.

Conclusions:
and relevance
In this cohort study using a large national registry, none of the tested machine learning models were associated with substantive improvement in the discrimination of in-hospital mortality after AMI, limiting their clinical utility. However, compared with logistic regression, XGBoost and meta-classifier models, but not the neural network, offered improved resolution of risk for high-risk individuals.



JAMA Cardiol: 31 May 2021; 6:633-641
Khera R, Haimovich J, Hurley NC, McNamara R, ... Mortazavi BJ, Krumholz HM
JAMA Cardiol: 31 May 2021; 6:633-641 | PMID: 33688915
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Impact:
Abstract

Metabolic Cost of Exercise Initiation in Patients With Heart Failure With Preserved Ejection Fraction vs Community-Dwelling Adults.

Shah RV, Schoenike MW, Armengol de la Hoz MÁ, Cunningham TF, ... Vasan RS, Lewis GD
Importance
Heart failure with preserved ejection fraction (HFpEF) is a joint metabolic and cardiovascular disorder with significant noncardiac contributions.
Objective
To define and quantify the metabolic cost of initiating exercise in individuals with and without HFpEF and its functional consequences.
Design, setting, and participants
This prospective cohort study included individuals with hemodynamically confirmed HFpEF from the Massachusetts General Hospital Exercise Study (MGH-ExS) and community-dwelling participants from the Framingham Heart Study (FHS). Analysis began April 2016 and ended November 2020.
Exposures
Internal work (IW), a measure of work equivalents required to initiate movement.
Main outcomes and measures
Using breath-by-breath oxygen uptake (V̇o2) measurements and V̇o2-work rate associations, cost of initiating exercise (IW) in patients with HFpEF (MGH-ExS) and in community-dwelling individuals (FHS) was quantified. Linear regression was used to estimate associations between IW and clinical/hemodynamic measures.
Results
Of 3231 patients, 184 (5.7%) had HFpEF and were from MGH-ExS, and 3047 (94.3%) were community-dwelling individuals from FHS. In the MGH-ExS cohort, 86 (47%) were women, the median (interquartile range) age was 63 (53-72) years, and the median (interquartile range) peak V̇o2 level was 13.33 (11.77-15.62) mL/kg/min. In the FHS cohort, 1620 (53%) were women, the median (interquartile range) age was 54 (48-60) years, and the median (interquartile range) peak V̇o2 level was 22.2 (17.85-27.35) mL/kg/min. IW was higher in patients with HFpEF and accounted for 27% (interquartile range, 21%-39%) of the total work (IW + measured external workload on the cycle), compared with 15% (interquartile range, 12%-20%) of that in FHS participants. Body mass index accounted for greatest explained variance in patients with HFpEF from MGH-ExS and FHS participants (22% and 18%, respectively), while resting cardiac output and biventricular filling pressures were not significantly associated with variance in IW in patients with HFpEF. A higher IW in patients with HFpEF was associated with a greater increase in left- and right-sided cardiac filing pressure during unloaded exercise, despite similar resting hemodynamic measures across IW.

Conclusions:
and relevance
This study found that internal work, a new body mass index-related measure reflecting the metabolic cost of initiating movement, is higher in individuals with HFpEF compared with middle-aged adults in the community and is associated with steep, early increases in cardiac filling pressures. These findings highlight the importance of quantifying heterogeneous responses to exercise initiation when evaluating functional intolerance in individuals at risk for or with HFpEF.



JAMA Cardiol: 31 May 2021; 6:653-660
Shah RV, Schoenike MW, Armengol de la Hoz MÁ, Cunningham TF, ... Vasan RS, Lewis GD
JAMA Cardiol: 31 May 2021; 6:653-660 | PMID: 33729454
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Impact:
Abstract

Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction: A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial.

Butt JH, Docherty KF, Petrie MC, Schou M, ... McMurray JJV, Køber L
Importance
Women may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men.
Objective
To investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).
Design, setting, and participants
Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B-type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021.
Interventions
Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy.
Main outcomes and measures
The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.
Results
A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of ≥5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of ≥5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women.

Conclusions:
and relevance
Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex.
Trial registration
ClinicalTrials.gov Identifier: NCT03036124.



JAMA Cardiol: 31 May 2021; 6:678-689
Butt JH, Docherty KF, Petrie MC, Schou M, ... McMurray JJV, Køber L
JAMA Cardiol: 31 May 2021; 6:678-689 | PMID: 33787831
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Impact:
Abstract

Assessment of Catheter Ablation or Antiarrhythmic Drugs for First-line Therapy of Atrial Fibrillation: A Meta-analysis of Randomized Clinical Trials.

Turagam MK, Musikantow D, Whang W, Koruth JS, ... Dukkipati SR, Reddy VY
Importance
Early rhythm control of atrial fibrillation (AF) with either antiarrhythmic drugs (AADs) or catheter ablation has been reported to improve cardiovascular outcomes compared with usual care; however, the optimal therapeutic modality to achieve early rhythm control is unclear.
Objective
To assess the safety and efficacy of AF ablation as first-line therapy when compared with AADs in patients with paroxysmal AF.
Data sources
PubMed/MEDLINE, Scopus, Google Scholar, and various major scientific conference sessions from January 1, 2000, through November 23, 2020.
Study selection
Randomized clinical trials (RCTs) published in English that had at least 12 months of follow-up and compared clinical outcomes of ablation vs AADs as first-line therapy in adults with AF. The quality of individual studies was assessed using the Cochrane risk of bias tool. Six RCTs met inclusion criteria, including 1212 patients.
Data extraction and synthesis
Two investigators independently extracted data. Reporting was performed in compliance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) guidelines. Analysis was performed using a random-effects model with the Mantel-Haenszel method, and results are presented as 95% CIs.
Main outcomes and measures
Main outcomes were safety and efficacy of AF ablation as first-line therapy when compared with AADs. Trials were evaluated as having low risk of selection and attrition biases, high risk of performance bias, and with unclear risk for detection biases due to unblinding and open-label designs.
Results
A total of 6 RCTs involving 1212 patients with AF were included (609 were randomized to AF ablation and 603 to drug therapy; mean [SD] age, 56 [11] years). Compared with AADs, catheter ablation use was associated with reductions in recurrent atrial arrhythmia (32.3% vs 53%; risk ratio [RR], 0.62; 95% CI, 0.51-0.74; P < .001; I2 = 40%), with a number needed to treat with ablation to prevent 1 arrhythmia of 5. Use of ablation was also associated with reduced symptomatic atrial arrhythmia (11.8% vs 26.4%; RR, 0.44; 95% CI, 0.27-0.72; P = .001; I2 = 54%) and hospitalization (5.6% vs 18.7%; RR, 0.32; 95% CI, 0.19-0.53; P < .001) with no significant difference in serious adverse events between the groups (4.2% vs 2.8%; RR, 1.52; 95% CI, 0.81-2.85; P = .19).

Conclusions:
and relevance
In this meta-analysis of randomized clinical trials including first-line therapy of patients with paroxysmal AF, catheter ablation compared with antiarrhythmic drugs was associated with reductions in recurrence of atrial arrhythmias and hospitalizations, with no difference in major adverse events.



JAMA Cardiol: 31 May 2021; 6:697-705
Turagam MK, Musikantow D, Whang W, Koruth JS, ... Dukkipati SR, Reddy VY
JAMA Cardiol: 31 May 2021; 6:697-705 | PMID: 33909022
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Impact:
Abstract

Performance of the American Heart Association/American College of Cardiology Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Self-reported Physical Activity Levels.

Pandey A, Mehta A, Paluch A, Ning H, ... Lloyd-Jones DM, Wilkins JT
Importance
The American Heart Association/American College of Cardiology pooled cohort equations (PCEs) are used for predicting 10-year atherosclerotic cardiovascular disease (ASCVD) risk. Pooled cohort equation risk prediction capabilities across self-reported leisure-time physical activity (LTPA) levels and the change in model performance with addition of LTPA to the PCE are unclear.
Objective
To evaluate PCE risk prediction performance across self-reported LTPA levels and the change in model performance by adding LTPA to the existing PCE model.
Design, setting, and participants
Individual-level pooling of data from 3 longitudinal cohort studies-Atherosclerosis Risk in Communities, Multi-Ethnic Study of Atherosclerosis, and Cardiovascular Health Study-was performed. A total of 18 824 participants were stratified into 4 groups based on self-reported LTPA levels: inactive (0 metabolic equivalent of task [MET]-min/wk), less than guideline-recommended (<500 MET-min/wk), guideline-recommended (500-1000 MET-min/week), and greater than guideline-recommended (>1000 MET-min/wk). Pooled cohort equation risk discrimination was studied using the C statistic and reclassification capabilities were studied using the Greenwood Nam-D\'Agostino χ2 goodness-of-fit test. Change in risk discrimination and reclassification on adding LTPA to PCEs was evaluated using change in C statistic, integrated discrimination index, and categorical net reclassification index.
Main outcomes and measures
Adjudicated ASCVD events during 10-year follow-up.
Results
Among 18 824 participants studied, 10 302 were women (54.7%); mean (SD) age was 57.6 (8.2) years. A total of 5868 participants (31.2%) were inactive, 3849 (20.4%) had less than guideline-recommended LTPA, 3372 (17.9%) had guideline-recommended LTPA, and 5735 (30.5%) had greater than guideline-recommended LTPA level. Higher LTPA levels were associated with a lower risk of ASCVD after adjustment for risk factors (hazard ratio [HR] per 1-SD higher LTPA, 0.91; 95% CI, 0.86-0.96). Across LTPA groups, PCE risk discrimination (C statistic, 0.76-0.78) and risk calibration (all χ2 P > .10) was similar. Addition of LTPA to the PCE model resulted in no significant change in the C statistic (0.0005; 95% CI, -0.0004 to 0.0015; P = .28) and categorical net reclassification index (-0.003; 95% CI, -0.010 to 0.010; P = .95), but a minimal improvement in the integrated discrimination index (0.0008; 95% CI, 0.0002-0.0013; P = .005) was observed. Similar results were noted when cohort-specific coefficients were used for creating the baseline model.

Conclusions:
and relevance
Higher self-reported LTPA levels appear to be associated with lower ASCVD risk and increasing LTPA promotes cardiovascular wellness. These findings suggest the American Heart Association/American College of Cardiology PCEs are accurate at estimating the probability of 10-year ASCVD risk regardless of LTPA level. The addition of self-reported LTPA to PCEs does not appear to be associated with improvement in risk prediction model performance.



JAMA Cardiol: 31 May 2021; 6:690-696
Pandey A, Mehta A, Paluch A, Ning H, ... Lloyd-Jones DM, Wilkins JT
JAMA Cardiol: 31 May 2021; 6:690-696 | PMID: 33909016
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Impact:
Abstract

Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes With Recent SARS-CoV-2 Infection: Results From the Big Ten COVID-19 Cardiac Registry.

Daniels CJ, Rajpal S, Greenshields JT, Rosenthal GL, ... Rink LD, Big Ten COVID-19 Cardiac Registry Investigators
Importance
Myocarditis is a leading cause of sudden death in competitive athletes. Myocardial inflammation is known to occur with SARS-CoV-2. Different screening approaches for detection of myocarditis have been reported. The Big Ten Conference requires comprehensive cardiac testing including cardiac magnetic resonance (CMR) imaging for all athletes with COVID-19, allowing comparison of screening approaches.
Objective
To determine the prevalence of myocarditis in athletes with COVID-19 and compare screening strategies for safe return to play.
Design, setting, and participants
Big Ten COVID-19 Cardiac Registry principal investigators were surveyed for aggregate observational data from March 1, 2020, through December 15, 2020, on athletes with COVID-19. For athletes with myocarditis, presence of cardiac symptoms and details of cardiac testing were recorded. Myocarditis was categorized as clinical or subclinical based on the presence of cardiac symptoms and CMR findings. Subclinical myocarditis classified as probable or possible myocarditis based on other testing abnormalities. Myocarditis prevalence across universities was determined. The utility of different screening strategies was evaluated.
Exposures
SARS-CoV-2 by polymerase chain reaction testing.
Main outcome and measure
Myocarditis via cardiovascular diagnostic testing.
Results
Representing 13 universities, cardiovascular testing was performed in 1597 athletes (964 men [60.4%]). Thirty-seven (including 27 men) were diagnosed with COVID-19 myocarditis (overall 2.3%; range per program, 0%-7.6%); 9 had clinical myocarditis and 28 had subclinical myocarditis. If cardiac testing was based on cardiac symptoms alone, only 5 athletes would have been detected (detected prevalence, 0.31%). Cardiac magnetic resonance imaging for all athletes yielded a 7.4-fold increase in detection of myocarditis (clinical and subclinical). Follow-up CMR imaging performed in 27 (73.0%) demonstrated resolution of T2 elevation in all (100%) and late gadolinium enhancement in 11 (40.7%).

Conclusions:
and relevance
In this cohort study of 1597 US competitive athletes with CMR screening after COVID-19 infection, 37 athletes (2.3%) were diagnosed with clinical and subclinical myocarditis. Variability was observed in prevalence across universities, and testing protocols were closely tied to the detection of myocarditis. Variable ascertainment and unknown implications of CMR findings underscore the need for standardized timing and interpretation of cardiac testing. These unique CMR imaging data provide a more complete understanding of the prevalence of clinical and subclinical myocarditis in college athletes after COVID-19 infection. The role of CMR in routine screening for athletes safe return to play should be explored further.



JAMA Cardiol: 26 May 2021; epub ahead of print
Daniels CJ, Rajpal S, Greenshields JT, Rosenthal GL, ... Rink LD, Big Ten COVID-19 Cardiac Registry Investigators
JAMA Cardiol: 26 May 2021; epub ahead of print | PMID: 34042947
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Impact:
Abstract

Cost-effectiveness of Dapagliflozin for Treatment of Patients With Heart Failure With Reduced Ejection Fraction.

Parizo JT, Goldhaber-Fiebert JD, Salomon JA, Khush KK, ... Heidenreich PA, Sandhu AT
Importance
In the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, dapagliflozin was shown to reduce cardiovascular mortality and hospitalizations due to heart failure while improving patient-reported health status. However, the cost-effectiveness of adding dapagliflozin therapy to standard of care (SOC) is unknown.
Objective
To estimate the cost-effectiveness of dapagliflozin therapy among patients with chronic heart failure with reduced ejection fraction (HFrEF).
Design, setting, and participants
This Markov cohort cost-effectiveness model used estimates of therapy effectiveness, transition probabilities, and utilities from the DAPA-HF trial and other published literature. Costs were derived from published sources. Patients with HFrEF included subgroups based on diabetes status and health status impairment due to heart failure. We compiled parameters from the literature including DAPA-HF, on which our model is based, and many other sources from December 2019 to February 27, 2021. We performed our analysis in February 2021.
Exposures
Dapagliflozin or SOC.
Main outcomes and measures
Hospitalizations for heart failure, life-years, quality-adjusted life-years (QALYs), costs, and the cost per QALY gained (incremental cost-effectiveness ratio).
Results
In the model, dapagliflozin therapy yielded a mean of 0.78 additional life-years and 0.46 additional QALYs compared with SOC at an incremental cost of $38 212, resulting in a cost per QALY gained of $83 650. The cost per QALY was similar for patients with or without diabetes and for patients with mild or moderate impairment of health status due to heart failure. The cost-effectiveness was most sensitive to estimates of the effect on mortality and duration of therapy effectiveness. If the cost of dapagliflozin decreased from $474 to $270 (43% decline), the cost per QALY gained would drop below $50 000.

Conclusions:
and relevance
These findings suggest that dapagliflozin provides intermediate value compared with SOC, based on American College of Cardiology/American Heart Association benchmarks. Additional data regarding the magnitude of mortality reduction would improve the precision of cost-effectiveness estimates.



JAMA Cardiol: 25 May 2021; epub ahead of print
Parizo JT, Goldhaber-Fiebert JD, Salomon JA, Khush KK, ... Heidenreich PA, Sandhu AT
JAMA Cardiol: 25 May 2021; epub ahead of print | PMID: 34037681
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Impact:
Abstract

Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.

Sturm AC, Truty R, Callis TE, Aguilar S, ... Vatta M, Rader DJ
Importance
Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants.
Objective
To identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)-based comprehensive testing.
Design, setting, and participants
This cross-sectional study compared comprehensive genetic test results for clinically significant variants associated with FH with results for a subset of 24 variants screened by a limited-variant array. Data were deidentified next-generation sequencing results from indication-based or proactive gene panels. Individuals receiving next-generation sequencing-based genetic testing, either for an FH indication between November 2015 and June 2020 or as proactive health screening between February 2016 and June 2020 were included. Ancestry was reported by clinicians who could select from preset options or enter free text on the test requisition form.
Main outcomes and measures
Number of pathogenic or likely pathogenic (P/LP) variants identified.
Results
This study included 4563 individuals who were referred for FH diagnostic testing and 6482 individuals who received next-generation sequencing of FH-associated genes as part of a proactive genetic test. Among individuals in the indication cohort, the median (interquartile range) age at testing was 49 (32-61) years, 55.4% (2528 of 4563) were female, and 63.6% (2902 of 4563) were self-reported White/Caucasian. In the indication cohort, the positive detection rate would have been 8.4% (382 of 4563) for a limited-variant screen compared with the 27.0% (1230 of 4563) observed with the next-generation sequencing-based comprehensive test. As a result, 68.9% (848 of 1230) of individuals with a P/LP finding in an FH-associated gene would have been missed by the limited screen. The potential for missed findings in the indication cohort varied by ancestry; among individuals with a P/LP finding, 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed by the limited-variant screen, compared with 33.3% (4 of 12) of Ashkenazi Jewish individuals. In the proactive cohort, the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test, and 61.8% (21 of 34) of individuals with an FH-associated P/LP finding would have been missed by a limited-variant screen.

Conclusions:
and relevance
Limited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry.



JAMA Cardiol: 25 May 2021; epub ahead of print
Sturm AC, Truty R, Callis TE, Aguilar S, ... Vatta M, Rader DJ
JAMA Cardiol: 25 May 2021; epub ahead of print | PMID: 34037665
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Impact:
Abstract

Association of Socioeconomic Disadvantage With Long-term Mortality After Myocardial Infarction: The Mass General Brigham YOUNG-MI Registry.

Berman AN, Biery DW, Ginder C, Singh A, ... Bhatt DL, Blankstein R
Importance
Socioeconomic disadvantage is associated with poor health outcomes. However, whether socioeconomic factors are associated with post-myocardial infarction (MI) outcomes in younger patient populations is unknown.
Objective
To evaluate the association of neighborhood-level socioeconomic disadvantage with long-term outcomes among patients who experienced an MI at a young age.
Design, setting, and participants
This cohort study analyzed patients in the Mass General Brigham YOUNG-MI Registry (at Brigham and Women\'s Hospital and Massachusetts General Hospital in Boston, Massachusetts) who experienced an MI at or before 50 years of age between January 1, 2000, and April 30, 2016. Each patient\'s home address was mapped to the Area Deprivation Index (ADI) to capture higher rates of socioeconomic disadvantage. The median follow-up duration was 11.3 years. The dates of analysis were May 1, 2020, to June 30, 2020.
Exposures
Patients were assigned an ADI ranking according to their home address and then stratified into 3 groups (least disadvantaged group, middle group, and most disadvantaged group).
Main outcomes and measures
The outcomes of interest were all-cause and cardiovascular mortality. Cause of death was adjudicated from national registries and electronic medical records. Cox proportional hazards regression modeling was used to evaluate the association of ADI with all-cause and cardiovascular mortality.
Results
The cohort consisted of 2097 patients, of whom 2002 (95.5%) with an ADI ranking were included (median [interquartile range] age, 45 [42-48] years; 1607 male individuals [80.3%]). Patients in the most disadvantaged neighborhoods were more likely to be Black or Hispanic, have public insurance or no insurance, and have higher rates of traditional cardiovascular risk factors such as hypertension and diabetes. Among the 1964 patients who survived to hospital discharge, 74 (13.6%) in the most disadvantaged group compared with 88 (12.6%) in the middle group and 41 (5.7%) in the least disadvantaged group died. Even after adjusting for a comprehensive set of clinical covariates, higher neighborhood disadvantage was associated with a 32% higher all-cause mortality (hazard ratio, 1.32; 95% CI, 1.10-1.60; P = .004) and a 57% higher cardiovascular mortality (hazard ratio, 1.57; 95% CI, 1.17-2.10; P = .003).

Conclusions:
and relevance
This study found that, among patients who experienced an MI at or before age 50 years, socioeconomic disadvantage was associated with higher all-cause and cardiovascular mortality even after adjusting for clinical comorbidities. These findings suggest that neighborhood and socioeconomic factors have an important role in long-term post-MI survival.



JAMA Cardiol: 18 May 2021; epub ahead of print
Berman AN, Biery DW, Ginder C, Singh A, ... Bhatt DL, Blankstein R
JAMA Cardiol: 18 May 2021; epub ahead of print | PMID: 34009238
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Impact:
Abstract

Incidence, Causes, and Outcomes Associated With Urgent Implantation of a Supplementary Valve During Transcatheter Aortic Valve Replacement.

Landes U, Witberg G, Sathananthan J, Kim WK, ... Kornowski R, Webb JG
Importance
Transcatheter aortic valve replacement (TAVR) failure is often managed by an urgent implantation of a supplementary valve during the procedure (2-valve TAVR [2V-TAVR]). Little is known about the factors associated with or sequelae of 2V-TAVR.
Objective
To examine the incidence, causes, and outcomes of 2V-TAVR.
Design, setting, and participants
A retrospective cohort study was performed using data from an international registry of 21 298 TAVR procedures performed from January 1, 2014, through February 28, 2019. Among the 21 298 patients undergoing TAVR, 223 patients (1.0%) undergoing 2V-TAVR were identified. Patient-level data were available for all the patients undergoing 2V-TAVR and for 12 052 patients (56.6%) undergoing 1V-TAVR. After excluding patients with missing 30-day follow-up or data inconsistencies, 213 2V-TAVR and 10 010 1V-TAVR patients were studied. The 2V-TAVR patients were compared against control TAVR patients undergoing a 1-valve TAVR (1V-TAVR) using 1:4 17 propensity score matching. Final analysis included 1065 (213:852) patients.
Exposures
Urgent implantation of a supplementary valve during TAVR.
Main outcomes and measures
Mortality at 30 days and 1 year.
Results
The 213 patients undergoing 2V-TAVR had similar age (mean [SD], 81.3 [0.5] years) and sex (110 [51.6%] female) as the 10 010 patients undergoing 1V-TAVR (mean [SD] age, 81.2 [0.5] years; 110 [51.6%] female). The 2V-TAVR incidence decreased from 2.9% in 2014 to 1.0% in 2018 and was similar between repositionable and nonrepositionable valves. Bicuspid aortic valve (odds ratio [OR], 2.20; 95% CI, 1.17-4.15; P = .02), aortic regurgitation of moderate or greater severity (OR, 2.02; 95% CI, 1.49-2.73; P < .001), atrial fibrillation (OR, 1.43; 95% CI, 1.07-1.93; P = .02), alternative access (OR, 2.59; 95% CI, 1.72-3.89; P < .001), early-generation valve (OR, 2.32; 95% CI, 1.69-3.19; P < .001), and self-expandable valve (OR, 1.69; 95% CI, 1.17-2.43; P = .004) were associated with higher 2V-TAVR risk. In 165 patients (80%), the supplementary valve was implanted because of residual aortic regurgitation after primary valve malposition (94 [46.4%] too high and 71 [34.2%] too low). In the matched 2V-TAVR vs 1V-TAVR cohorts, the rate of device success was 147 (70.4%) vs 783 (92.2%) (P < .001), the rate of coronary obstruction was 5 (2.3%) vs 3 (0.4%) (P = .10), stroke rate was 9 (4.6%) vs 13 (1.6%) (P = .09), major bleeding rates were 25 (11.8%) vs 46 (5.5%) (P = .03) and annular rupture rate was 7 (3.3%) vs 3 (0.4%) (P = .03). The hazard ratios for mortality were 2.58 (95% CI, 1.04-6.45; P = .04) at 30 days, 1.45 (95% CI, 0.84-2.51; P = .18) at 1 year, and 1.20 (95% CI, 0.77-1.88; P = .42) at 2 years. Nontransfemoral access and certain periprocedural complications were independently associated with higher risk of death 1 year after 2V-TAVR.

Conclusions:
and relevance
In this cohort study, valve malposition was the most common indication for 2V-TAVR. Incidence decreased over time and was low overall, although patients with a bicuspid or regurgitant aortic valve, nontransfemoral access, and early-generation or self-expandable valve were at higher risk. These findings suggest that compared with 1V-TAVR, 2V-TAVR is associated with high burden of complications and mortality at 30 days but not at 1 year.



JAMA Cardiol: 18 May 2021; epub ahead of print
Landes U, Witberg G, Sathananthan J, Kim WK, ... Kornowski R, Webb JG
JAMA Cardiol: 18 May 2021; epub ahead of print | PMID: 34009236
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Impact:
Abstract

Evaluation of the Risk of Stroke Without Anticoagulation Therapy in Men and Women With Atrial Fibrillation Aged 66 to 74 Years Without Other CHA2DS2-VASc Factors.

Abdel-Qadir H, Singh SM, Pang A, Austin PC, ... Dorian P, Ko DT
Importance
There are limited clinical trial data and discrepant recommendations regarding use of anticoagulation therapy in patients with atrial fibrillation (AF) aged 65 to 74 years without other stroke risk factors.
Objectives
To evaluate the risk of stroke without anticoagulation therapy in men and women with AF aged 66 to 74 years without other CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke, vascular disease, age 65-74 years, female sex) risk factors and examine the association of stroke incidence with patient age.
Design, setting, and participants
A population-based retrospective cohort study was conducted using linked administrative databases. The population included 16 351 individuals aged 66 to 74 years who were newly diagnosed with AF in Ontario, Canada, between April 1, 2007, and March 31, 2017. Exclusion criteria included long-term care residence, prior anticoagulation therapy, valvular disease, heart failure, hypertension, diabetes, stroke, and vascular disease. The cumulative incidence function was used to estimate the 1-year incidence of stroke in patients who did not receive anticoagulation therapy. Fine-Gray regression was used to study the association of patient characteristics with stroke incidence and derive estimates of stroke risk at each age. Death was treated as a competing risk and patients were censored if they initiated anticoagulation therapy. Inverse probability of censoring weights was used to account for patient censoring. Data analysis was performed from May 26, 2019, to December 9, 2020.
Exposures
Atrial fibrillation and age.
Main outcomes and measures
Hospitalizations for stroke.
Results
Of the 16 351 individuals with AF (median [interquartile range] age, 70 [68-72] years), 8352 (51.1%) were men; 6314 individuals (38.6%) started anticoagulation therapy during follow-up. The overall 1-year stroke incidence among patients who did not receive anticoagulation therapy was 1.1% (95% CI, 1.0%-1.3%) and the incidence of death without stroke was 8.1% (95% CI, 7.7%-8.5%). The incidence of stroke was not significantly associated with sex. The estimated 1-year stroke risk increased with patient age from 66 years (0.7%; 95% CI, 0.5%-0.9%) to 74 years (1.7%; 95% CI, 1.3%-2.1%).

Conclusions:
and relevance
The risk of stroke more than doubled in this study as men and women with AF but no other CHA2DS2-VASc risk factors aged from 66 to 74 years. These data suggest that anticoagulation therapy is more likely to benefit older individuals within this group of patients, whereas younger individuals are less likely to gain net clinical benefit from anticoagulation therapy.



JAMA Cardiol: 18 May 2021; epub ahead of print
Abdel-Qadir H, Singh SM, Pang A, Austin PC, ... Dorian P, Ko DT
JAMA Cardiol: 18 May 2021; epub ahead of print | PMID: 34009232
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Impact:
Abstract

State of the Nation\'s Cardiovascular Health and Targeting Health Equity in the United States: A Narrative Review.

Diaz CL, Shah NS, Lloyd-Jones DM, Khan SS
Importance
Cardiovascular disease is the leading cause of death in the US. The burden of cardiovascular disease morbidity and mortality disproportionately affects racial/ethnic minority groups, who now compose almost 40% of the US population in aggregate. As part of the 2010 American Heart Association (AHA) Strategic Impact Goal, the AHA established 7 cardiovascular health (CVH) metrics (also known as Life\'s Simple 7) with the goal to improve the CVH of all individuals in the US by 20% by 2020. National estimates of CVH are important to track and monitor at the population level but may mask important differences across and within racial/ethnic minority groups. It is critical to understand how CVH may differ between racial/ethnic minority groups and consider how these differences in CVH may contribute to disparities in cardiovascular disease burden and overall longevity.
Observations
This narrative review summarizes the available literature on individual CVH metrics and composite CVH scores across different race/ethnic minority groups (specifically Hispanic/Latino, Asian, and non-Hispanic Black individuals) in the US. Disparities in CVH persist among racial/ethnic groups, but key gaps in knowledge exist, in part, owing to underrepresentation of these racial/ethnic groups in research or misrepresentation of CVH because of aggregation of race/ethnicity subgroups. A comprehensive, multilevel approach is needed to target health equity and should include (1) access to high-quality health care, (2) community-engaged approaches to adapt disruptive health care delivery innovations, (3) equitable economic investment in the social and built environment, and (4) increasing funding for research in racial/ethnic minority populations.

Conclusions:
and relevance
Significant differences in CVH exist within racial/ethnic groups. Given the rapid growth of diverse, minority populations in the US, focused investigation is needed to identify strategies to optimize CVH. Opportunities exist to address inequities in CVH and to successfully achieve both the interim (AHA 2024) and longer-term (AHA 2030) Impact Goals in the coming years.



JAMA Cardiol: 18 May 2021; epub ahead of print
Diaz CL, Shah NS, Lloyd-Jones DM, Khan SS
JAMA Cardiol: 18 May 2021; epub ahead of print | PMID: 34009231
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Impact:
Abstract

Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular Risk: A Secondary Analysis of the STRENGTH Trial.

Nissen SE, Lincoff AM, Wolski K, Ballantyne CM, ... Menon V, Nicholls SJ
Importance
In patients treated with ω-3 fatty acids, it remains uncertain whether achieved levels of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) are associated with cardiovascular outcomes.
Objective
To determine the association between plasma levels of EPA and DHA and cardiovascular outcomes in a trial of ω-3 fatty acids compared with corn oil placebo.
Design, setting, and participants
A double-blind, multicenter trial enrolled patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol at 675 centers (enrollment from October 30, 2014, to June 14, 2017; study termination January 8, 2020; last visit May 14, 2020).
Interventions
Participants were randomized to receive 4 g daily of ω-3 carboxylic acid (CA) or an inert comparator, corn oil.
Main outcomes and measures
The primary prespecified end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The primary outcome measure was the hazard ratio, adjusted for baseline characteristics, for patients treated with the ω-3 CA compared with corn oil for the top tertile of achieved EPA and DHA plasma levels 12 months after randomization.
Results
Of the 13 078 total participants, 6539 (50%) were randomized to receive ω-3 CA and 6539 (50%) randomized to corn oil. ω-3 Fatty acid levels were available at both baseline and 12 months after randomization in 10 382 participants (5175 ω-3 CA patients [49.8%] and 5207 corn oil-treated patients [50.2%]; mean [SD] age, 62.5 [8.9] years, 3588 [34.6%] were women, 9025 [86.9%] were White, and 7285 [70.2%] had type 2 diabetes). The median plasma levels at 12 months in ω-3 CA patients were 89 μg/mL (interquartile range [IQR], 46-131 μg/mL) for EPA and 91 μg/mL (IQR, 71-114 μg/mL) for DHA with top tertile levels of 151 μg/mL (IQR, 132-181 μg/mL) and 118 μg/mL (IQR, 102-143 μg/mL), respectively. Compared with corn oil, the adjusted hazard ratios for the highest tertile of achieved plasma levels were 0.98 (95% CI, 0.83-1.16; P = .81) for EPA, and 1.02 (95% CI, 0.86-1.20; P = .85 for DHA. Sensitivity analyses based on changes in plasma and red blood cell levels of EPA and DHA and primary and secondary prevention subgroups showed similar results.

Conclusions:
and relevance
Among patients treated with ω-3 CA, the highest achieved tertiles of EPA and DHA were associated with neither benefit nor harm in patients at high cardiovascular risk.
Trial registration
ClinicalTrials.gov Identifier: NCT02104817.



JAMA Cardiol: 15 May 2021; epub ahead of print
Nissen SE, Lincoff AM, Wolski K, Ballantyne CM, ... Menon V, Nicholls SJ
JAMA Cardiol: 15 May 2021; epub ahead of print | PMID: 33993205
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Impact:
Abstract

Sex Differences Among Patients With High Risk Receiving Ticagrelor With or Without Aspirin After Percutaneous Coronary Intervention: A Subgroup Analysis of the TWILIGHT Randomized Clinical Trial.

Vogel B, Baber U, Cohen DJ, Sartori S, ... Huber K, Mehran R
Importance
Shortened dual antiplatelet therapy followed by potent P2Y12 receptor inhibitor monotherapy reduces bleeding without increasing ischemic events after percutaneous coronary intervention (PCI).
Objective
To explore sex differences and evaluate the association of sex with outcomes among patients treated with ticagrelor monotherapy vs ticagrelor plus aspirin.
Design, setting, and participants
This was a prespecified secondary analysis of TWILIGHT, an investigator-initiated, placebo-controlled randomized clinical trial conducted at 187 sites across 11 countries. Study participants included patients who underwent successful PCI with drug-eluting stents, were planned for discharge with ticagrelor plus aspirin, and who had at least 1 clinical and at least 1 angiographic feature associated with high risk of ischemic or bleeding events. Data were analyzed from May to July 2020.
Interventions
At 3 months after PCI, patients adherent to ticagrelor and aspirin without major adverse event were randomized to either aspirin or placebo for an additional 12 months along with ticagrelor.
Main outcomes and measures
The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding at 12 months after randomization. The primary ischemic end point was a composite of death, myocardial infarction, or stroke.
Results
Of 9006 enrolled patients, 7119 underwent randomization (mean [SD] age, 63.9 [10.2] years; 5421 [76.1%] men). Women were older (mean [SD] age, 65.5 [9.6] years in women vs 63.4 [10.3] years in men) with higher prevalence of chronic kidney disease (347 women [21.2%] vs 764 men [14.7%]). The primary bleeding end point occurred more often in women than men (hazard ratio [HR], 1.32; 95% CI, 1.06-1.64; P = .01). After multivariate adjustment, incremental bleeding risk associated with female sex was no longer significant (adjusted HR, 1.20; 95% CI, 0.95-1.52; P = .12). Ischemic end points were similar between sexes. Ticagrelor plus placebo vs ticagrelor plus aspirin was associated with lower risk of BARC type 2, 3, or 5 bleeding in women (adjusted HR, 0.62; 95% CI, 0.42-0.92; P = .02) and men (adjusted HR, 0.57; 95% CI, 0.44-0.73; P < .001; P for interaction = .69). Ischemic end points were similar between treatment groups in both sexes.

Conclusions:
and relevance
These findings suggest that the higher bleeding risk in women compared with men was mostly attributable to baseline differences, whereas ischemic events were similar between sexes. In this high-risk PCI population, the benefits of early aspirin withdrawal with continuation of ticagrelor were generally comparable in women and men.
Trial registration
ClinicalTrials.gov Identifier: NCT02270242.



JAMA Cardiol: 14 May 2021; epub ahead of print
Vogel B, Baber U, Cohen DJ, Sartori S, ... Huber K, Mehran R
JAMA Cardiol: 14 May 2021; epub ahead of print | PMID: 33991416
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Impact:
Abstract

Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent Ventricular Arrhythmia and End-stage Heart Failure.

Akhtar MM, Lorenzini M, Pavlou M, Ochoa JP, ... Elliott PM, European Genetic Cardiomyopathies Initiative Investigators
Importance
Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia.
Objective
To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv).
Design, setting, and participants
This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020.
Main outcomes and measures
The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only.
Results
In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF ≤35%) LVSD (HR, 1.29 [95% CI, 0.45-3.72]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03).

Conclusions:
and relevance
The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.



JAMA Cardiol: 11 May 2021; epub ahead of print
Akhtar MM, Lorenzini M, Pavlou M, Ochoa JP, ... Elliott PM, European Genetic Cardiomyopathies Initiative Investigators
JAMA Cardiol: 11 May 2021; epub ahead of print | PMID: 33978673
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Impact:
Abstract

Quality of Life in Patients With Heart Failure With Recovered Ejection Fraction.

Wohlfahrt P, Nativi-Nicolau J, Zhang M, Selzman CH, ... Spertus JA, Stehlik J
Importance
Heart failure with recovered ejection fraction (HFrecEF) is a recently recognized phenotype of patients with a history of reduced left ventricular ejection fraction (LVEF) that has subsequently normalized. It is unknown whether such LVEF improvement is associated with improvements in health status.
Objective
To examine changes in health-related quality of life in patients with heart failure with reduced ejection fraction (HFrEF) whose LVEF normalized, compared with those whose LVEF remains reduced and those with HF with preserved EF (HFpEF).
Design, setting, and participants
This prospective cohort study was conducted at a tertiary care hospital from November 2016 to December 2018. Consecutive patients seen in a heart failure clinic who completed patient-reported outcome assessments were included. Clinical data were abstracted from the electronic health record. Data analysis was completed from February to December 2020.
Main outcomes and measures
Changes in Kansas City Cardiomyopathy Questionnaire overall summary score, Visual Analog Scale score, and Patient-Reported Outcomes Measurement Information System domain scores on physical function, fatigue, depression, and satisfaction with social roles over 1-year follow-up.
Results
The study group included 319 patients (mean [SD] age, 60.4 [15.5] years; 120 women [37.6%]). At baseline, 212 patients (66.5%) had HFrEF and 107 (33.5%) had HFpEF. At a median follow-up of 366 (interquartile range, 310-421) days, LVEF had increased to 50% or more in 35 patients with HFrEF (16.5%). Recovery of systolic function was associated with heart failure-associated quality-of-life improvement, such that for each 10% increase in LVEF, the Kansas City Cardiomyopathy Questionnaire score improved by an mean (SD) of 4.8 (1.6) points (P = .003). Recovery of LVEF was also associated with improvement of physical function, satisfaction with social roles, and a reduction in fatigue.

Conclusions:
and relevance
Among patients with HFrEF in this study, normalization of left ventricular systolic function was associated with a significant improvement in health-related quality of life.



JAMA Cardiol: 04 May 2021; epub ahead of print
Wohlfahrt P, Nativi-Nicolau J, Zhang M, Selzman CH, ... Spertus JA, Stehlik J
JAMA Cardiol: 04 May 2021; epub ahead of print | PMID: 33950162
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Impact:
Abstract

Comparison of Days Alive Out of Hospital With Initial Invasive vs Conservative Management: A Prespecified Analysis of the ISCHEMIA Trial.

White HD, O\'Brien SM, Alexander KP, Boden WE, ... Hochman JS, Maron DJ
Importance
Traditional time-to-event analyses rate events occurring early as more important than later events, even if later events are more severe, eg, death. Days alive out of hospital (DAOH) adds a patient-focused perspective beyond trial end points.
Objective
To compare DAOH between invasive management and conservative management, including invasive protocol-assigned stays, in the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) randomized clinical trial.
Design, setting, and participants
In this prespecified analysis of the ISCHEMIA trial, DAOH was compared between 5179 patients with stable coronary disease and moderate or severe ischemia randomized to invasive management or conservative management. Participants were recruited from 320 sites in 37 countries. Stays included overnight stays in hospital or extended care facility (skilled nursing facility, rehabilitation, or nursing home). DAOH was separately analyzed excluding invasive protocol-assigned procedures. Data were collected from July 2012 to June 2019, and data were analyzed from July 2020 to April 2021.
Interventions
Invasive management with angiography and revascularization if feasible or conservative management, with both groups receiving optimal medical therapy.
Main outcomes and measures
The hypothesis was formulated before data lock in July 2020. The primary end point was mean DAOH per patient between randomization and 4 years. Initial stays for invasive protocol-assigned procedures were prespecified to be excluded.
Results
Of 5179 included patients, 1168 (22.6%) were female, and the median (interquartile range) age was 64 (58-70) years. The average DAOH was higher in the conservative management group compared with the invasive management group at 1 month (30.8 vs 28.4 days; P < .001), 1 year (362.2 vs 355.9 days; P < .001), and 2 years (718.4 vs 712.1 days; P = .001). At 4 years, the 2 groups\' DAOH were not significantly different (1415.0 vs 1412.2 days; P = .65). In the invasive management group, 2434 of 4002 stays (60.8%) were for protocol-assigned procedures. There were no clear differences at any time point in DAOH when protocol-assigned procedures were excluded from the invasive management group. There were more hospital and extended care stays in the invasive management vs conservative management group during follow-up (4002 vs 1897; P < .001). Excluding protocol-assigned procedures, there were fewer stays in the invasive vs conservative group (1568 vs 1897; P = .001). Cardiovascular stays following the initial assigned procedures were lower in the invasive management group (685 of 4002 [17.1%] vs 1095 of 1897 [57.8%]; P < .001) due to decreased spontaneous myocardial infarction stays (65 [1.6%] vs 123 [6.5%]; P < .001) and unstable angina stays (119 [3.0%] vs 216 [11.4%]; P < .001).

Conclusions:
and relevance
DAOH was higher for patients in the conservative management group in the first 2 years but not different at 4 years. DAOH was decreased early in the invasive management group due to protocol-assigned procedures. Hospital stays for myocardial infarction and unstable angina during follow-up were lower in the invasive management group. DAOH provides a patient-focused metric that can be used by clinicians and patients in shared decision-making for management of stable coronary artery disease.
Trial registration
ClinicalTrials.gov Identifier: NCT01471522.



JAMA Cardiol: 02 May 2021; epub ahead of print
White HD, O'Brien SM, Alexander KP, Boden WE, ... Hochman JS, Maron DJ
JAMA Cardiol: 02 May 2021; epub ahead of print | PMID: 33938917
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Impact:
Abstract

Estimated Prevalence of Masked Asleep Hypertension in US Adults.

Li S, Schwartz JE, Shimbo D, Muntner P, ... Bellows BK, Zhang Y
Importance
High blood pressure (BP) during sleep (asleep blood pressure) is associated with an increased risk of cardiovascular disease, but a national prevalence estimate of masked asleep hypertension (high BP while sleeping but without high BP measured in the clinic [clinic BP]) for the United States is lacking.
Objectives
To estimate the prevalence of masked asleep hypertension among US adults by using BP thresholds from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) and the 2017 American College of Cardiology-American Heart Association (ACC-AHA) BP guidelines.
Design, setting, and participants
This cohort analysis pooled data from 3000 participants in 4 US population-based studies that conducted 24-hour ambulatory BP monitoring (ABPM) and 17 969 participants in the 2011-2016 National Health and Nutrition Examination Survey (NHANES) without ABPM. Masked asleep hypertension status in NHANES was imputed using a 2-stage multiple imputation process. Data were collected from 2000 to 2016 and analyzed from March 4, 2019, to June 29, 2020.
Main outcomes and measures
High clinic BP was defined as clinic systolic BP (SBP)/diastolic BP (DBP) of at least 140/90 mm Hg using JNC7 and at least 130/80 mm Hg using 2017 ACC-AHA guidelines. High asleep BP was defined as mean asleep SBP/DBP of at least 120/70 mm Hg for JNC7 and at least 110/65 mm Hg for the 2017 ACC-AHA guidelines. Masked asleep hypertension was defined as high asleep BP without high clinic BP.
Results
For the 3000 pooled cohort participants, the mean (SD) age was 52.0 (12.0) years, and 62.6% were women. For the 17 969 NHANES participants, the mean (SD) age was 46.7 (17.5) years, and 51.8% (weighted) were women. The estimated prevalence of masked asleep hypertension among US adults was 18.8% (95% CI, 16.7%-20.8%; 44.4 million US adults) using the JNC7 guideline and 22.7% (95% CI, 20.6%-24.8%; 53.7 million US adults) using the 2017 ACC-AHA guideline criteria. The prevalence of masked asleep hypertension was higher among older adults (aged ≥65 years, 24.4% [95% CI, 20.7%-28.0%]), men (27.0% [95% CI, 24.1%-29.9%]), non-Hispanic Black individuals (28.7% [95% CI, 25.4%-32.0%]), those who were taking antihypertensives (24.4% [95% CI, 21.1%-27.8%]), those who had masked daytime hypertension (44.7% [95% CI, 40.1%-49.3%]), and those with diabetes (27.6% [95% CI, 23.5%-31.8%]), obesity (24.3% [95% CI, 21.8%-26.9%]), or chronic kidney disease (21.5% [95% CI, 17.3%-25.6%]) using the 2017 ACC-AHA guideline. An estimated 11.9% of US adults (28.2 million) had isolated masked asleep hypertension (masked asleep hypertension but without high awake BP) using JNC7 guideline criteria, as did an estimated 13.3% (31.5 million) using 2017 ACC-AHA guideline criteria.

Conclusions:
and relevance
These findings suggest that the prevalence of masked asleep hypertension is high among US adults. Data are needed on the cardiovascular risk reduction benefits of treating asleep hypertension.



JAMA Cardiol: 30 Apr 2021; 6:568-573
Li S, Schwartz JE, Shimbo D, Muntner P, ... Bellows BK, Zhang Y
JAMA Cardiol: 30 Apr 2021; 6:568-573 | PMID: 33112362
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Impact:
Abstract

Association of Circulating Monocyte Chemoattractant Protein-1 Levels With Cardiovascular Mortality: A Meta-analysis of Population-Based Studies.

Georgakis MK, de Lemos JA, Ayers C, Wang B, ... Benjamin EJ, Dichgans M
Importance
Human genetics and studies in experimental models support a key role of monocyte-chemoattractant protein-1 (MCP-1) in atherosclerosis. Yet, the associations of circulating MCP-1 levels with risk of coronary heart disease and cardiovascular death in the general population remain largely unexplored.
Objective
To explore whether circulating levels of MCP-1 are associated with risk of incident coronary heart disease, myocardial infarction, and cardiovascular mortality in the general population.
Data sources and selection
Population-based cohort studies, identified through a systematic review, that have examined associations of circulating MCP-1 levels with cardiovascular end points.
Data extraction and synthesis
Using a prespecified harmonized analysis plan, study-specific summary data were obtained from Cox regression models after excluding individuals with overt cardiovascular disease at baseline. Derived hazard ratios (HRs) were synthesized using random-effects meta-analyses.
Main outcomes and measures
Incident coronary heart disease (myocardial infarction, coronary revascularization, and unstable angina), nonfatal myocardial infarction, and cardiovascular death (from cardiac or cerebrovascular causes).
Results
The meta-analysis included 7 cohort studies involving 21 401 individuals (mean [SD] age, 53.7 [10.2] years; 10 012 men [46.8%]). Mean (SD) follow-up was 15.3 (4.5) years (326 392 person-years at risk). In models adjusting for age, sex, and race/ethnicity, higher MCP-1 levels at baseline were associated with increased risk of coronary heart disease (HR per 1-SD increment in MCP-1 levels: 1.06 [95% CI, 1.01-1.11]; P = .01), nonfatal myocardial infarction (HR, 1.07 [95% CI, 1.01-1.13]; P = .02), and cardiovascular death (HR, 1.12 [95% CI, 1.05-1.20]; P < .001). In analyses comparing MCP-1 quartiles, these associations followed dose-response patterns. After additionally adjusting for vascular risk factors, the risk estimates were attenuated, but the associations of MCP-1 levels with cardiovascular death remained statistically significant, as did the association of MCP-1 levels in the upper quartile with coronary heart disease. There was no significant heterogeneity; the results did not change in sensitivity analyses excluding events occurring in the first 5 years after MCP-1 measurement, and the risk estimates were stable after additional adjustments for circulating levels of interleukin-6 and high-sensitivity C-reactive protein.

Conclusions:
and relevance
Higher circulating MCP-1 levels are associated with higher long-term cardiovascular mortality in community-dwelling individuals free of overt cardiovascular disease. These findings provide further support for a key role of MCP-1-signaling in cardiovascular disease.



JAMA Cardiol: 30 Apr 2021; 6:587-592
Georgakis MK, de Lemos JA, Ayers C, Wang B, ... Benjamin EJ, Dichgans M
JAMA Cardiol: 30 Apr 2021; 6:587-592 | PMID: 33146689
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Impact:
Abstract

Temporal Changes and Institutional Variation in Use of Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction With Multivessel Coronary Artery Disease in the United States: An NCDR Research to Practice Project.

Secemsky EA, Butala N, Raja A, Khera R, ... Bhatt D, Yeh RW
Importance
After disparate results from observational and small randomized studies, the COMPLETE trial demonstrated superiority of multivessel (MV) percutaneous coronary intervention (PCI) over culprit-only PCI for ST-elevation myocardial infarction (STEMI).
Objective
To describe temporal trends and institutional variation of MV PCI use for STEMI in the United States to inform how new evidence may influence clinical practice.
Design, setting, and participants
This cohort study included STEMI admissions involving MV disease from 1598 institutions in the National Cardiovascular Data Registry CathPCI Registry from the third quarter of 2009 to the first quarter of 2018. An MV PCI was defined as a PCI to a nonculprit lesion within 45 days of the index procedure.
Exposures
Multivessel PCI, defined as placement of coronary stents in 2 or more major epicardial vessels or the staged placement of 1 or more coronary stents in a major epicardial vessel distinct from the index culprit vessel, within 45 days of the index PCI.
Main outcomes and measures
Outcomes included the proportional use of MV PCI among STEMI admissions with MV disease, and the timing of MV PCI (an index procedure, a staged procedure during index hospitalization, or a postdischarge procedure within 45 days).
Results
Among 359 879 admissions with STEMI and MV disease, MV PCI was performed in 38.5% (n = 138 380; mean [SD] age of patients, 62.3 [12.3] years; 102 266 men [73.9%]) within 45 days. Of those receiving MV PCIs, 30.8% (n = 42 629) had a procedure performed during the index procedure, 31.6% (n = 43 696) as a staged procedure during the index hospitalization, and 37.6% (n = 52 055) within 45 days of discharge. Complete revascularization of all diseased arteries was performed in 76.2% (n = 105 389). From the third quarter of 2009 to the second quarter of 2013, MV PCI use declined by 10%, from 42.7% (3230 of 7572 cases) to a nadir of 32.7% (3386 of 10 342 cases), followed by an increase to 44.0% (5062 of 11 497 cases) by the fourth quarter of 2017. During this time, there was a 13.6% decline in use of postdischarge staged MV PCI (from 23.4% of STEMI cases [1772 of 7572 cases] in the third quarter of 2009 to 9.9% [1094 of 11 171 cases] in the fourth quarter of 2014) and an 12.5% increase in MV PCI performed during the index admission (from 19.3% [1458 of 7572 cases] in the third quarter of 2009 to 31.8% [3557 of 11 171 cases] in the first quarter of 2018). Multivessel PCI use varied substantially across institutions, with a median use of 37.9% (interquartile range, 30.0%-46.5%).

Conclusions:
and relevance
In this large, nationwide analysis, MV PCI use for patients with STEMI has been increasing through early 2018 but was used in the minority of patients and with wide variability across US institutions. The adoption of new trial results into guidelines and practice may further promote the growth of MV PCI.



JAMA Cardiol: 30 Apr 2021; 6:574-580
Secemsky EA, Butala N, Raja A, Khera R, ... Bhatt D, Yeh RW
JAMA Cardiol: 30 Apr 2021; 6:574-580 | PMID: 33146666
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Impact:
Abstract

Interpretation of the Seattle Angina Questionnaire as an Outcome Measure in Clinical Trials and Clinical Care: A Review.

Thomas M, Jones PG, Arnold SV, Spertus JA
Importance
Patient-reported outcomes are increasingly used as end points in clinical trials, assessments in clinical care, and tools for population health, with an increasing role in quality assessment. For patients with coronary artery disease, the Seattle Angina Questionnaire (SAQ) has emerged as the most commonly used measure of disease-specific health status to quantify patients\' symptoms of angina and the extent to which their angina affects their functioning and quality of life. This review explains how to interpret the SAQ and describes the construction and face validity of the SAQ, focusing on aligning scores and changes in scores with clinical constructs.
Observations
The SAQ asks questions similar to those an experienced clinician would ask of a patient with stable ischemic heart disease. Therefore, SAQ scores can be aligned with clinical constructs (eg, scores on the SAQ angina frequency scale of 0-30 points indicate daily angina, 31-60 points indicate weekly angina, 61-99 points indicate monthly angina, and 100 points indicate no angina), and changes in scores can be described by aligning them with changes in question responses. After clinical thresholds are defined, it is important for clinical trials to not simply report mean differences between treatment arms but to also report the distributions of patients who have had clinically important benefits so that a number needed to treat can be generated.

Conclusions:
and relevance
The widespread use of the SAQ is a consequence of its well-established validity, reproducibility, prognostic importance, and sensitivity to clinical change. Nevertheless, interpreting the SAQ can be challenging because of lack of familiarity with the clinical importance of its domains, either cross-sectionally or longitudinally. This review provides an overview of the interpretability of the SAQ as a foundation for its use as an end point in clinical trials, a tool to support more patient-centered care, and a means of facilitating population health strategies to provide a better foundation for the integration of patient experiences with clinical care.



JAMA Cardiol: 30 Apr 2021; 6:593-599
Thomas M, Jones PG, Arnold SV, Spertus JA
JAMA Cardiol: 30 Apr 2021; 6:593-599 | PMID: 33566062
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Impact:
Abstract

Use of Artificial Intelligence and Deep Neural Networks in Evaluation of Patients With Electrocardiographically Concealed Long QT Syndrome From the Surface 12-Lead Electrocardiogram.

Bos JM, Attia ZI, Albert DE, Noseworthy PA, Friedman PA, Ackerman MJ
Importance
Long QT syndrome (LQTS) is characterized by prolongation of the QT interval and is associated with an increased risk of sudden cardiac death. However, although QT interval prolongation is the hallmark feature of LQTS, approximately 40% of patients with genetically confirmed LQTS have a normal corrected QT (QTc) at rest. Distinguishing patients with LQTS from those with a normal QTc is important to correctly diagnose disease, implement simple LQTS preventive measures, and initiate prophylactic therapy if necessary.
Objective
To determine whether artificial intelligence (AI) using deep neural networks is better than the QTc alone in distinguishing patients with concealed LQTS from those with a normal QTc using a 12-lead electrocardiogram (ECG).
Design, setting, and participants
A diagnostic case-control study was performed using all available 12-lead ECGs from 2059 patients presenting to a specialized genetic heart rhythm clinic. Patients were included if they had a definitive clinical and/or genetic diagnosis of type 1, 2, or 3 LQTS (LQT1, 2, or 3) or were seen because of an initial suspicion for LQTS but were discharged without this diagnosis. A multilayer convolutional neural network was used to classify patients based on a 10-second, 12-lead ECG, AI-enhanced ECG (AI-ECG). The convolutional neural network was trained using 60% of the patients, validated in 10% of the patients, and tested on the remaining patients (30%). The study was conducted from January 1, 1999, to December 31, 2018.
Main outcomes and measures
The goal of the study was to test the ability of the convolutional neural network to distinguish patients with LQTS from those who were evaluated for LQTS but discharged without this diagnosis, especially among patients with genetically confirmed LQTS but a normal QTc value at rest (referred to as genotype positive/phenotype negative LQTS, normal QT interval LQTS, or concealed LQTS).
Results
Of the 2059 patients included, 1180 were men (57%); mean (SD) age at first ECG was 21.6 (15.6) years. All 12-lead ECGs from 967 patients with LQTS and 1092 who were evaluated for LQTS but discharged without this diagnosis were included for AI-ECG analysis. Based on the ECG-derived QTc alone, patients were classified with an area under the curve (AUC) value of 0.824 (95% CI, 0.79-0.858); using AI-ECG, the AUC was 0.900 (95% CI, 0.876-0.925). Furthermore, in the subset of patients who had a normal resting QTc (<450 milliseconds), the QTc alone distinguished those with LQTS from those without LQTS with an AUC of 0.741 (95% CI, 0.689-0.794), whereas the AI-ECG increased this discrimination to an AUC of 0.863 (95% CI, 0.824-0.903). In addition, the AI-ECG was able to distinguish the 3 main genotypic subgroups (LQT1, LQT2, and LQT3) with an AUC of 0.921 (95% CI, 0.890-0.951) for LQT1 compared with LQT2 and 3, 0.944 (95% CI, 0.918-0.970) for LQT2 compared with LQT1 and 3, and 0.863 (95% CI, 0.792-0.934) for LQT3 compared with LQT1 and 2.

Conclusions:
and relevance
In this study, the AI-ECG was found to distinguish patients with electrocardiographically concealed LQTS from those discharged without a diagnosis of LQTS and provide a nearly 80% accurate pregenetic test anticipation of LQTS genotype status. This model may aid in the detection of LQTS in patients presenting to an arrhythmia clinic and, with validation, may be the stepping stone to similar tools to be developed for use in the general population.



JAMA Cardiol: 30 Apr 2021; 6:532-538
Bos JM, Attia ZI, Albert DE, Noseworthy PA, Friedman PA, Ackerman MJ
JAMA Cardiol: 30 Apr 2021; 6:532-538 | PMID: 33566059
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Impact:
Abstract

Magnetic Resonance Imaging in Patients With Cardiac Implantable Electronic Devices With Abandoned Leads.

Schaller RD, Brunker T, Riley MP, Marchlinski FE, Nazarian S, Litt H
Importance
Magnetic resonance imaging (MRI) is the modality of choice for many conditions. Conditional devices and novel protocols for imaging patients with legacy cardiac implantable electronic devices (CIEDs) have increased access to MRI in patients with devices. However, the presence of abandoned leads remains an absolute contraindication.
Objective
To assess if the performance of an MRI in the presence of an abandoned CIED lead is safe and whether there are deleterious effects on concomitant active CIED leads.
Design, setting, and participants
This cohort study included consecutive CIED recipients undergoing 1.5-T MRI with at least 1 abandoned lead between January 2013 and June 2020. MRI scans were performed at the Hospital of the University of Pennsylvania. No patients were excluded.
Exposures
CIEDs were reprogrammed based on patient-specific pacing needs. Electrocardiography telemetry and pulse oximetry were monitored continuously, and live contact with the patient throughout the scan via visual and voice contact was performed if possible. After completion of the MRI, CIED evaluation was repeated and programming returned to baseline or to a clinically appropriate setting.
Main outcomes and measures
Variation in pre- and post-MRI capture threshold of 50% or more, ventricular sensing 40% or more, and lead impedance 30% or more, as well as clinical sequelae such as pain and sustained tachyarrhythmia were considered significant. Long-term follow-up lead-related data were analyzed if available.
Results
A total of 139 consecutive patients (110 men [79%]) with a mean (SD) age of 65.6 (13.4) years underwent 200 MRIs of various anatomic regions including the thorax. Repeat examinations were common with a maximum of 16 examinations for 1 patient. There was a total of 243 abandoned leads with a mean (SD) of 1.22 (0.45) per patient. The mean (SD) number of active leads was 2.04 (0.78) and 64 patients (46%) were pacemaker dependent. A transmit-receive radiofrequency coil was used in 41 patients (20.5%), all undergoing MRI of the brain. There were no abnormal vital signs or sustained tachyarrhythmias. No changes in battery voltage, power-on reset events, or changes of pacing rate were noted. CIED parameter changes including decreased right atrial sensing in 4 patients and decreased left ventricular R-wave amplitude in 1 patient were transiently noted. One patient with an abandoned subcutaneous array experienced sternal heating that subsided on premature cessation of the study.

Conclusions:
and relevance
The risk of MRI in patients with abandoned CIED leads was low in this large observational study, including patients who underwent examination of the thorax. The growing aggregate of data questions the absolute contraindication for MRI in patients with abandoned CIED leads.



JAMA Cardiol: 30 Apr 2021; 6:549-556
Schaller RD, Brunker T, Riley MP, Marchlinski FE, Nazarian S, Litt H
JAMA Cardiol: 30 Apr 2021; 6:549-556 | PMID: 33595595
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Impact:
Abstract

Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection Fraction.

Berg DD, Jhund PS, Docherty KF, Murphy SA, ... McMurray JJV, Sabatine MS
Importance
Dapagliflozin has been shown to reduce the risk of cardiovascular death or worsening heart failure (HF) in patients with chronic HF and reduced ejection fraction (HFrEF). However, clinical inertia often underlies deferred initiation of effective therapies.
Objective
To examine timing of onset of clinical benefit with dapagliflozin and magnitude as a function of proximity to prior HF hospitalization.
Design, setting, and participants
This is a secondary analysis of a completed multinational trial. The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure trial was a double-blind, placebo-controlled randomized clinical trial of dapagliflozin in patients with chronic HFrEF (n = 4744). From February 2017 to August 2018, the study enrolled patients in New York Heart Association classes II through IV and with left ventricular ejection fraction of 40% or less; the median (range) follow-up time was 18.2 (0-27.8) months. Hazard ratios (HRs) were calculated for the primary efficacy outcome with dapagliflozin vs placebo by time following randomization. Efficacy and safety of dapagliflozin were assessed according to the timing of the most recent HF hospitalization prior to trial enrollment.
Exposures
None.
Main outcomes and measures
Composite of cardiovascular death or worsening HF.
Results
A total of 4744 patients were included (1109 women [23.4%]; mean [SD] age, 66.3 [10.9] years). The reduction in the primary outcome with dapagliflozin was rapidly apparent, with a sustained statistically significant benefit by 28 days after randomization (HR at 28 days, 0.51 [95% CI, 0.28-0.94]; P = .03). A total of 2251 patients (47.4%) had been previously hospitalized for HF, and 1301 (27.4%) had been hospitalized within 12 months prior to enrollment. Among patients treated with placebo, there was a stepwise gradient of risk for the primary outcome according to timing of most recent HF hospitalization, with 2-year Kaplan-Meier rates of 21.1%, 25.3%, and 33.8% (adjusted P = .003) for patients with a prior HF hospitalization never, more than 12 months ago, and 12 or fewer months ago, respectively. Across these subgroups, dapagliflozin reduced the relative risk of the primary outcome by 16% (HR, 0.84 [95% CI, 0.69-1.01]), 27% (HR, 0.73 [95% CI, 0.54-0.99]), and 36% (HR, 0.64 [95% CI, 0.51-0.80]), respectively (P = .07 for trend). Accordingly, patients with a more recent HF hospitalization tended to experience greater absolute risk reductions with dapagliflozin at 2 years: 2.1% (95% CI, -1.9% to 6.1%), 4.1% (95% CI, -3.6% to 11.7%), and 9.9% (95% CI, 3.3%-16.5%), respectively (P = .05 for trend).

Conclusions:
and relevance
In this study, treatment with dapagliflozin was associated with rapid reduction in the risk of cardiovascular death or worsening HF, with a sustained statistically significant benefit emerging very early after randomization. Patients with a more recent HF hospitalization were at particularly high risk and experienced greater relative and absolute risk reductions with dapagliflozin.
Trial registration
ClinicalTrials.gov Identifier NCT03036124.



JAMA Cardiol: 30 Apr 2021; 6:499-507
Berg DD, Jhund PS, Docherty KF, Murphy SA, ... McMurray JJV, Sabatine MS
JAMA Cardiol: 30 Apr 2021; 6:499-507 | PMID: 33595593
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Impact:
Abstract

Screening for Atrial Fibrillation in the Older Population: A Randomized Clinical Trial.

Gladstone DJ, Wachter R, Schmalstieg-Bahr K, Quinn FR, ... Healey JS, SCREEN-AF Investigators and Coordinators
Importance
Atrial fibrillation (AF) is a major cause of preventable strokes. Screening asymptomatic individuals for AF may increase anticoagulant use for stroke prevention.
Objective
To evaluate 2 home-based AF screening interventions.
Design, setting, and participants
This multicenter randomized clinical trial recruited individuals from primary care practices aged 75 years or older with hypertension and without known AF. From April 5, 2015, to March 26, 2019, 856 participants were enrolled from 48 practices.
Interventions
The control group received standard care (routine clinical follow-up plus a pulse check and heart auscultation at baseline and 6 months). The screening group received a 2-week continuous electrocardiographic (cECG) patch monitor to wear at baseline and at 3 months, in addition to standard care. The screening group also received automated home blood pressure (BP) machines with oscillometric AF screening capability to use twice-daily during the cECG monitoring periods.
Main outcomes and measures
With intention-to-screen analysis, the primary outcome was AF detected by cECG monitoring or clinically within 6 months. Secondary outcomes included anticoagulant use, device adherence, and AF detection by BP monitors.
Results
Of the 856 participants, 487 were women (56.9%); mean (SD) age was 80.0 (4.0) years. Median cECG wear time was 27.4 of 28 days (interquartile range [IQR], 18.4-28.0 days). In the primary analysis, AF was detected in 23 of 434 participants (5.3%) in the screening group vs 2 of 422 (0.5%) in the control group (relative risk, 11.2; 95% CI, 2.7-47.1; P = .001; absolute difference, 4.8%; 95% CI, 2.6%-7.0%; P < .001; number needed to screen, 21). Of those with cECG-detected AF, median total time spent in AF was 6.3 hours (IQR, 4.2-14.0 hours; range 1.3 hours-28 days), and median duration of the longest AF episode was 5.7 hours (IQR, 2.9-12.9 hours). Anticoagulation was initiated in 15 of 20 patients (75.0%) with cECG-detected AF. By 6 months, anticoagulant therapy had been prescribed for 18 of 434 participants (4.1%) in the screening group vs 4 of 422 (0.9%) in the control group (relative risk, 4.4; 95% CI, 1.5-12.8; P = .007; absolute difference, 3.2%; 95% CI, 1.1%-5.3%; P = .003). Twice-daily AF screening using the home BP monitor had a sensitivity of 35.0% (95% CI, 15.4%-59.2%), specificity of 81.0% (95% CI, 76.7%-84.8%), positive predictive value of 8.9% (95% CI, 4.9%-15.5%), and negative predictive value of 95.9% (95% CI, 94.5%-97.0%). Adverse skin reactions requiring premature discontinuation of cECG monitoring occurred in 5 of 434 participants (1.2%).

Conclusions:
and relevance
In this randomized clinical trial, among older community-dwelling individuals with hypertension, AF screening with a wearable cECG monitor was well tolerated, increased AF detection 10-fold, and prompted initiation of anticoagulant therapy in most cases. Compared with continuous ECG, intermittent oscillometric screening with a BP monitor was an inferior strategy for detecting paroxysmal AF. Large trials with hard clinical outcomes are now needed to evaluate the potential benefits and harms of AF screening.
Trial registration
ClinicalTrials.gov Identifier: NCT02392754.



JAMA Cardiol: 30 Apr 2021; 6:558-567
Gladstone DJ, Wachter R, Schmalstieg-Bahr K, Quinn FR, ... Healey JS, SCREEN-AF Investigators and Coordinators
JAMA Cardiol: 30 Apr 2021; 6:558-567 | PMID: 33625468
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Impact:
Abstract

Long-term Clinical and Echocardiographic Outcomes in Young and Middle-aged Adults Undergoing the Ross Procedure.

Romeo JLR, Papageorgiou G, da Costa FFD, Sievers HH, ... Takkenberg JJM, Mokhles MM
Importance
There is no ideal valve substitute for young adults requiring aortic valve replacement. Multicenter data supporting use of the Ross procedure with respect to long-term postoperative valve-related mortality and reintervention, as well as function of the autograft and pulmonary homograft, are needed.
Objective
To determine the long-term clinical and echocardiographic outcomes in young and middle-aged patients undergoing the Ross procedure.
Design, setting, and participants
A retrospective multicenter international cohort study with a median follow-up period of 9.2 years was conducted in 5 experienced centers regularly performing the Ross procedure. Consecutive patients aged 18 to 65 years were included by each center between 1991 and 2018.
Main outcomes and measures
Survival and autograft-related and homograft-related reintervention. Serial echocardiographic measurements of valve function were analyzed using mixed-effects modeling.
Results
During the study period, 1431 patients (74.3% men; n = 1063) were operated on at a median age of 48.5 years (mean [SD], 47.7 [9.5]; range, 18.1-65; interquartile range, 42.7-54.0). Implantation techniques were root inclusion in 355 (24.9%), root replacement in 485 (34.0%), and subcoronary implantation in 587 (41.1%). Right ventricular outflow tract reconstruction was performed with homografts in 98.6% (n = 1189) and bioprostheses in 1.4% (n = 17). Ten patients (0.7%) died before discharge. Median follow-up was 9.2 years (13 015 total patient-years). Survival after 10 and 15 years was 95.1% (95% CI, 93.8%-96.5%) and 88.5% (95% CI, 85.9%-91.1%), respectively. Freedom from autograft and homograft reintervention after 15 years was 92.0% and 97.2%, respectively. Late events were autograft endocarditis in 14 patients (0.11% per patient-year), homograft endocarditis in 11 patients (0.08% per patient-year), and stroke in 37 patients (0.3% per patient-year).

Conclusions:
and relevance
Given its excellent short-term and long-term outcome in young and middle-aged adults in this study, the Ross procedure should be considered in young and middle-aged adults who require aortic valve replacement. Patients should be referred to an experienced center with a program dedicated to the Ross procedure.



JAMA Cardiol: 30 Apr 2021; 6:539-548
Romeo JLR, Papageorgiou G, da Costa FFD, Sievers HH, ... Takkenberg JJM, Mokhles MM
JAMA Cardiol: 30 Apr 2021; 6:539-548 | PMID: 33656518
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Impact:
Abstract

Association of Left Ventricular Systolic Function With Incident Heart Failure in Late Life.

Reimer Jensen AM, Zierath R, Claggett B, Skali H, ... Biering-Sørensen T, Shah AM
Importance
Limited data exist regarding the association of subtle subclinical systolic dysfunction and incident heart failure (HF) in late life.
Objective
To assess the independent associations of subclinical impairments in systolic performance with incident HF in late life.
Design, setting, and participants
This study was a time-to-event analysis of participants without heart failure in the Atherosclerosis Risk in Communities (ARIC) study, a prospective, community-based cohort study, who underwent protocol echocardiography at the fifth study visit (January 1, 2011, to December 31, 2013). Findings were validated independently in participants in the Copenhagen City Heart Study (CCHS). Data analysis was performed from June 1, 2018, to February 28, 2020.
Exposures
Left ventricular ejection fraction (LVEF), longitudinal strain (LS), and circumferential strain (CS) measured by 2-dimensional and strain echocardiography.
Main outcomes and measures
Main outcomes were incident adjudicated HF and HF with preserved and reduced LVEF at a median follow-up of 5.5 years (interquartile range, 5.0-5.8 years). Cox proportional hazards regression models adjusted for demographics, hypertension, diabetes, obesity, smoking, coronary disease, estimated glomerular filtration rate, LV mass index, e\', E/e\', and left atrial volume index. Lower 10th percentile limits were determined in 374 participants free of cardiovascular disease or risk factors.
Results
Among 4960 ARIC participants (mean [SD] age, 75 [5] years; 2933 [59.0%] female; 965 [19%] Black), LVEF was less than 50% in only 76 (1.5%). In the 3552 participants with complete assessment of LVEF, LS, and CS, 983 (27.7%) had 1 or more of the following findings: LVEF less than 60%, LS less than 16.0%, or CS less than 23.7%. Modeled continuously or dichotomized, worse LVEF, LS, and CS were each independently associated with incident HF. The adjusted hazard ratio (HR) per SD decrease in LVEF was 1.41 (95% CI, 1.29-1.55); the HR for LVEF less than 60% was 2.59 (95% CI, 1.99-3.37). Similar findings were observed for continuous LS (HR, 1.37; 95% CI, 1.22-1.53) and dichotomized LS (HR, 1.93; 95% CI, 1.46-2.55) and for continuous CS (HR, 1.39; 95% CI, 1.22-1.57) and dichotomized CS (HR, 2.30; 95% CI, 1.64-3.22). Although the magnitude of risk for incident HF or death associated with impaired LVEF was greater using guideline (HR, 2.99; 95% CI, 2.19-4.09) compared with ARIC-based limits (HR, 1.88; 95% CI, 1.58-2.25), the number of participants classified as impaired was less (104 [2.1%] based on guideline thresholds compared with 692 [13.9%] based on LVEF <60%). The population-attributable risk associated with LVEF less than 60% was 11% compared with 5% using guideline-based limits, a finding replicated in 908 participants in the CCHS.

Conclusions:
and relevance
These findings suggest that relatively subtle impairments of systolic function (detected based on LVEF or strain) are independently associated with incident HF and HF with reduced LVEF in late life. Current recommended assessments of LV function may substantially underestimate the prevalence of prognostically important impairments in systolic function in this population.



JAMA Cardiol: 30 Apr 2021; 6:509-520
Reimer Jensen AM, Zierath R, Claggett B, Skali H, ... Biering-Sørensen T, Shah AM
JAMA Cardiol: 30 Apr 2021; 6:509-520 | PMID: 33729428
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Impact:
Abstract

Comparison of New York Heart Association Class and Patient-Reported Outcomes for Heart Failure With Reduced Ejection Fraction.

Greene SJ, Butler J, Spertus JA, Hellkamp AS, ... Hernandez AF, Fonarow GC
Importance
It is unclear how New York Heart Association (NYHA) functional class compares with patient-reported outcomes among patients with heart failure (HF) in contemporary US clinical practice.
Objective
To characterize longitudinal changes and concordance between NYHA class and the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS), and their associations with clinical outcomes.
Design, setting, and participants
This cohort study included 2872 US outpatients with chronic HF with reduced ejection fraction across 145 practices enrolled in the CHAMP-HF registry between December 2015 and October 2017. All patients had complete NYHA class and KCCQ-OS data at baseline and 12 months. Longitudinal changes and correlations between the 2 measure were examined. Multivariable models landmarked at 12 months evaluated associations between improvement in NYHA and KCCQ-OS from baseline to 12 months with clinical outcomes occurring from months 12 through 24. Statistical analyses were performed from March to August 2020.
Exposure
Change in health status, as defined by 12-month change in NYHA class or KCCQ-OS.
Main outcomes and measures
All-cause mortality, HF hospitalization, and mortality or HF hospitalization.
Results
In total, 2872 patients were included in this analysis (median [interquartile range] age, 68 [59-75] years; 872 [30.4%] were women; and 2156 [75.1%] were of White race). At baseline, 312 patients (10.9%) were NYHA class I, 1710 patients (59.5%) were class II, 804 patients (28.0%) were class III, and 46 patients (1.6%) were class IV. For KCCQ-OS, 1131 patients (39.4%) scored 75 to 100 (best health status), 967 patients (33.7%) scored 50 to 74, 612 patients (21.3%) scored 25 to 49, and 162 patients (5.6%) scored 0 to 24 (worst health status). At 12 months, 1002 patients (34.9%) had a change in NYHA class (599 [20.9%] with improvement; 403 [14.0%] with worsening) and 2158 patients (75.1%) had a change of 5 or more points in KCCQ-OS (1388 [48.3%] with improvement; 770 [26.8%] with worsening). The most common trajectory for NYHA class was no change (1870 [65.1%]), and the most common trajectory for KCCQ-OS was an improvement of at least 10 points (1047 [36.5%]). After adjustment, improvement in NYHA class was not associated with subsequent clinical outcomes, whereas an improvement of 5 or more points in KCCQ-OS was independently associated with decreased mortality (hazard ratio, 0.59; 95% CI, 0.44-0.80; P < .001) and mortality or HF hospitalization (hazard ratio, 0.73; 95% CI, 0.59-0.89; P = .002).

Conclusions:
and relevance
Findings of this cohort study suggest that, in contemporary US clinical practice, compared with NYHA class, KCCQ-OS is more sensitive to clinically meaningful changes in health status over time. Changes in KCCQ-OS may have more prognostic value than changes in NYHA class.



JAMA Cardiol: 30 Apr 2021; 6:522-531
Greene SJ, Butler J, Spertus JA, Hellkamp AS, ... Hernandez AF, Fonarow GC
JAMA Cardiol: 30 Apr 2021; 6:522-531 | PMID: 33760037
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Impact:

This program is still in alpha version.