Showing papers in "JAMA Cardiology in 2021"

Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis.

Abstract: Importance Sodium-glucose cotransporter 2 (SGLT2) inhibitors favorably affect cardiovascular (CV) and kidney outcomes; however, the consistency of outcomes across the class remains uncertain. Objective To perform meta-analyses that assess the CV and kidney outcomes of all 4 available SGLT2 inhibitors in patients with type 2 diabetes. Data Sources A systematic literature search was conducted in PubMed from January 1, 2015, to January 31, 2020. Study Selection One hundred forty-five records were initially identified; 137 were excluded because of study design or topic of interest. As a result, a total of 6 randomized, placebo-controlled CV and kidney outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes were identified, with contributory data from 9 publications. All analyses were conducted on the total patient population of these trials. Data Extraction and Synthesis Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were analyzed using a fixed-effect model. Main Outcomes and Measures Outcomes included time to the first event of (1) the composite of major adverse CV events of myocardial infarction, stroke, or CV death, and each component, (2) the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and each component, and (3) kidney composite outcomes. For outcomes in the overall trial populations and in selected subgroups, hazard ratios (HRs) and 95% CIs were pooled and meta-analyzed across trials. Results Data from 6 trials comprised 46 969 unique patients with type 2 diabetes, including 31 116 (66.2%) with atherosclerotic CV disease. The mean (SD) age of all trial participants was 63.7 (7.9) years; 30 939 (65.9%) were men, and 36 849 (78.5%) were White. The median number of participants per trial was 8246 (range, 4401-17 160). Overall, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events (HR, 0.90; 95% CI, 0.85-0.95; Q statistic,P = .27), HHF/CV death (HR, 0.78; 95% CI, 0.73-0.84; Q statistic,P = .09), and kidney outcomes (HR, 0.62; 95% CI, 0.56-0.70; Q statistic,P = .09), with no significant heterogeneity of associations with outcome. Associated risk reduction for HHF was consistent across the trials (HR, 0.68; 95% CI, 0.61-0.76;I2 = 0.0%), whereas significant heterogeneity of associations with outcome was observed for CV death (HR, 0.85; 95% CI, 0.78-0.93; Q statistic,P = .02;I2 = 64.3%). The presence or absence of atherosclerotic CV disease did not modify the association with outcomes for major adverse CV events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 0.94; 95% CI, 0.83-1.07, respectively;P = .63 for interaction), with similar absence of associations with outcome modification by prevalent atherosclerotic CV disease for HHF/CV death (P = .62 for interaction), HHF (P = .26 for interaction), or kidney outcomes (P = .73 for interaction). Conclusions and Relevance In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events; in addition, results suggest significant heterogeneity in associations with CV death. The largest benefit across the class was for an associated reduction in risk for HHF and kidney outcomes, with benefits for HHF risk being the most consistent observation across the trials.

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

Abstract: 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.

Patients With Acute Myocarditis Following mRNA COVID-19 Vaccination.

Abstract: 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.

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

Abstract: 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 [604%]) Thirty-seven (including 27 men) were diagnosed with COVID-19 myocarditis (overall 23%; range per program, 0%-76%); 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, 031%) Cardiac magnetic resonance imaging for all athletes yielded a 74-fold increase in detection of myocarditis (clinical and subclinical) Follow-up CMR imaging performed in 27 (730%) demonstrated resolution of T2 elevation in all (100%) and late gadolinium enhancement in 11 (407%) Conclusions and Relevance In this cohort study of 1597 US competitive athletes with CMR screening after COVID-19 infection, 37 athletes (23%) 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

Prevalence of Inflammatory Heart Disease Among Professional Athletes With Prior COVID-19 Infection Who Received Systematic Return-to-Play Cardiac Screening.

Abstract: Importance The major North American professional sports leagues were among the first to return to full-scale sport activity during the coronavirus disease 2019 (COVID-19) pandemic. Given the unknown incidence of adverse cardiac sequelae after COVID-19 infection in athletes, these leagues implemented a conservative return-to-play (RTP) cardiac testing program aligned with American College of Cardiology recommendations for all athletes testing positive for COVID-19. Objective To assess the prevalence of detectable inflammatory heart disease in professional athletes with prior COVID-19 infection, using current RTP screening recommendations. Design, Setting, and Participants This cross-sectional study reviewed RTP cardiac testing performed between May and October 2020 on professional athletes who had tested positive for COVID-19. The professional sports leagues (Major League Soccer, Major League Baseball, National Hockey League, National Football League, and the men’s and women’s National Basketball Association) implemented mandatory cardiac screening requirements for all players who had tested positive for COVID-19 prior to resumption of team-organized sports activities. Exposures Troponin testing, electrocardiography (ECG), and resting echocardiography were performed after a positive COVID-19 test result. Interleague, deidentified cardiac data were pooled for collective analysis. Those with abnormal screening test results were referred for additional testing, including cardiac magnetic resonance imaging and/or stress echocardiography. Main Outcomes and Measures The prevalence of abnormal RTP test results potentially representing COVID-19–associated cardiac injury, and results and outcomes of additional testing generated by the initial screening process. Results The study included 789 professional athletes (mean [SD] age, 25 [3] years; 777 men [98.5%]). A total of 460 athletes (58.3%) had prior symptomatic COVID-19 illness, and 329 (41.7%) were asymptomatic or paucisymptomatic (minimally symptomatic). Testing was performed a mean (SD) of 19 (17) days (range, 3-156 days) after a positive test result. Abnormal screening results were identified in 30 athletes (3.8%; troponin, 6 athletes [0.8%]; ECG, 10 athletes [1.3%]; echocardiography, 20 athletes [2.5%]), necessitating additional testing; 5 athletes (0.6%) ultimately had cardiac magnetic resonance imaging findings suggesting inflammatory heart disease (myocarditis, 3; pericarditis, 2) that resulted in restriction from play. No adverse cardiac events occurred in athletes who underwent cardiac screening and resumed professional sport participation. Conclusions and Relevance This study provides large-scale data assessing the prevalence of relevant COVID-19–associated cardiac pathology with implementation of current RTP screening recommendations. While long-term follow-up is ongoing, few cases of inflammatory heart disease have been detected, and a safe return to professional sports activity has thus far been achieved.

Coronavirus Disease 2019 and the Athletic Heart: Emerging Perspectives on Pathology, Risks, and Return to Play.

Abstract: Importance Cardiac injury with attendant negative prognostic implications is common among patients hospitalized with coronavirus disease 2019 (COVID-19) infection. Whether cardiac injury, including myocarditis, also occurs with asymptomatic or mild-severity COVID-19 infection is uncertain. There is an ongoing concern about COVID-19–associated cardiac pathology among athletes because myocarditis is an important cause of sudden cardiac death during exercise. Observations Prior to relaxation of stay-at-home orders in the US, the American College of Cardiology’s Sports and Exercise Cardiology Section endorsed empirical consensus recommendations advising a conservative return-to-play approach, including cardiac risk stratification, for athletes in competitive sports who have recovered from COVID-19. Emerging observational data coupled with widely publicized reports of athletes in competitive sports with reported COVID-19–associated cardiac pathology suggest that myocardial injury may occur in cases of COVID-19 that are asymptomatic and of mild severity. In the absence of definitive data, there is ongoing uncertainty about the optimal approach to cardiovascular risk stratification of athletes in competitive sports following COVID-19 infection. Conclusions and Relevance This report was designed to address the most common questions regarding COVID-19 and cardiac pathology in athletes in competitive sports, including the extension of return-to-play considerations to discrete populations of athletes not addressed in prior recommendations. Multicenter registry data documenting cardiovascular outcomes among athletes in competitive sports who have recovered from COVID-19 are currently being collected to determine the prevalence, severity, and clinical relevance of COVID-19–associated cardiac pathology and efficacy of targeted cardiovascular risk stratification. While we await these critical data, early experiences in the clinical oversight of athletes following COVID-19 infection provide an opportunity to address key areas of uncertainty relevant to cardiology and sports medicine practitioners.

Evaluation for Myocarditis in Competitive Student Athletes Recovering From Coronavirus Disease 2019 With Cardiac Magnetic Resonance Imaging.

Abstract: Importance The utility of cardiac magnetic resonance imaging (MRI) as a screening tool for myocarditis in competitive student athletes returning to training after recovering from coronavirus disease 2019 (COVID-19) infection is unknown. Objective To describe the prevalence and severity of cardiac MRI findings of myocarditis in a population of competitive student athletes recovering from COVID-19. Design, Setting, and Participants In this case series, an electronic health record search was performed at our institution (University of Wisconsin) to identify all competitive athletes (a consecutive sample) recovering from COVID-19, who underwent gadolinium-enhanced cardiac MRI between January 1, 2020, and November 29, 2020. The MRI findings were reviewed by 2 radiologists experienced in cardiac imaging, using the updated Lake Louise criteria. Serum markers of myocardial injury and inflammation (troponin-I, B-type natriuretic peptide, C-reactive protein, and erythrocyte sedimentation rate), an electrocardiogram, transthoracic echocardiography, and relevant clinical data were obtained. Exposures COVID-19 infection, confirmed using reverse transcription–polymerase chain reaction testing. Main Outcomes and Measures Prevalence and severity of MRI findings consistent with myocarditis among young competitive athletes recovering from COVID-19. Results A total of 145 competitive student athletes (108 male and 37 female individuals; mean age, 20 years; range, 17-23 years) recovering from COVID-19 were included. Most patients had mild (71 [49.0%]) or moderate (40 [27.6%]) symptoms during the acute infection or were asymptomatic (24 [16.6%]). Symptoms were not specified or documented in 10 patients (6.9%). No patients required hospitalization. Cardiac MRIs were performed a median of 15 days (range, 11-194 days) after patients tested positive for COVID-19. Two patients had MRI findings consistent with myocarditis (1.4% [95% CI, 0.4%-4.9%]). Of these, 1 patient had marked nonischemic late gadolinium enhancement and T2-weighted signal abnormalities over multiple segments, along with an abnormal serum troponin-I level; the second patient had 1-cm nonischemic mild late gadolinium enhancement and mild T2-weighted signal abnormalities, with normal laboratory values. Conclusions and Relevance In this case series study, based on MRI findings, there was a low prevalence of myocarditis (1.4%) among student athletes recovering from COVID-19 with no or mild to moderate symptoms. Thus, the utility of cardiac MRI as a screening tool for myocarditis in this patient population is questionable.

Association of Myocarditis With BNT162b2 Messenger RNA COVID-19 Vaccine in a Case Series of Children.

Abstract: Importance The BNT162b2 (Pfizer-BioNTech) messenger RNA COVID-19 vaccine was authorized on May 10, 2021, for emergency use in children aged 12 years and older. Initial reports showed that the vaccine was well tolerated without serious adverse events; however, cases of myocarditis have been reported since approval. Objective To review results of comprehensive cardiac imaging in children with myocarditis after COVID-19 vaccine. Design, setting, and participants This study was a case series of children younger than 19 years hospitalized with myocarditis within 30 days of BNT162b2 messenger RNA COVID-19 vaccine. The setting was a single-center pediatric referral facility, and admissions occurred between May 1 and July 15, 2021. Main outcomes and measures All patients underwent cardiac evaluation including an electrocardiogram, echocardiogram, and cardiac magnetic resonance imaging. Results Fifteen patients (14 male patients [93%]; median age, 15 years [range, 12-18 years]) were hospitalized for management of myocarditis after receiving the BNT162b2 (Pfizer) vaccine. Symptoms started 1 to 6 days after receipt of the vaccine and included chest pain in 15 patients (100%), fever in 10 patients (67%), myalgia in 8 patients (53%), and headache in 6 patients (40%). Troponin levels were elevated in all patients at admission (median, 0.25 ng/mL [range, 0.08-3.15 ng/mL]) and peaked 0.1 to 2.3 days after admission. By echocardiographic examination, decreased left ventricular (LV) ejection fraction (EF) was present in 3 patients (20%), and abnormal global longitudinal or circumferential strain was present in 5 patients (33%). No patient had a pericardial effusion. Cardiac magnetic resonance imaging findings were consistent with myocarditis in 13 patients (87%) including late gadolinium enhancement in 12 patients (80%), regional hyperintensity on T2-weighted imaging in 2 patients (13%), elevated extracellular volume fraction in 3 patients (20%), and elevated LV global native T1 in 2 patients (20%). No patient required intensive care unit admission, and median hospital length of stay was 2 days (range 1-5). At follow-up 1 to 13 days after hospital discharge, 11 patients (73%) had resolution of symptoms. One patient (7%) had persistent borderline low LV systolic function on echocardiogram (EF 54%). Troponin levels remained mildly elevated in 3 patients (20%). One patient (7%) had nonsustained ventricular tachycardia on ambulatory monitor. Conclusions and relevance In this small case series study, myocarditis was diagnosed in children after COVID-19 vaccination, most commonly in boys after the second dose. In this case series, in short-term follow-up, patients were mildly affected. The long-term risks associated with postvaccination myocarditis remain unknown. Larger studies with longer follow-up are needed to inform recommendations for COVID-19 vaccination in this population.

Outcomes for Out-of-Hospital Cardiac Arrest in the United States During the Coronavirus Disease 2019 Pandemic

Abstract: Importance Recent reports from communities severely affected by the coronavirus disease 2019 (COVID-19) pandemic found lower rates of sustained return of spontaneous circulation (ROSC) for out-of-hospital cardiac arrest (OHCA). Whether the pandemic has affected OHCA outcomes more broadly is unknown. Objective To assess the association between the COVID-19 pandemic and OHCA outcomes, including in areas with low and moderate COVID-19 disease burden. Design, Setting, and Participants This study used a large US registry of OHCAs to compare outcomes during the pandemic period of March 16 through April 30, 2020, with those from March 16 through April 30, 2019. Cases were geocoded to US counties, and the COVID-19 mortality rate in each county was categorized as very low (0-25 per million residents), low (26-100 per million residents), moderate (101-250 per million residents), high (251-500 per million residents), or very high (>500 per million residents). As additional controls, the study compared OHCA outcomes during the prepandemic period (January through February) and peripandemic period (March 1 through 15). Exposure The COVID-19 pandemic. Main Outcomes and Measures Sustained ROSC (≥20 minutes), survival to discharge, and OHCA incidence. Results A total of 19 303 OHCAs occurred from March 16 through April 30 in both years, with 9863 cases in 2020 (mean [SD] age, 62.6 [19.3] years; 6040 men [61.3%]) and 9440 in 2019 (mean [SD] age, 62.2 [19.2] years; 5922 men [62.7%]). During the pandemic, rates of sustained ROSC were lower than in 2019 (23.0% vs 29.8%; adjusted rate ratio, 0.82 [95% CI, 0.78-0.87];P Conclusions and Relevance Early during the pandemic, rates of sustained ROSC for OHCA were lower throughout the US, even in communities with low COVID-19 mortality rates. Overall survival was lower, primarily in communities with moderate or high COVID-19 mortality.

Evolving Trends in Adult Heart Transplant With the 2018 Heart Allocation Policy Change.

Abstract: Importance The US heart allocation policy was changed on October 18, 2018. The association of this change with recipient and donor selection and outcomes remains to be elucidated. Objective To evaluate changes in patient characteristics, wait list outcomes, and posttransplant outcomes after the recent allocation policy change in heart transplant. Design, Setting, and Participants In this cohort study, all 15 631 adults undergoing heart transplants, excluding multiorgan transplants, in the US as identified by the United Network for Organ Sharing multicenter, national registry were reviewed. Patients were stratified according to prepolicy change (October 1, 2015, to October 1, 2018) and postpolicy change (October 18, 2018 or after). Follow-up data were available through March 31, 2020. Exposures Heart transplants after the policy change. Main Outcomes and Measures Competing risk regression for wait list outcomes was performed. Posttransplant survival was compared using the Kaplan-Meier method, and risk adjustment was performed using multivariable Cox proportional hazards regression analysis. Results In this cohort study, of the 15 631 patients undergoing transplant, 10 671 (mean [SD] age, 53.1 [12.7] years; 7823 [73.3%] male) were wait listed before and 4960 (mean [SD] age, 52.7 [13.0] years; 3610 [72.8%] male) were wait listed after the policy change. Competing risk regression demonstrated reduced likelihood of mortality or deterioration (subhazard ratio [SHR], 0.60; 95% CI, 0.52-0.69;P Conclusions and Relevance Substantial changes have occurred in adult heart transplant in the US after the policy change in October 2018. Wait list outcomes have improved, although posttransplant survival has decreased. These data confirm findings from earlier preliminary analyses and demonstrate that these trends have persisted to 1-year follow-up, underscoring the importance of continued reevaluation of the new heart allocation policy.

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

Abstract: 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.

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

Abstract: 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% (adjustedP = .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 IdentifierNCT03036124

Clinical Utility of Lipoprotein(a) and LPA Genetic Risk Score in Risk Prediction of Incident Atherosclerotic Cardiovascular Disease

Abstract: Importance Lipoprotein(a) is a highly heritable biomarker independently associated with atherosclerotic cardiovascular disease (ASCVD). It is unclear whether measured lipoprotein(a) or genetic factors associated with lipoprotein(a) can provide comparable or additional prognostic information for primary prevention. Objective To determine whether a genetic risk score (GRS) comprising 43 variants at theLPAgene, which encodes apolipoprotein(a), has clinical utility in assessing ASCVD risk compared with and in addition to lipoprotein(a) measurement. Design, Setting, and Participants The UK Biobank is a prospective observational study of approximately 500 000 volunteers aged 40 to 69 years who were recruited from 22 sites across the United Kingdom between 2006 and 2010. Using externally derived weights, anLPAGRS was calculated for 374 099 unrelated individuals with array-derived genotypes and lipoprotein(a) measures. Data were analyzed from April 2020 to March 2020. Exposures Measured lipoprotein(a) andLPAGRS. Main Outcomes and Measures We estimated the associations between measured lipoprotein(a) andLPAGRS with the incidence of ASCVD (peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) using Cox proportional hazards models. To determine the utility of using measured lipoprotein(a) andLPAGRS as risk enhancers for ASCVD, we assessed the potential improvement in ASCVD risk discrimination by QRISK3 and Pooled Cohort Equations among individuals with borderline to intermediate risk (n = 113 703 and 144 350, respectively). Results The mean age of the overall study population was 57.6 years, and 204 355 individuals were female (54.6%). During a median follow-up of 11.1 years (interquartile range, 1.4 years), 15 444 individuals developed an incident ASCVD event (5.1%). TheLPAGRS explained approximately 60% of the variation in measured lipoprotein(a) for White/European individuals. Independently, both lipoprotein(a) andLPAGRS were associated with incident, composite ASCVD (hazard ratio per 120 nmol/L increase, 1.26; 95% CI, 1.23-1.28 vs hazard ratio, 1.29; 95% CI, 1.26-1.33;P Conclusions and Relevance When indicated, cardiovascular risk assessment with lipoprotein(a) at middle-age may include direct measurement or anLPAGRS.

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

Abstract: 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.

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

Abstract: 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 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

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

Abstract: Background Heart failure (HF) is a major cause of morbidity and mortality worldwide. HF with preserved ejection fraction (HFpEF) now accounts for around half of the HF population. To date, no treatments for HFpEF have proven effect and outcomes have not improved in recent decades. The heterogeneity of the HFpEF population and the failure of randomised controlled trials (RCTs) to demonstrate effective therapies has led to attempts to identify sub-phenotypes of HFpEF which may respond to targeted therapies. Recent studies suggest that epicardial coronary artery disease (CAD) and coronary microvascular dysfunction (CMD) may play an important role in a substantial group of patients with HFpEF. A novel paradigm has been proposed suggesting that endothelium-dependent CMD may play a key role in the unifying pathophysiology of HFpEF. I performed a systematic review of the literature describing the prevalence of epicardial CAD and CMD in HFpEF populations. Most studies were retrospective observational and population-based studies with inconsistent definitions of HF, preserved left ventricular ejection fraction (LVEF) and CAD. Studies which documented CAD angiographically were almost exclusively performed in highly-selected convenience cohorts. Consequently, prevalence estimates of CAD in HFpEF varied considerably between studies. Similarly, studies assessing CMD in HFpEF reported inconsistent results due to variable definitions of CMD and methods of assessing coronary microvascular function. Therefore, the prevalence of epicardial CAD and CMD have not been prospectively and systematically studied in an unselected HFpEF population. Aims The main aims of this study were to determine the prevalence of obstructive epicardial CAD, CMD and previous myocardial infarction (MI) in an unselected cohort of patients hospitalised with HFpEF using reference standard invasive investigations. Methods This was a prospective, multicentre, observational study of patients hospitalised with HFpEF. All patients recruited had a confirmed diagnosis of HFpEF according to the 2016 European Society of Cardiology (ESC) HF guidelines. Participants underwent invasive coronary angiography with guidewire-based assessment of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR), followed by vasoreactivity testing with intra-coronary acetylcholine. This allowed the comprehensive assessment of epicardial and microvascular structure and function to determine the prevalence of CAD, CMD and coronary endothelial dysfunction in the cohort. Adenosine perfusion cardiac magnetic resonance (CMR) imaging was also performed to assess the burden of myocardial infarction (MI), diffuse fibrosis and inducible ischaemia in the study population. Patients were followed up by electronic medical record linkage for a minimum of 12 months. Results Of 2285 near-consecutive patients hospitalised with suspected HF, 628 were confirmed to have a diagnosis of HFpEF, and 106 HFpEF patients met the inclusion criteria and agreed to participate in the study. A total of 83 participants underwent invasive coronary angiography or CMR. Seventy-five participants underwent invasive coronary angiography, 62 had guidewire-based coronary physiology testing, and 41 underwent vasoreactivity testing. Fifty-two participants underwent CMR and 44 had both invasive coronary angiography and CMR. Twenty-three patients did not proceed to the study investigations, predominantly due to a decline in health, functional status or renal function making proceeding with the study investigations inappropriate or unsafe. In this unselected hospitalised HFpEF cohort, the prevalence of obstructive epicardial CAD on invasive assessment was 51% (95% confidence interval [CI] 39-62%); half of patients with obstructive epicardial disease had no clinical history of CAD. On invasive coronary physiological testing, 41 patients (66% [95% CI 53-77%]) had endothelium-independent CMD, and 10 (24% [95% CI 13-40%]) had endothelium-dependent CMD. Overall, 91% of participants had evidence of macrovascular and/or microvascular CAD. Of those who underwent CMR, 27% (95% CI 16-41%) had evidence of previous MI and 32% (95% CI 19-48%) had inducible ischaemia. Over half of patients with CMR-proven MI had no history of clinically apparent MI. Over a median follow-up period of 18 months, study participants with obstructive epicardial CAD had significantly more hospitalisations (for any cause, a cardiovascular cause or HF) than those without obstructive CAD. There was no significant difference in outcomes between those with or without endothelium-independent or -dependent CMD. Conclusion Both epicardial CAD and CMD are common in the HFpEF population, and there is a high prevalence of clinically unrecognised obstructive epicardial CAD and previous MI. Patients with obstructive epicardial CAD had significantly more hospitalisations than those without obstructive disease. Treatments for epicardial CAD (e.g. coronary revascularisation) might improve quality of life and reduce hospitalisations in HFpEF patients with CAD. Although it has been hypothesised that CMD in HFpEF is the result of endothelial dysfunction, it appears to be predominantly due to endothelium-independent mechanisms. This may have important implications for future treatments directed at CMD in patients with HFpEF.

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

Abstract: 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

Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine-Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis: A Review.

Abstract: Importance: The COVID-19 pandemic saw one of the fastest developments of vaccines in an effort to combat an out-of-control pandemic. The 2 most common COVID-19 vaccine platforms currently in use, messenger RNA (mRNA) and adenovirus vector, were developed on the basis of previous research in use of this technology. Postauthorization surveillance of COVID-19 vaccines has identified safety signals, including unusual cases of thrombocytopenia with thrombosis reported in recipients of adenoviral vector vaccines. One of the devastating manifestations of this syndrome, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), is cerebral venous sinus thrombosis (CVST). This review summarizes the current evidence and indications regarding biology, clinical characteristics, and pharmacological management of VITT with CVST. Observations: VITT appears to be similar to heparin-induced thrombocytopenia (HIT), with both disorders associated with thrombocytopenia, thrombosis, and presence of autoantibodies to platelet factor 4 (PF4). Unlike VITT, HIT is triggered by recent exposure to heparin. Owing to similarities between these 2 conditions and lack of high-quality evidence, interim recommendations suggest avoiding heparin and heparin analogues in patients with VITT. Based on initial reports, female sex and age younger than 60 years were identified as possible risk factors for VITT. Treatment consists of therapeutic anticoagulation with nonheparin anticoagulants and prevention of formation of autoantibody-PF4 complexes, the latter being achieved by administration of high-dose intravenous immunoglobin (IVIG). Steroids, which can theoretically inhibit the production of new antibodies, have been used in combination with IVIG. In severe cases, plasma exchange should be used for clearing autoantibodies. Monoclonal antibodies, such as rituximab and eculizumab, can be considered when other therapies fail. Routine platelet transfusions, aspirin, and warfarin should be avoided because of the possibility of worsening thrombosis and magnifying bleeding risk. Conclusions and Relevance: Adverse events like VITT, while uncommon, have been described despite vaccination remaining the most essential component in the fight against the COVID-19 pandemic. While it seems logical to consider the use of types of vaccines (eg, mRNA-based administration) in individuals at high risk, treatment should consist of therapeutic anticoagulation mostly with nonheparin products and IVIG.

Association of Adverse Childhood Experiences With Cardiovascular Disease Later in Life: A Review.

Abstract: Importance Adverse childhood experiences (ACEs) are potentially harmful events that occur during childhood, spanning neglect, physical or sexual abuse, parental separation, or death, among others. At least 50% of the US adult population has experienced 1 or more ACEs before the age of 18 years, but in clinical practice, ACEs remain underrecognized. Adults who have experienced ACEs are at increased risk of developing health risk behaviors and, ultimately, cardiovascular disease (CVD). This review summarizes the evidence regarding the association of ACEs with CVD and the accompanying diagnostic and therapeutic approaches in the adult population. Observations ACEs are commonly classified into 3 domains: abuse (psychological, physical, or sexual), household dysfunction (eg, substance use by household members, mental illness, parental separation), and neglect. These experiences elicit chronic activation of the stress response system, leading to autonomic, neuroendocrine, and inflammatory dysfunction. The subsequent development of traditional risk factors, such as diabetes, hypertension, smoking, and obesity, results in the onset of CVD and premature mortality. Adults with 4 or more ACEs compared with those with none have a more than 2-fold higher risk of developing CVD and an almost 2-fold higher risk of premature mortality. Conclusions and relevance Identifying methods of mitigating the health consequences of ACEs may lead to better cardiovascular outcomes. Inquiry into ACE exposure during clinical encounters and subsequent referral to psychological services when appropriate may be helpful, but strategies aimed at CVD prevention via management of ACEs in adults continue to lack adequate evidence.

National Trends in Heart Failure Hospitalizations and Readmissions From 2010 to 2017.

Abstract: Author(s): Agarwal, Manyoo A; Fonarow, Gregg C; Ziaeian, Boback | Abstract: ImportancePrevious studies have described the secular trends of overall heart failure (HF) hospitalizations, but the literature describing the national trends of unique index hospitalizations and readmission visits for the primary management of HF is lackingObjectivesTo examine contemporary overall and sex-specific trends of unique primary HF (grouped by number of visits for the same patient in a given year) and 30-day readmission visits in a large national US administrative database from 2010 to 2017Design, setting, and participantsThis cohort study used data from all adult hospitalizations in the Nationwide Readmission Database from January 1, 2010, to December 31, 2017, with a primary diagnosis of HF Data analyses were conducted from March to November 2020ExposuresAdmission for a primary diagnosis of HF at dischargeMain outcomes and measuresUnique and overall hospitalizations with a primary diagnosis of HF and postdischarge readmissions Unique primary HF hospitalizations were grouped by number of visits for the same patient in a given yearResultsThere were 8 273 270 primary HF hospitalizations with a single primary HF admission present in 5 092 626 unique patients, and 1 269 109 had 2 or more HF hospitalizations The mean age was 721 (95% CI, 720-723) years, and 489% (95% CI, 487-490) were women The primary HF hospitalization rates per 1000 US adults declined from 44 in 2010 to 41 in 2013 and then increased from 42 in 2014 to 49 in 2017 The rates per 1000 US adults for postdischarge HF readmissions (10 in 2010 to 09 in 2014 to 11 in 2017) and all-cause 30-day readmissions (08 in 2010 to 07 in 2014 to 09 in 2017) had similar trendsConclusions and relevanceIn this analysis of a nationally representative administrative data set, for primary HF admissions, crude rates of overall and unique patient hospitalizations declined from 2010 to 2014 followed by an increase from 2014 to 2017 Additionally, readmission visits after index HF hospitalizations followed a similar trend Future studies are needed to verify these findings to improve policies for HF management

Association of Apolipoprotein B-Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis: Distinguishing Between Particle Concentration, Type, and Content.

Abstract: Importance Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content. Objective To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins. Design, Setting, and Participants This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389 529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40 430 patients with established atherosclerosis who were receiving statin treatment. Exposures ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG. Main Outcome and Measures The primary study outcome was incident myocardial infarction (MI). Results Of the 389 529 individuals in the primary prevention group, 224 097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40 430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001). Similarly, only apoB was associated with MI in the secondary prevention cohort. Adjusting for apoB, there was no association between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and risk of MI, implying that for a given concentration of apoB-containing lipoproteins, the relative proportions of particle subpopulations may no longer be a predictor of risk. Conclusions and Relevance In this cohort study, risk of MI was best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). This suggests that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the focus of therapeutic strategies.

Assessment of Neutrophil Extracellular Traps in Coronary Thrombus of a Case Series of Patients With COVID-19 and Myocardial Infarction.

Abstract: Importance Severe coronavirus disease 2019 (COVID-19) is characterized by the intense formation of neutrophil extracellular traps (NETs), leading to the occlusion of microvessels, as shown in pulmonary samples. The occurrence of ST-elevated myocardial infarction (STEMI) is a serious cardiac manifestation of COVID-19; the intrinsic mechanism of coronary thrombosis appears to still be unknown. Objective To determine the role of NETs in coronary thrombosis in patients with COVID-19. Design, Setting, and Participants This was a consecutive series of patients with COVID-19 at an academic tertiary hospital in Madrid, Spain, who underwent primary coronary interventions for STEMI in which coronary aspirates were obtained in the catheterization laboratory using a thrombus aspiration device. Patients with COVID-19 who experienced a STEMI between March 23 and April 11, 2020, from whom coronary thrombus samples were aspirated during primary coronary intervention, were included in the analysis. These patients were compared with a series conducted from July 2015 to December 2015 of patients with STEMI. Main Outcomes and Measures The presence and quantity of NETs in coronary aspirates from patients with STEMI and COVID-19. The method for the analysis of NETs in paraffin-embedded coronary thrombi was based on the use of confocal microscopy technology and image analysis for the colocalization of myeloperoxidase-DNA complexes and citrullinated histone H3. Immunohistochemical analysis of thrombi was also performed. Clinical and angiographic variables were prospectively collected. Results Five patients with COVID-19 were included (4 men [80%]; mean [SD] age, 62 [14] years); the comparison group included 50 patients (44 males [88%]; mean [SD] age, 58 [12] years). NETs were detected in the samples of all 5 patients with COVID-19, and the median density of NETs was 61% (95% CI, 43%-91%). In the historical series of patients with STEMI, NETs were found in 34 of 50 thrombi (68%), and the median NET density was 19% (95% CI, 13%-22%;P Conclusions and Relevance In this small case series of patients with COVID-19 and myocardial infarction, NETs seem to play a major role in the pathogenesis of STEMI in COVID-19 disease. Our findings support the idea that targeting intravascular NETs might be a relevant goal of treatment and a feasible way to prevent coronary thrombosis in patients with severe COVID-19 disease.

Mechanical Complications of Acute Myocardial Infarction: A Review.

Abstract: Importance Mechanical complications of acute myocardial infarction include left ventricular free-wall rupture, ventricular septal rupture, papillary muscle rupture, pseudoaneurysm, and true aneurysm. With the introduction of early reperfusion therapies, these complications now occur in fewer than 0.1% of patients following an acute myocardial infarction. However, mortality rates have not decreased in parallel, and mechanical complications remain an important determinant of outcomes after myocardial infarction. Early diagnosis and management are crucial to improving outcomes and require an understanding of the clinical findings that should raise suspicion of mechanical complications and the evolving surgical and percutaneous treatment options. Observations Mechanical complications most commonly occur within the first week after myocardial infarction. Cardiogenic shock or acute pulmonary edema are frequent presentations. Echocardiography is usually the first test used to identify the type, location, and hemodynamic consequences of the mechanical complication. Hemodynamic stabilization often requires a combination of medical therapy and mechanical circulatory support. Surgery is the definitive treatment, but the optimal timing remains unclear. Percutaneous therapies are emerging as an alternative treatment option for patients at prohibitive surgical risk. Conclusions and Relevance Mechanical complications present with acute and dramatic hemodynamic deterioration requiring rapid stabilization. Heart team involvement is required to determine appropriate management strategies for patients with mechanical complications after acute myocardial infarction.

Association of Lipid, Inflammatory, and Metabolic Biomarkers With Age at Onset for Incident Coronary Heart Disease in Women.

Abstract: Importance Risk profiles for premature coronary heart disease (CHD) are unclear. Objective To examine baseline risk profiles for incident CHD in women by age at onset. Design, Setting, and Participants A prospective cohort of US female health professionals participating in the Women’s Health Study was conducted; median follow-up was 21.4 years. Participants included 28 024 women aged 45 years or older without known cardiovascular disease. Baseline profiles were obtained from April 30, 1993, to January 24, 1996, and analyses were conducted from October 1, 2017, to October 1, 2020. Exposures More than 50 clinical, lipid, inflammatory, and metabolic risk factors and biomarkers. Main Outcomes and Measures Four age groups were examined ( Results Of the clinical factors in the women, diabetes had the highest aHR for CHD onset at any age, ranging from 10.71 (95% CI, 5.57-20.60) at CHD onset in those younger than 55 years to 3.47 (95% CI, 2.47-4.87) at CHD onset in those 75 years or older. Risks that were also noted for CHD onset in participants younger than 55 years included metabolic syndrome (aHR, 6.09; 95% CI, 3.60-10.29), hypertension (aHR, 4.58; 95% CI, 2.76-7.60), obesity (aHR, 4.33; 95% CI, 2.31-8.11), and smoking (aHR, 3.92; 95% CI, 2.32-6.63). Myocardial infarction in a parent before age 60 years was associated with 1.5- to 2-fold risk of CHD in participants up to age 75 years. From approximately 50 biomarkers, lipoprotein insulin resistance had the highest standardized aHR: 6.40 (95% CI, 3.14-13.06) for CHD onset in women younger than 55 years, attenuating with age. In comparison, weaker but significant associations with CHD in women younger than 55 years were noted (per SD increment) for low-density lipoprotein cholesterol (aHR, 1.38; 95% CI, 1.10-1.74), non–high-density lipoprotein cholesterol (aHR, 1.67; 95% CI, 1.36-2.04), apolipoprotein B (aHR, 1.89; 95% CI, 1.52-2.35), triglycerides (aHR, 2.14; 95% CI, 1.72-2.67), and inflammatory biomarkers (1.2- to 1.8-fold)—all attenuating with age. Some biomarkers had similar CHD age associations (eg, physical inactivity, lipoprotein[a], total high-density lipoprotein particles), while a few had no association with CHD onset at any age. Most risk factors and biomarkers had associations that attenuated with increasing age at onset. Conclusions and Relevance In this cohort study, diabetes and insulin resistance, in addition to hypertension, obesity, and smoking, appeared to be the strongest risk factors for premature onset of CHD. Most risk factors had attenuated relative rates at older ages.

Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

Abstract: Importance The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. Objective To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. Design, Setting, and Participants A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. Intervention Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. Main Outcomes and Measures The area under the curve (AUC) for the ratio of N-terminal pro–brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. Results Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08;P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non–life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%];P = .04), there were no observed safety concerns. Conclusions and Relevance The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. Trial Registration ClinicalTrials.gov Identifier:NCT02816736

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

Abstract: 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%]; allP 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.

Value of Coronary Artery Calcium Scanning in Association With the Net Benefit of Aspirin in Primary Prevention of Atherosclerotic Cardiovascular Disease.

Abstract: Importance Higher coronary artery calcium (CAC) identifies individuals at increased atherosclerotic cardiovascular disease (ASCVD) risk. Whether it can also identify individuals likely to derive net benefit from aspirin therapy is unclear. Objective To examine the association between CAC, bleeding, and ASCVD and explore the net estimated effect of aspirin at different CAC thresholds. Design, Setting, and Participants Prospective population-based cohort study of Dallas Heart Study participants, free from ASCVD and not taking aspirin at baseline. Data were analyzed between February 1, 2020, and July 15, 2020. Exposures Coronary artery calcium score in the following categories: 0, 1-99, and 100 or higher. Main Outcomes and Measures Major bleeding and ASCVD events were identified fromInternational Statistical Classification of Diseases and Related Health Problems, Ninth Revision codes. Meta-analysis–derived aspirin effect estimates were applied to observed ASCVD and bleeding rates to model the net effect of aspirin at different CAC thresholds. Results A total of 2191 participants (mean [SD], age 44 [9.1] years, 1247 women [57%], and 1039 black individuals [47%]) had 116 major bleeding and 123 ASCVD events over a median follow-up of 12.2 years. Higher CAC categories (CAC 1-99 and ≥100 vs CAC 0) were associated with both ASCVD and bleeding events (hazard ratio [HR], 1.6; 95% CI, 1.1-2.4; HR, 2.6; 95% CI, 1.5-4.3; HR, 4.8; 95% CI, 2.8-8.2;P Conclusions and Relevance Higher CAC is associated with both ASCVD and bleeding events, with a stronger association with ASCVD. A high CAC score identifies individuals estimated to derive net benefit from primary prevention aspirin therapy from those who would not, but only in the setting of lower bleeding risk and estimated ASCVD risk that is not low.

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

Abstract: 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.