Journal: JAMA Cardiol

Sorted by: date / impact
Abstract

Association of Age With the Diagnostic Value of Coronary Artery Calcium Score for Ruling Out Coronary Stenosis in Symptomatic Patients.

Mortensen MB, Gaur S, Frimmer A, Bøtker HE, ... Nørgaard BL, Jensen JM
Importance
The diagnostic value is unclear of a 0 coronary artery calcium (CAC) score to rule out obstructive coronary artery disease (CAD) and near-term clinical events across different age groups.
Objective
To assess the diagnostic value of a CAC score of 0 for reducing the likelihood of obstructive CAD and to assess the implications of such a CAC score and obstructive CAD across different age groups.
Design, setting, and participants
This cohort study obtained data from the Western Denmark Heart Registry and had a median follow-up time of 4.3 years. Included patients were aged 18 years or older who underwent computed tomography angiography (CTA) between January 1, 2008, and December 31, 2017, because of symptoms that were suggestive of CAD. Data analysis was performed from April 5 to July 7, 2021.
Exposures
Obstructive CAD, which was defined as 50% or more luminal stenosis.
Main outcomes and measures
Proportion of individuals with obstructive CAD who had a CAC score of 0. Risk-adjusted diagnostic likelihood ratios were used to assess the diagnostic value of a CAC score of 0 for reducing the likelihood of obstructive CAD beyond clinical variables. Risk factors associated with myocardial infarction and death were estimated.
Results
A total of 23 759 symptomatic patients, of whom 12 771 (54%) had a CAC score of 0, were included. This cohort had a median (IQR) age of 58 (49-65) years and was primarily composed of women (13 160 [55%]). Overall, the prevalence of obstructive CAD was relatively low across all age groups, ranging from 3% (39 of 1278 patients) in those who were younger than 40 years to 8% (52 of 619) among those who were 70 years or older. In patients with obstructive CAD, 14% (725 of 5043) had a CAC score of 0, and the prevalence varied across age groups from 58% (39 of 68) among those who were younger than 40 years, 34% (192 of 562) among those aged 40 to 49 years, 18% (268 of 1486) among those aged 50 to 59 years, 9% (174 of 1963) among those aged 60 to 69 years, to 5% (52 of 964) among those who were 70 years or older. The added diagnostic value of a CAC score of 0 decreased at a younger age, with a risk factor-adjusted diagnostic likelihood ratio of a CAC score of 0 ranging from 0.68 (approximately 32% lower likelihood of obstructive CAD than expected) in those who were younger than 40 years to 0.18 (approximately 82% lower likelihood than expected) in those who were 70 years or older. The presence of obstructive vs nonobstructive CAD among those with a CAC score of 0 was associated with a multivariable adjusted hazard ratio of 1.51 (95% CI, 0.98-2.33) for myocardial infarction and all-cause death; however, this hazard ratio varied from 1.80 (95% CI, 1.02-3.19) in those who were younger than 60 years to 1.24 (95% CI, 0.64-2.39) in those who were 60 years or older.

Conclusions:
and relevance
This cohort study found that the diagnostic value of a CAC score of 0 to rule out obstructive CAD beyond clinical variables was dependent on age, with the added diagnostic value being smaller for younger patients. In symptomatic patients who were younger than 60 years, a sizable proportion of obstructive CAD occurred among those without CAC and was associated with an increased risk of myocardial infarction and all-cause death.



JAMA Cardiol: 26 Oct 2021; epub ahead of print
Mortensen MB, Gaur S, Frimmer A, Bøtker HE, ... Nørgaard BL, Jensen JM
JAMA Cardiol: 26 Oct 2021; epub ahead of print | PMID: 34705022
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Impact:
Abstract

Interventions to Mitigate Risk of Cardiovascular Disease After Adverse Pregnancy Outcomes: A Review.

Jowell AR, Sarma AA, Gulati M, Michos ED, ... Powe CE, Honigberg MC
Importance
A growing body of evidence suggests that adverse pregnancy outcomes (APOs), including hypertensive disorders of pregnancy, gestational diabetes (GD), preterm birth, and intrauterine growth restriction, are associated with increased risk of cardiometabolic disease and cardiovascular disease (CVD) later in life. Adverse pregnancy outcomes may therefore represent an opportunity to intervene to prevent or delay onset of CVD. The objective of this review was to summarize the current evidence for targeted postpartum interventions and strategies to reduce CVD risk in women with a history of APOs.
Observations
A search of PubMed and Ovid for English-language randomized clinical trials, cohort studies, descriptive studies, and guidelines published from January 1, 2000, to April 30, 2021, was performed. Four broad categories of interventions were identified: transitional clinics, lifestyle interventions, pharmacotherapy, and patient and clinician education. Observational studies suggest that postpartum transitional clinics identify women who are at elevated risk for CVD and may aid in the transition to longitudinal primary care. Lifestyle interventions to increase physical activity and improve diet quality may help reduce the incidence of type 2 diabetes in women with prior GD; less is known about women with other prior APOs. Metformin hydrochloride may prevent development of type 2 diabetes in women with prior GD. Evidence is lacking in regard to specific pharmacotherapies after other APOs. Cardiovascular guidelines endorse using a history of APOs to refine CVD risk assessment and guide statin prescription for primary prevention in women with intermediate calculated 10-year CVD risk. Research suggests a low level of awareness of the link between APOs and CVD among both patients and clinicians.

Conclusions:
and relevance
These findings suggest that transitional clinics, lifestyle intervention, targeted pharmacotherapy, and clinician and patient education represent promising strategies for improving postpartum maternal cardiometabolic health in women with APOs; further research is needed to develop and rigorously evaluate these interventions. Future efforts should focus on strategies to increase maternal postpartum follow-up, improve accessibility to interventions across diverse racial and cultural groups, expand awareness of sex-specific CVD risk factors, and define evidence-based precision prevention strategies for this high-risk population.



JAMA Cardiol: 26 Oct 2021; epub ahead of print
Jowell AR, Sarma AA, Gulati M, Michos ED, ... Powe CE, Honigberg MC
JAMA Cardiol: 26 Oct 2021; epub ahead of print | PMID: 34705020
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Impact:
Abstract

Analysis of Respiratory Fluoroquinolones and the Risk of Sudden Cardiac Death Among Patients Receiving Hemodialysis.

Assimon MM, Pun PH, Wang LC, Al-Khatib SM, ... Winkelmayer WC, Flythe JE
Importance
Respiratory fluoroquinolone antibiotics are some of the most common medications with QT interval-prolonging potential prescribed to patients with hemodialysis-dependent kidney failure-individuals who have a very high risk of sudden cardiac death (SCD). To date, there have been no large-scale, population-specific studies evaluating the cardiac safety of respiratory fluoroquinolones in the hemodialysis population.
Objective
To investigate the cardiac safety of respiratory fluoroquinolones among individuals with hemodialysis-dependent kidney failure.
Design, setting, and participants
A retrospective cohort study examining safety using an active comparator new-user design was conducted using administrative claims data from a US-wide kidney failure registry from January 1, 2007, to December 31, 2016, including 264 968 Medicare beneficiaries receiving in-center maintenance hemodialysis. Data analysis was performed from January 4 to August 16, 2021.
Exposures
Respiratory fluoroquinolone (levofloxacin or moxifloxacin) vs amoxicillin-based (amoxicillin or amoxicillin with clavulanic acid) antibiotic treatment.
Main outcomes and measures
Sudden cardiac death within 5 days of outpatient initiation of a study antibiotic. Inverse probability of treatment-weighted survival models to estimate hazard ratios (HRs), risk differences (RDs), and corresponding 95% CIs. Death due to a cause other than SCD was treated as a competing event. Fracture was considered as a negative control outcome.
Results
The study cohort included 264 968 unique in-center hemodialysis patients and 626 322 study antibiotic treatment episodes: 251 726 respiratory fluoroquinolone treatment episodes (40.2%) and 374 596 amoxicillin-based treatment episodes (59.8%). Of the 264 968 patients, 135 236 (51.0%) were men, and the mean (SD) age was 61 (15) years. Respiratory fluoroquinolone vs amoxicillin-based antibiotic treatment was associated with a higher relative and absolute 5-day risk of SCD (weighted HR, 1.95; 95% CI, 1.57-2.41; and weighted RD per 100 000 treatment episodes, 44.0; 95% CI, 31.0-59.2). Respiratory fluoroquinolone vs amoxicillin-based antibiotic treatment was not associated with the 5-day risk of fracture.

Conclusions:
and relevance
In this study, compared with amoxicillin-based antibiotic treatment, respiratory fluoroquinolone treatment was associated with a higher short-term risk of SCD among patients with hemodialysis-dependent kidney failure. This finding suggests that decisions between the use of respiratory fluoroquinolones and amoxicillin-based antibiotics should be individualized, with prescribers considering both the clinical benefits and potential cardiac risks.



JAMA Cardiol: 19 Oct 2021; epub ahead of print
Assimon MM, Pun PH, Wang LC, Al-Khatib SM, ... Winkelmayer WC, Flythe JE
JAMA Cardiol: 19 Oct 2021; epub ahead of print | PMID: 34668928
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Impact:
Abstract

Preterm Delivery and Long-term Risk of Hypertension in Women.

Crump C, Sundquist J, Sundquist K
Importance
Preterm delivery has been associated with future cardiometabolic disorders in women. However, the long-term risks of chronic hypertension associated with preterm delivery and whether such risks are attributable to familial confounding are unclear. Such knowledge is needed to improve long-term risk assessment, clinical monitoring, and cardiovascular prevention strategies in women.
Objective
To examine the long-term risks of chronic hypertension associated with preterm delivery in a large population-based cohort of women.
Design, setting, and participants
This national cohort study assessed all 2 195 989 women in Sweden with a singleton delivery from January 1, 1973, to December 31, 2015. Data analyses were conducted from March 8, 2021, to August 20, 2021.
Exposures
Pregnancy duration identified from nationwide birth records.
Main outcomes and measures
New-onset chronic hypertension identified from primary care, specialty outpatient, and inpatient diagnoses using administrative data. Cox proportional hazards regression was used to compute hazard ratios (HRs) while adjusting for preeclampsia, other hypertensive disorders of pregnancy, and other maternal factors. Cosibling analyses were assessed for potential confounding by shared familial (genetic and/or environmental) factors.
Results
In 46.1 million person-years of follow-up, 351 189 of 2 195 989 women (16.0%) were diagnosed with hypertension (mean [SD] age, 55.4 [9.9] years). Within 10 years after delivery, the adjusted HR for hypertension associated with preterm delivery (gestational age <37 weeks) was 1.67 (95% CI, 1.61-1.74) and when further stratified was 2.23 (95% CI, 1.98-2.52) for extremely preterm (22-27 weeks of gestation), 1.85 (95% CI, 1.74-1.97) for moderately preterm (28-33 weeks of gestation), 1.55 (95% CI, 1.48-1.63) for late preterm (34-36 weeks of gestation), and 1.26 (95% CI, 1.22-1.30) for early-term (37-38 weeks of gestation) compared with full-term (39-41 weeks of gestation) delivery. These risks decreased but remained significantly elevated at 10 to 19 years (preterm vs full-term delivery: adjusted HR, 1.40; 95% CI, 1.36-1.44), 20 to 29 years (preterm vs full-term delivery: adjusted HR, 1.20; 95% CI, 1.18-1.23), and 30 to 43 years (preterm vs full-term delivery: adjusted HR, 95% CI, 1.12; 1.10-1.14) after delivery. These findings were not explained by shared determinants of preterm delivery and hypertension within families.

Conclusions:
and relevance
In this large national cohort study, preterm delivery was associated with significantly higher future risks of chronic hypertension. These associations remained elevated at least 40 years later and were largely independent of other maternal and shared familial factors. Preterm delivery should be recognized as a lifelong risk factor for hypertension in women.



JAMA Cardiol: 12 Oct 2021; epub ahead of print
Crump C, Sundquist J, Sundquist K
JAMA Cardiol: 12 Oct 2021; epub ahead of print | PMID: 34643643
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Impact:
Abstract

Assessment of Omecamtiv Mecarbil for the Treatment of Patients With Severe Heart Failure: A Post Hoc Analysis of Data From the GALACTIC-HF Randomized Clinical Trial.

Felker GM, Solomon SD, Claggett B, Diaz R, ... Malik FI, Teerlink JR
Importance
Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients\' condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies.
Objective
To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial.
Design, setting, and participants
The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months.
Interventions
Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo.
Main outcomes and measures
The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability.
Results
Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08; P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25]; P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo.

Conclusions:
and relevance
In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited.
Trial registration
ClinicalTrials.gov Identifier: NCT02929329.



JAMA Cardiol: 12 Oct 2021; epub ahead of print
Felker GM, Solomon SD, Claggett B, Diaz R, ... Malik FI, Teerlink JR
JAMA Cardiol: 12 Oct 2021; epub ahead of print | PMID: 34643642
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Impact:
Abstract

Role of Coronary Artery Calcium Testing for Risk Assessment in Primary Prevention of Atherosclerotic Cardiovascular Disease: A Review.

Greenland P, Lloyd-Jones DM
Importance
Current guidelines recommend a few different approaches to the use of coronary artery calcium (CAC) testing as a tool for risk assessment and decision-making regarding drug therapy for primary prevention of atherosclerotic cardiovascular disease (ASCVD).
Observations
Coronary artery calcium testing is not recommended for universal screening, particularly in patients at very low or high predicted risk for ASCVD, where its yield and utility for altering clinical decisions are limited. Use of CAC testing appears to be optimal when used in selected patients who are at intermediate or borderline risk of ASCVD as a sequential decision aid after initial quantitative risk assessment and consideration of individual patient risk-enhancing factors (eg, strong family history of premature ASCVD, chronic kidney disease). Although convincing clinical trials have not been completed, observational studies strongly suggest that, in those at intermediate risk, CAC testing can meaningfully reclassify risk and can support improved targeting of drug therapy to patients most likely to benefit.

Conclusions:
and relevance
This narrative review summarizes the evidence available about the appropriate role of CAC testing for ASCVD risk assessment. Coronary artery calcium testing should be used selectively in patients who are at intermediate risk of ASCVD, when there is persistent uncertainty after performing standard risk assessment using traditional risk factors in a risk score, and after consideration of additional individual risk-enhancing factors. In these situations, the result of the CAC test can be helpful to clarify whether the patient\'s true risk is high enough to justify initiation of primary prevention medications, such as statins or aspirin.



JAMA Cardiol: 05 Oct 2021; epub ahead of print
Greenland P, Lloyd-Jones DM
JAMA Cardiol: 05 Oct 2021; epub ahead of print | PMID: 34613362
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Impact:
Abstract

Association of Smoking With Postprocedural Complications Following Open and Endovascular Interventions for Intermittent Claudication.

Reitz KM, Althouse AD, Meyer J, Arya S, ... Hall DE, Tzeng E
Importance
Smoking is a key modifiable risk factor in the development and progression of peripheral artery disease, which often manifests as intermittent claudication (IC). Smoking cessation is a first-line therapy for IC, yet a minority of patients quit smoking prior to elective revascularization.
Objective
To assess if preprocedural smoking is associated with an increased risk of early postprocedural complications following elective open and endovascular revascularization.
Design, setting, and participants
This retrospective cohort study used nearest-neighbor (1:1) propensity score matching of 2011 to 2019 data from the Veterans Affairs Surgical Quality Improvement Program, including all cases with a primary diagnosis of IC and excluding emergent cases, primary procedures that were not lower extremity revascularization, and patients with chronic limb-threatening ischemia within 30 days of the intervention. All data were abstracted June 18, 2020, and analyzed from July 26, 2020, to June 30, 2021.
Exposures
Preprocedural cigarette smoking.
Main outcomes and measures
Any and organ system-specific (ie, wound, respiratory, thrombosis, kidney, cardiac, sepsis, and neurological) 30-day complications and mortality, overall and in prespecified subgroups.
Results
Of 14 350 included cases of revascularization, 14 090 patients (98.2%) were male, and the mean (SD) age was 65.7 (7.0) years. A total of 7820 patients (54.5%) were smoking within the preprocedural year. There were a total of 4417 endovascular revascularizations (30.8%), 4319 hybrid revascularizations (30.1%), and 5614 open revascularizations (39.1%). A total of 1594 patients (11.1%) had complications, and 57 (0.4%) died. Among 7710 propensity score-matched cases (including 3855 smokers and 3855 nonsmokers), 484 smokers (12.6%) and 34 nonsmokers (8.9%) experienced complications, an absolute risk difference (ARD) of 3.68% (95% CI, 2.31-5.06; P < .001). Compared with nonsmokers, any complication was higher for smokers following endovascular revascularization (26 [4.3%] vs 52 [2.1%]; ARD, 2.19%; 95% CI, 0.77-3.60; P = .003), hybrid revascularization (204 [17.3%] vs 163 [14.1%]; ARD, 3.18%; 95% CI, 0.23-6.13; P = .04), and open revascularization (228 [15.4%] vs 153 [10.3%]; ARD, 5.18%; 95% CI, 2.78-7.58; P < .001). Compared with nonsmokers, respiratory complications were higher for smokers following endovascular revascularization (20 [1.7%] vs 6 [0.5%]; ARD, 1.17%; 95% CI, 0.35-2.00; P = .009), hybrid revascularization (33 [2.8%] vs 10 [0.9%]; ARD, 1.93%; 95% CI, 0.85-3.02; P = .001), and open revascularization (32 [2.2%] vs 19 [1.3%]; ARD, 0.89%; 95% CI, 0-1.80; P = .06). Wound complications and graft failure were higher for smokers compared with nonsmokers following open interventions (wound complications: 146 [9.9%] vs 87 [5.8%]; ARD, 4.05%; 95% CI, 2.12-5.99; P < .001; graft failure: 33 [2.2%] vs 11 [0.7%]; ARD, 1.50%; 95% CI, 0.63-2.37; P = .001). In a sensitivity analysis, compared with active smokers (n = 5173; smoking within 2 weeks before the procedure), the risk of any complication was decreased by 65% for never smokers (n = 1197; adjusted odds ratio, 0.45; 95% CI, 0.34-0.59) and 29% for former smokers (n = 4755; cessation more than 1 year before the procedure; adjusted odds ratio, 0.71; 95% CI, 0.61-0.83; P = .001 for interaction).

Conclusions:
and relevance
In this cohort study, more than half of patients with IC were smoking prior to elective revascularization, and complication risks were higher across all modalities of revascularization. These findings stress the importance of smoking cessation to optimize revascularization outcomes.



JAMA Cardiol: 05 Oct 2021; epub ahead of print
Reitz KM, Althouse AD, Meyer J, Arya S, ... Hall DE, Tzeng E
JAMA Cardiol: 05 Oct 2021; epub ahead of print | PMID: 34613348
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Impact:
Abstract

Long-term Benefits and Harms Associated With Genetic Cholesteryl Ester Transfer Protein Deficiency in the General Population.

Nordestgaard LT, Christoffersen M, Lauridsen BK, Afzal S, ... Frikke-Schmidt R, Tybjærg-Hansen A
Importance
The balance between the potential long-term clinical benefits and harms associated with genetic cholesteryl ester transfer protein (CETP) deficiency, mimicking pharmacologic CETP inhibition, is unknown.
Objective
To assess the relative benefits and harms associated with genetic CETP deficiency.
Design, setting, and participants
This study examined 2 similar prospective cohorts of the Danish general population, with data on a total of 102 607 participants collected from October 10, 1991, through December 7, 2018.
Exposures
Weighted CETP allele scores.
Main outcomes and measures
Incident cardiovascular mortality, ischemic heart disease, myocardial infarction, ischemic stroke, peripheral arterial disease, vascular dementia, Alzheimer disease, all-cause mortality, and age-related macular degeneration (AMD). The study first tested whether a CETP allele score was associated with morbidity and mortality, when scaled to genetically lower levels of non-high-density lipoprotein (HDL) cholesterol (ie, 17 mg/dL), corresponding to the reduction observed for anacetrapib vs placebo in the Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial. Second, the study assessed how much of the change in morbidity and mortality was associated with genetically lower levels of non-HDL cholesterol. Finally, the balance between the potential long-term clinical benefits and harms associated with genetic CETP deficiency was quantified. For AMD, the analyses also included higher levels of HDL cholesterol associated with genetic CETP deficiency.
Results
Of 102 607 individuals in the study, 56 559 (55%) were women (median age, 58 years [IQR, 47-67 years]). Multivariable adjusted hazard ratios showed that a genetically lower level of non-HDL cholesterol (ie, 17 mg/dL) was associated with a lower risk of cardiovascular mortality (hazard ratio [HR], 0.77 [95% CI, 0.62-0.95]), ischemic heart disease (HR, 0.80 [95% CI, 0.68-0.95]), myocardial infarction (HR, 0.72 [95% CI, 0.55-0.93]), peripheral arterial disease (HR, 0.80 [95% CI, 0.63-1.02]), and vascular dementia (HR, 0.38 [95% CI, 0.18-0.80]) and an increased risk of AMD (HR, 2.33 [95% CI, 1.63-3.30]) but was not associated with all-cause mortality (HR, 0.91 [95% CI, 0.81-1.02]), ischemic stroke (HR, 1.05 [95% CI, 0.81-1.36]), or Alzheimer disease (HR, 1.25 [95% CI, 0.89-1.76]). When scaled to a higher level of HDL cholesterol, the increased risk of AMD was even larger. A considerable fraction of the lower risk of cardiovascular end points was associated with genetically lower levels of non-HDL cholesterol, while the higher risk of AMD was associated with genetically higher levels of HDL cholesterol. Per 1 million person-years, the projected 1916 more AMD events associated with genetically higher levels of HDL cholesterol was similar to the 1962 fewer events of cardiovascular mortality and myocardial infarction combined associated with genetically lower levels of non-HDL cholesterol.

Conclusions:
and relevance
This study suggests that genetic CETP deficiency, mimicking pharmacologic CETP inhibition, was associated with a lower risk of cardiovascular morbidity and mortality, but with a markedly higher risk of AMD.



JAMA Cardiol: 05 Oct 2021; epub ahead of print
Nordestgaard LT, Christoffersen M, Lauridsen BK, Afzal S, ... Frikke-Schmidt R, Tybjærg-Hansen A
JAMA Cardiol: 05 Oct 2021; epub ahead of print | PMID: 34613338
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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: 30 Sep 2021; 6:1196-1201
Kim HW, Jenista ER, Wendell DC, Azevedo CF, ... Parker MA, Kim RJ
JAMA Cardiol: 30 Sep 2021; 6:1196-1201 | 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: 30 Sep 2021; 6:1202-1206
Montgomery J, Ryan M, Engler R, Hoffman D, ... Sanou A, Cooper LT
JAMA Cardiol: 30 Sep 2021; 6:1202-1206 | PMID: 34185045
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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: 30 Sep 2021; 6:1121-1129
Coughlan JJ, Aytekin A, Lahu S, Ndrepepa G, ... Schüpke S, Kastrati A
JAMA Cardiol: 30 Sep 2021; 6:1121-1129 | PMID: 34190967
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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: 30 Sep 2021; 6:1144-1151
Fernandez-Mendoza J, He F, Calhoun SL, Vgontzas AN, Liao D, Bixler EO
JAMA Cardiol: 30 Sep 2021; 6:1144-1151 | 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: 30 Sep 2021; 6:1130-1143
Rush CJ, Berry C, Oldroyd KG, Rocchiccioli JP, ... McMurray JJV, Petrie MC
JAMA Cardiol: 30 Sep 2021; 6:1130-1143 | PMID: 34160566
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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: 30 Sep 2021; 6:1152-1160
Machado S, Sumarsono A, Vaduganathan M
JAMA Cardiol: 30 Sep 2021; 6:1152-1160 | PMID: 34190965
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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: 30 Sep 2021; 6:1177-1186
Demolder A, Timmermans F, Duytschaever M, Muiño-Mosquera L, De Backer J
JAMA Cardiol: 30 Sep 2021; 6:1177-1186 | PMID: 34232254
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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: 30 Sep 2021; 6:1207-1216
O'Donnell CJ, Schwartz Longacre L, Cohen BE, Fayad ZA, ... Sopko G, Stein MB
JAMA Cardiol: 30 Sep 2021; 6:1207-1216 | PMID: 34259831
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Impact:
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: 30 Sep 2021; 6:1171-1176
Pilgrim T, Vollenbroich R, Deckarm S, Gräni C, ... Windecker S, Lanz J
JAMA Cardiol: 30 Sep 2021; 6:1171-1176 | PMID: 34259826
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Impact:
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: 30 Sep 2021; 6:1161-1170
Patel J, Pallazola VA, Dudum R, Greenland P, ... Martin SS, Al Rifai M
JAMA Cardiol: 30 Sep 2021; 6:1161-1170 | PMID: 34259820
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Impact:
Abstract

Contemporaneous Comparison of Outcomes Among Patients Implanted With a Leadless vs Transvenous Single-Chamber Ventricular Pacemaker.

Piccini JP, El-Chami M, Wherry K, Crossley GH, ... Hinnenthal J, Bockstedt L
Importance
The safety and efficacy of leadless VVI pacemakers have been demonstrated in multiple clinical trials, but the comparative performance of the device in a large, real-world population has not been examined.
Objective
To compare patient characteristics and complications among patients implanted with leadless VVI and transvenous VVI pacemakers.
Design, setting, participants
The Longitudinal Coverage With Evidence Development Study on Micra Leadless Pacemakers (Micra CED) is a continuously enrolling observational cohort study evaluating complications, utilization, and outcomes of leadless VVI pacemakers in the US Medicare fee-for-service population. Patients implanted between March 9, 2017, and December 1, 2018, were identified and included. All Medicare patients implanted with leadless VVI and transvenous VVI pacemakers during the study period were enrolled. Patients with less than 12 months of continuous enrollment in Medicare prior to leadless VVI or transvenous VVI implant and with evidence of a prior cardiovascular implantable electronic device were excluded, leaving 5746 patients with leadless VVI pacemakers and 9662 patients with transvenous VVI pacemakers. Data were analyzed from May 2018 to April 2021.
Exposures
Medicare patients implanted with leadless VVI pacemakers or transvenous VVI pacemakers.
Main outcomes and measures
The main outcomes were acute (30-day) complications and 6-month complications.
Results
Of 15 408 patients, 6701 (43.5%) were female, and the mean (SD) age was 81.0 (8.7) years. Compared with patients with transvenous VVI pacemakers, patients with leadless VVI pacemakers were more likely to have end-stage kidney disease (690 [12.0%] vs 226 [2.3%]; P < .001) and a higher mean (SD) Charlson Comorbidity Index score (5.1 [3.4] vs 4.6 [3.0]; P < .001). The unadjusted acute complication rate was higher in patients with leadless VVI pacemakers relative to transvenous VVI pacemakers (484 of 5746 [8.4%] vs 707 of 9662 [7.3%]; P = .02). However, there was no significant difference in overall acute complication rates following adjustment for patient characteristics (7.7% vs 7.4%; risk difference, 0.3; 95% CI, -0.6 to 1.3; P = .49). Pericardial effusion and/or perforation within 30 days was significantly higher among patients with leadless VVI pacemakers compared with patients with transvenous VVI pacemakers in both unadjusted and adjusted models (unadjusted, 47 of 5746 [0.8%] vs 38 of 9662 [0.4%]; P < .001; adjusted, 0.8% vs 0.4%; risk difference, 0.4; 95% CI, 0.1 to 0.7; P = .004). Patients implanted with leadless VVI pacemakers had a lower rate of 6-month complications compared with patients implanted with transvenous VVI pacemakers (unadjusted hazard ratio, 0.84; 95% CI, 0.68-1.03; P = .10; adjusted hazard ratio, 0.77; 95% CI, 0.62-0.96; P = .02).

Conclusions:
and relevance
In this study, despite significant differences in patient characteristics, patients in whom a leadless pacemaker was implanted were observed to have higher rates of pericardial effusion and/or perforation but lower rates of other device-related complications and requirements for device revision at 6 months. Understanding the benefits and risks associated with leadless VVI pacemakers compared with transvenous VVI pacemakers can help clinicians and patients make informed treatment decisions.



JAMA Cardiol: 30 Sep 2021; 6:1187-1195
Piccini JP, El-Chami M, Wherry K, Crossley GH, ... Hinnenthal J, Bockstedt L
JAMA Cardiol: 30 Sep 2021; 6:1187-1195 | PMID: 34319383
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Impact:
Abstract

Temporal Association Between Episodes of Atrial Fibrillation and Risk of Ischemic Stroke.

Singer DE, Ziegler PD, Koehler JL, Sarkar S, Passman RS
Importance
Understanding the temporal association between atrial fibrillation (AF) and ischemic stroke informs our understanding of the AF-stroke mechanism and treatment of paroxysmal AF.
Objective
To define the temporal association between episodes of AF and stroke in patients with cardiac implantable electronic devices (CIEDs).
Design, setting, and participants
In this case-crossover study, data from a large national electronic health record database were linked with a single-vendor database of heart rhythm records of patients with CIEDs capable of continuous heart rhythm monitoring. Patients with CIEDs who sustained an ischemic stroke who also had 120 days of continuous remote rhythm monitoring prestroke were included. Data were collected from January 2007 to March 2017, and data were analyzed from November 2019 to June 2020.
Exposure
AF for 5.5 hours or more on any given day during days 1 to 30 vs days 91 to 120 prestroke.
Main outcomes and measures
Odds ratio for stroke comparing AF during days 1 to 30 vs 91 to 120 prestroke. This analysis was planned prior to the study.
Results
From 466 635 patients included in both the Optum electronic health record and CareLink databases, 891 patients with CIEDs and ischemic stroke with continuous monitoring in the 120 days prestroke were identified. Of 891 included patients, 575 (64.5%) were male, and the median (interquartile range) age was 76 (67-82) years. The vast majority of patients with stroke had either no AF meeting the threshold duration of 5.5 hours or more in both the case and control periods (682 of 891 [76.5%]) or AF of 5.5 hours or more in both periods (143 of 891 [16.0%]). For those not meeting the 5.5-hour AF threshold in either period, there was no or very little AF throughout the 120 days prestroke. A total of 66 patients had informative, discordant arrhythmic states, with 52 having AF of 5.5 hours or more in the case period vs 14 in the control period (odds ratio [OR], 3.71; 95% CI, 2.06-6.70). Stroke risk was increased most in days 1 to 5 following an AF episode (OR, 5.00; 95% CI, 2.62-9.55). AF greater than 23 hours on a given day was associated with the clearest increase in stroke risk (OR, 5.00; 95% CI, 2.08-12.01).

Conclusions:
and relevance
In this large cohort of patients with CIEDs and continuous rhythm monitoring prior to ischemic stroke, excess stroke risk above baseline was highest within 5 days of an episode of AF of 5.5 hours or more in duration and diminished rapidly thereafter. Our findings are consistent with the traditional view that AF is directly and transiently associated with ischemic stroke. These results provide support for trials of time-delimited anticoagulation for patients with infrequent multihour episodes of AF and rigorous, continuous rhythm monitoring.



JAMA Cardiol: 28 Sep 2021; epub ahead of print
Singer DE, Ziegler PD, Koehler JL, Sarkar S, Passman RS
JAMA Cardiol: 28 Sep 2021; epub ahead of print | PMID: 34586356
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Impact:
Abstract

Comparison of Long-term Clinical Outcomes of Skeletonized vs Pedicled Internal Thoracic Artery Harvesting Techniques in the Arterial Revascularization Trial.

Gaudino M, Audisio K, Rahouma M, Chadow D, ... Taggart DP, ART Investigators
Importance
Recent evidence has suggested that skeletonization of the internal thoracic artery (ITA) is associated with worse clinical outcomes in patients undergoing coronary artery bypass surgery (CABG).
Objective
To compare the long-term clinical outcomes of skeletonized and pedicled ITA for CABG.
Design, setting, and participants
The Arterial Revascularization Trial (ART) was a 2-group, multicenter trial comparing the use of a bilateral ITA vs a single ITA for CABG at 10 years. Patients in the ART trial were stratified by ITA harvesting technique: skeletonized vs pedicled. Data were collected from June 2004 to December 2017, and data were analyzed from June to July 2021.
Interventions
In this analysis, the 10-year clinical outcomes were compared between patients who received skeletonized vs pedicled ITAs.
Main outcomes and measures
The primary outcome was all-cause mortality. The secondary outcomes were a composite of major adverse cardiac events (MACE) including all-cause mortality, myocardial infarction, and repeated revascularization and a composite including MACE and sternal wound complication (SWC). Cox regression and propensity score matching were used.
Results
Of 2161 included patients, 295 (13.7%) were female, and the median (interquartile range) age was 65.0 (58.0-70.0) years. At 10 years, the risk of all-cause mortality was not significantly different between the pedicled and skeletonized groups (hazard ratio [HR], 1.12; 95% CI, 0.92-1.36; P = .27). However, the long-term risks of the secondary outcomes were significantly higher in the skeletonized group compared with the pedicled group (MACE: HR, 1.25; 95% CI, 1.06-1.47; P = .01; MACE and SWC: HR, 1.22; 95% CI, 1.05-1.43; P = .01). The difference was not seen when considering only patients operated on by surgeons who enrolled 51 patients or more in the trial (MACE: HR, 1.07; 95% CI, 0.82-1.39; P = .62; MACE and SWC: HR, 1.04; 95% CI, 0.80-1.34; P = .78).

Conclusions:
and relevance
While the long-term survival of patients was not different between groups, the rate of adverse cardiovascular events was consistently higher in the skeletonized group and the difference was associated with surgeon-related factors. Further evidence on the outcome of skeletonized ITA is needed.



JAMA Cardiol: 28 Sep 2021; epub ahead of print
Gaudino M, Audisio K, Rahouma M, Chadow D, ... Taggart DP, ART Investigators
JAMA Cardiol: 28 Sep 2021; epub ahead of print | PMID: 34586338
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Impact:
Abstract

Association of Mortality With Aortic Stenosis Severity in Outpatients: Results From the VALVENOR Study.

Coisne A, Montaigne D, Aghezzaf S, Ridon H, ... Bauters C, VALVENOR Investigators
Importance
Modern data regarding incidence and modes of death of patients with aortic stenosis (AS) are restricted to tertiary centers or studies of aortic valve replacement (AVR).
Objective
To provide new insights into the natural history of outpatients with native AS based on a large regionwide population study with inclusion by all cardiologists regardless of their mode of practice.
Design, setting, and participants
Between May 2016 and December 2017, consecutive outpatients with mild (peak aortic velocity, 2.5-2.9 m/s), moderate (peak aortic velocity, 3-3.9 m/s), and severe (peak aortic velocity, ≥4 m/s) native AS graded by echocardiography were included by 117 cardiologists from the Nord-Pas-de-Calais region in France. Analysis took place between August and November 2020.
Main outcomes and measures
Natural history, need for AVR, and survival of patients with AS were followed up. Indications for AVR were based on current guideline recommendations.
Results
Among 2703 patients (mean [SD] age, 76.0 [10.8] years; 1260 [46.6%] women), 233 (8.6%) were recruited in a university public hospital, 757 (28%) in nonuniversity public hospitals, and 1713 (63.4%) by cardiologists working in private practice. A total of 1154 patients (42.7%) had mild, 1122 (41.5%) had moderate, and 427 (15.8%) had severe AS. During a median (interquartile range) of 2.1 (1.4-2.7) years, 634 patients underwent AVR and 448 died prior to AVR. Most deaths were cardiovascular (200 [44.7%]), mainly associated with congestive heart failure (101 [22.6%]) or sudden death (60 [13.4%]). Deaths were noncardiovascular in 186 patients (41.5%) and from unknown causes in 62 patients (13.8%). Compared with patients with mild AS, there was increased cardiovascular mortality in those with moderate (hazard ratio, 1.47 [95% CI, 1.07-2.02]) and severe (hazard ratio, 3.66 [95% CI, 2.52-5.31]) AS. The differences remained significant when adjusted for baseline characteristics or in time-dependent analyses considering AS progression. In asymptomatic patients, moderate and mild AS were associated with similar cardiovascular mortality (hazard ratio, 0.99 [95% CI, 0.44-2.21]).

Conclusions:
and relevance
While patients in this study with moderate AS had a slightly higher risk of cardiovascular death than patients with mild AS, this risk was much lower than that observed in patients with severe AS. Moreover, in asymptomatic patients, moderate and mild AS were associated with similar cardiovascular mortality.



JAMA Cardiol: 28 Sep 2021; epub ahead of print
Coisne A, Montaigne D, Aghezzaf S, Ridon H, ... Bauters C, VALVENOR Investigators
JAMA Cardiol: 28 Sep 2021; epub ahead of print | PMID: 34586336
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Impact:
Abstract

A Simplified Method for the Diagnosis of Constrictive Pericarditis in the Cardiac Catheterization Laboratory.

Jain CC, Miranda WR, El Sabbagh A, Nishimura RA
Importance
Enhanced ventricular interdependence is a highly sensitive and specific criterion for the diagnosis of constrictive pericarditis (CP), but simultaneous ventricular measurements can be challenging at cardiac catheterization. Ejection times (ETs) correlate with stroke volumes and can be easily measured from arterial pressure tracings.
Objective
To assess respirophasic changes in pulmonary artery (PA) ETs and aorta (Ao) ETs as a marker for enhanced ventricular interdependence.
Design, setting, and participants
Retrospective analysis of simultaneous left-side and right-side heart catheterizations between January 2006 and January 2017 was performed. The data were analyzed in June 2020. All catheterizations were performed at the Mayo Clinic, Rochester, Minnesota. This study evaluated patients undergoing left-side and right-side heart catheterization for assessment of CP after noninvasive evaluation was inconclusive.
Main outcomes and measures
Measurements of the PA and Ao ETs were made during inspiration and expiration. Ventricular interaction was mainly assessed by evaluating the difference of ETs from expiration to inspiration as well as the difference in Ao minus the difference in PA.
Results
A total of 10 patients with surgically proven CP and 10 patients without CP (restrictive cardiomyopathy or severe tricuspid regurgitation) were identified. Of these 20 included patients, 10 (50%) were female, and the median (interquartile range) age was 59.5 (47.0-67.5) years. There were no significant differences in demographic characteristics or baseline hemodynamic measurements. In patients with CP compared with those without CP, there was a significantly greater decrease in PA ET (mean [SD], -31.8 [28.6] vs 5.1 [9.5]; P < .001) and a nonsignificantly greater increase in Ao ET (mean [SD], 19.0 [15.7] vs 10.5 [9.1]; P = 0.20) during expiration vs inspiration. Thus, the difference in Ao ET minus the difference in PA ET during expiration vs inspiration was significantly greater in those with CP compared with those without CP (mean [SD], 50.8 [22.5] milliseconds vs 5.4 [15.2] milliseconds; P < .001).

Conclusions:
and relevance
In this study, PA and Ao measurements of ETs throughout the respiratory cycle were a simple, easily obtainable, and accurate parameter for the diagnosis of CP.



JAMA Cardiol: 21 Sep 2021; epub ahead of print
Jain CC, Miranda WR, El Sabbagh A, Nishimura RA
JAMA Cardiol: 21 Sep 2021; epub ahead of print | PMID: 34550314
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Impact:
Abstract

Pulmonary Circulation Discovery Before Ibn Nafis-Ancient Persian and Greek Theories: A Narrative Review.

Zargaran A
Importance
The recognition of the pulmonary circulation is a complex evolution in medical history and draws on theories across eras and cultures.
Observations
This narrative review summarizes evidence suggesting that the recognition of pulmonary circulation is older than the time of Ibn Nafis. The theory of pulmonary circulation originated in ancient Persia (ad 224-637), was overshadowed by Greek theory from the 11th century, and reestablished by Ibn Nafis in the 13th century.

Conclusions:
and relevance
The findings of this review may help contextualize the story of the discovery of pulmonary circulation in ancient Persian and Greek theories before Ibn Nafis.



JAMA Cardiol: 21 Sep 2021; epub ahead of print
Zargaran A
JAMA Cardiol: 21 Sep 2021; epub ahead of print | PMID: 34550308
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Impact:
Abstract

Association Between Cumulative Low-Density Lipoprotein Cholesterol Exposure During Young Adulthood and Middle Age and Risk of Cardiovascular Events.

Zhang Y, Pletcher MJ, Vittinghoff E, Clemons AM, ... de Ferranti SD, Moran AE
Importance
Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease (CVD). Most observational studies on the association between LDL-C and CVD have focused on LDL-C level at a single time point (usually in middle or older age), and few studies have characterized long-term exposures to LDL-C and their role in CVD risk.
Objective
To evaluate the associations of cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C, and the LDL-C slope change during young adulthood and middle age with incident CVD later in life.
Design, setting, and participants
This cohort study analyzed pooled data from 4 prospective cohort studies in the US (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Framingham Heart Study Offspring Cohort, and Multi-Ethnic Study of Atherosclerosis). Participants were included if they had 2 or more LDL-C measures that were at least 2 years apart between ages 18 and 60 years, with at least 1 of the LDL-C measures occurring during middle age at 40 to 60 years. Data from 1971 to 2017 were collected and analyzed from September 25, 2020, to January 10, 2021.
Exposures
Cumulative exposure to LDL-C, TWA LDL-C, and LDL-C slope from age 18 to 60 years.
Main outcomes and measures
Incident coronary heart disease (CHD), ischemic stroke, and heart failure (HF).
Results
A total of 18 288 participants were included in this study. These participants had a mean (SD) age of 56.4 (3.7) years and consisted of 10 309 women (56.4%). During a median follow-up of 16 years, 1165 CHD, 599 ischemic stroke, and 1145 HF events occurred. In multivariable Cox proportional hazards regression models that adjusted for the most recent LDL-C level measured during middle age and for other CVD risk factors, the hazard ratios for CHD were as follows: 1.57 (95% CI, 1.10-2.23; P for trend = .01) for cumulative LDL-C level, 1.69 (95% CI, 1.23-2.31; P for trend <.001) for TWA LDL-C level, and 0.88 (95% CI, 0.69-1.12; P for trend = .28) for LDL-C slope. No association was found between any of the LDL-C variables and ischemic stroke or HF.

Conclusions:
and relevance
This cohort study showed that cumulative LDL-C and TWA LDL-C during young adulthood and middle age were associated with the risk of incident CHD, independent of midlife LDL-C level. These findings suggest that past levels of LDL-C may inform strategies for primary prevention of CHD and that maintaining optimal LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic CVD.



JAMA Cardiol: 21 Sep 2021; epub ahead of print
Zhang Y, Pletcher MJ, Vittinghoff E, Clemons AM, ... de Ferranti SD, Moran AE
JAMA Cardiol: 21 Sep 2021; epub ahead of print | PMID: 34550307
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Impact:
Abstract

Association of Myocardial Blood Flow Reserve With Adverse Left Ventricular Remodeling in Patients With Aortic Stenosis: The Microvascular Disease in Aortic Stenosis (MIDAS) Study.

Zhou W, Sun YP, Divakaran S, Bajaj NS, ... O\'Gara P, Di Carli MF
Importance
Impaired myocardial flow reserve (MFR) and stress myocardial blood flow (MBF) on positron emission tomography (PET) myocardial perfusion imaging may identify adverse myocardial characteristics, including myocardial stress and injury in aortic stenosis (AS).
Objective
To investigate whether MFR and stress MBF are associated with LV structure and function derangements, and whether these parameters improve after aortic valve replacement (AVR).
Design, setting, and participants
In this single-center prospective observational study in Boston, Massachusetts, from 2018 to 2020, patients with predominantly moderate to severe AS underwent ammonia N13 PET myocardial perfusion imaging for myocardial blood flow (MBF) quantification, resting transthoracic echocardiography (TTE) for assessment of myocardial structure and function, and measurement of circulating biomarkers for myocardial injury and wall stress. Evaluation of health status and functional capacity was also performed. A subset of patients underwent repeated assessment 6 months after AVR. A control group included patients without AS matched for age, sex, and summed stress score who underwent symptom-prompted ammonia N13 PET and TTE within 90 days.
Exposures
MBF and MFR quantified on ammonia N13 PET myocardial perfusion imaging.
Main outcomes and measures
LV structure and function parameters, including echocardiographic global longitudinal strain (GLS), circulating high-sensitivity troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), health status, and functional capacity.
Results
There were 34 patients with AS (1 mild, 9 moderate, and 24 severe) and 34 matched control individuals. MFR was independently associated with GLS and LV ejection fraction, (β,-0.31; P = .03; β, 0.41; P = .002, respectively). Stress MBF was associated with hs-cTnT (unadjusted β, -0.48; P = .005) and log NT-pro BNP (unadjusted β, -0.37; P = .045). The combination of low stress MBF and high hs-cTnT was associated with higher interventricular septal thickness in diastole, relative wall thickness, and worse GLS compared with high stress MBF and low hs-cTnT (12.4 mm vs 10.0 mm; P = .008; 0.62 vs 0.46; P = .02; and -13.47 vs -17.11; P = .006, respectively). In 9 patients studied 6 months after AVR, mean (SD) MFR improved from 1.73 (0.57) to 2.11 (0.50) (P = .008).

Conclusions:
and relevance
In this study, in AS, MFR and stress MBF were associated with adverse myocardial characteristics, including markers of myocardial injury and wall stress, suggesting that MFR may be an early sensitive marker for myocardial decompensation.



JAMA Cardiol: 14 Sep 2021; epub ahead of print
Zhou W, Sun YP, Divakaran S, Bajaj NS, ... O'Gara P, Di Carli MF
JAMA Cardiol: 14 Sep 2021; epub ahead of print | PMID: 34524397
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Impact:
Abstract

Potential Implications of Expanded US Food and Drug Administration Labeling for Sacubitril/Valsartan in the US.

Vaduganathan M, Claggett BL, Greene SJ, Aggarwal R, ... Fonarow GC, Solomon SD
Importance
The US Food and Drug Administration (FDA) expanded labeling for sacubitril/valsartan for use in individuals with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal. The population-level implications of implementation of sacubitril/valsartan at higher LVEF ranges is unknown. While the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial did not meet its primary end point, the trial may provide useful information in projecting expected clinical events among treated individuals.
Objective
To quantify newly eligible treatment candidates for sacubitril/valsartan under the expanded FDA labeling and to apply treatment effects and the number needed to treat (NNT) to prevent 1 worsening HF event derived from subgroups of the PARAGON-HF trial who fall under the revised FDA label.
Design, setting, and participants
Newly eligible treatment candidates were estimated by mapping the LVEF distribution from 559 520 adult patients hospitalized between 2014 and 2019 in the Get With The Guidelines-Heart Failure registry to adults self-identifying with HF in the National Health and Nutrition Examination Survey (2015 to 2018). The NNT with 3 years of treatment for 3 end points of interest (total HF hospitalizations, total HF hospitalizations and cardiovascular death, and total HF hospitalizations and urgent HF visits and cardiovascular death) were estimated from the PARAGON-HF trial. Data were analyzed from February to June 2021.
Main outcomes and measures
Number of worsening HF events prevented or postponed if eligible patients were treated with sacubitril/valsartan for 3 years.
Results
Of an estimated 4 682 098 adults, the mean (SE) age was 66.3 (0.8) years, 1 995 037 (42.6%) were women, and 748 045 (16.0%) were Black. The potential number of adults projected to be newly eligible varied by the definition of FDA labeling of lower than normal LVEF from 643 161 (95% CI, 534 433-751 888; LVEF of 41% to 50%) to 1 838 756 (95% CI, 1 527 911-2 149 601; LVEF of 41% to 60%). In the PARAGON-HF trial, the NNT to prevent a worsening HF event (range, 7 to 12 patients) was consistent irrespective of specific LVEF range selected. Comprehensive implementation of sacubitril/valsartan among newly eligible patients was empirically estimated to prevent up to 69 268 (95% CI, 57 558-80 978) worsening HF events (LVEF of 41% to 50%) to 182 592 (95% CI, 151 725-213 460) worsening HF events (LVEF of 41% to 60%).

Conclusions:
and relevance
The expanded FDA labeling is positioned to substantially increase the potential HF population eligible for sacubitril/valsartan by up to 1.8 million individuals and has the potential to prevent or postpone as many as 180 000 worsening HF events, depending on the definition of normal LVEF.



JAMA Cardiol: 14 Sep 2021; epub ahead of print
Vaduganathan M, Claggett BL, Greene SJ, Aggarwal R, ... Fonarow GC, Solomon SD
JAMA Cardiol: 14 Sep 2021; epub ahead of print | PMID: 34524394
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Impact:
Abstract

Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.

Yoneda ZT, Anderson KC, Quintana JA, O\'Neill MJ, ... Roden DM, Shoemaker MB
Importance
Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome.
Objective
To examine the results of genetic testing for early-onset AF.
Design, setting, and participants
This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute\'s Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021.
Exposures
Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories.
Main outcomes and measures
Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders.
Results
Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8).

Conclusions:
and relevance
In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.



JAMA Cardiol: 07 Sep 2021; epub ahead of print
Yoneda ZT, Anderson KC, Quintana JA, O'Neill MJ, ... Roden DM, Shoemaker MB
JAMA Cardiol: 07 Sep 2021; epub ahead of print | PMID: 34495297
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Impact:
Abstract

Gender Differences in Medicare Payments Among Cardiologists.

Raber I, Al Rifai M, McCarthy CP, Vaduganathan M, ... Mehran R, McEvoy JW
Importance
Women cardiologists receive lower salaries than men; however, it is unknown whether US Centers for Medicare & Medicaid Services (CMS) reimbursement also differs by gender and contributes to the lower salaries.
Objective
To determine whether gender differences exist in the reimbursements, charges, and reimbursement per charge from CMS.
Design, setting, and participants
This cross-sectional analysis used the CMS database to obtain 2016 reimbursement data for US cardiologists. These included reimbursements to cardiologists, charges submitted, and unique billing codes. Gender differences in reimbursement for evaluation and management and procedural charges from both inpatient and outpatient settings were also assessed. Analysis took place between April 2019 and December 2020.
Main outcomes and measures
Outcomes included median CMS payments received and median charges submitted in the inpatient and outpatient settings in 2016.
Results
In 2016, 17 524 cardiologists (2312 women [13%] and 15 212 men [87%]) received CMS payments in the inpatient setting, and 16 929 cardiologists (2151 women [13%] and 14 778 men [87%]) received CMS payments in the outpatient setting. Men received higher median payments in the inpatient (median [interquartile range], $62 897 [$30 904-$104 267] vs $45 288 [$21 371-$73 191]; P < .001) and outpatient (median [interquartile range], $91 053 [$34 820-$196 165] vs $51 975 [$15 622-$120 175]; P < .001) practice settings. Men submitted more median charges in the inpatient (median [interquartile range], 1190 [569-2093] charges vs 959 [569-2093] charges; P < .001) and outpatient settings (median [interquartile range], 1685 [644-3328] charges vs 870 [273-1988] charges; P < .001). In a multivariable-adjusted linear regression analysis, women received less CMS payments compared with men (log-scale β = -0.06; 95% CI, -0.11 to -0.02) after adjustment for number of charges, number of unique billing codes, complexity of patient panel, years since graduation of physicians, and physician subspecialty. Payment by billing codes, both inpatient and outpatient, did not differ by gender.

Conclusions:
and relevance
There may be potential differences in CMS payments between men and women cardiologists, which appear to stem from gender differences in the number and types of charges submitted. The mechanisms behind these differences merit further research, both to understand why such gender differences exist and also to facilitate reductions in pay disparities.



JAMA Cardiol: 07 Sep 2021; epub ahead of print
Raber I, Al Rifai M, McCarthy CP, Vaduganathan M, ... Mehran R, McEvoy JW
JAMA Cardiol: 07 Sep 2021; epub ahead of print | PMID: 34495296
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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: 31 Aug 2021; 6:1023-1031
White HD, O'Brien SM, Alexander KP, Boden WE, ... Hochman JS, Maron DJ
JAMA Cardiol: 31 Aug 2021; 6:1023-1031 | PMID: 33938917
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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: 31 Aug 2021; 6:1032-1041
Vogel B, Baber U, Cohen DJ, Sartori S, ... Huber K, Mehran R
JAMA Cardiol: 31 Aug 2021; 6:1032-1041 | PMID: 33991416
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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: 31 Aug 2021; 6:1050-1059
Peterson GG, Pu J, Magid DJ, Barterian L, ... McCall N, Markovich P
JAMA Cardiol: 31 Aug 2021; 6:1050-1059 | PMID: 34076665
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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: 31 Aug 2021; 6:1069-1077
Bhattacharya R, Zekavat SM, Uddin MM, Pirruccello J, ... Bick A, Natarajan P
JAMA Cardiol: 31 Aug 2021; 6:1069-1077 | 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: 31 Aug 2021; 6:1000-1011
Machipisa T, Chong M, Muhamed B, Chishala C, ... Engel ME, Paré G
JAMA Cardiol: 31 Aug 2021; 6:1000-1011 | PMID: 34106200
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Impact:
Abstract

Associations of High-Sensitivity Troponin and Natriuretic Peptide Levels With Outcomes After Intensive Blood Pressure Lowering: Findings From the SPRINT Randomized Clinical Trial.

Berry JD, Nambi V, Ambrosius WT, Chen H, ... Ballantyne CM, de Lemos JA
Importance
Elevated high-sensitivity cardiac troponin T (hscTnT) and N-terminal pro-B-type natriuretic peptide (NTproBNP) levels are associated with risk of heart failure (HF) and mortality among individuals in the general population. However, it is unknown if this risk is modifiable.
Objective
To test the hypothesis that elevated hscTnT and NTproBNP levels would identify individuals with the greatest risk for mortality and HF and the largest benefit associated with intensive systolic blood pressure (SBP) lowering.
Design, setting, and participants
This is a nonprespecified post hoc analysis of the multicenter, prospective, randomized clinical Systolic Blood Pressure Intervention Trial (SPRINT), conducted from October 20, 2010, to August 20, 2015. A total of 9361 patients without diabetes with increased risk for cardiovascular disease were randomized to receive intensive vs standard SBP lowering. Statistical analysis was performed on an intention-to-treat basis from September 30, 2019, to July 29, 2021.
Interventions
Participants were randomized to undergo intensive (<120 mm Hg) or standard (<140 mm Hg) SBP lowering. High-sensitivity cardiac troponin T and NTproBNP levels were measured from stored specimens collected at enrollment, with elevated levels defined as 14 ng/L or more for hscTnT (to convert to micrograms per liter, multiply by 0.001) and 125 pg/mL or more for NTproBNP (to convert to nanograms per liter, multiply by 1.0).
Main outcomes and measures
The primary outcome of this ancillary study was HF and mortality.
Results
Of the 9361 participants enrolled in SPRINT, 8828 (5578 men [63.2%]; mean [SD] age, 68.0 [9.5] years) had measured hscTnT levels and 8836 (5585 men [63.2%]; mean [SD] age, 68.0 [9.5] years) had measured NTproBNP levels; 2262 of 8828 patients (25.6%) had elevated hscTnT levels, 3371 of 8836 patients (38.2%) had elevated NTproBNP, and 1411 of 8828 patients (16.0%) had both levels elevated. Randomization to the intensive SBP group led to a 4.9% (95% CI, 1.7%-7.5%) absolute risk reduction (ARR) over 4 years in death and HF (421 events) for those with elevated hscTnT and a 1.7% (95% CI, 0.7%-2.5%) ARR for those without elevated levels. Similarly, for those with elevated NTproBNP, the ARR for death and HF over 4 years was 4.6% (95% CI, 2.3%-6.5%) vs 1.8% (95% CI, 0.9%-2.5%) in those without elevated levels. For those with elevated levels of both biomarkers, the ARR for death and HF over 4 years was 7.8% (95% CI, 3.3%-11.3%) vs 1.7% (95% CI, 0.8%-2.3%) in those with neither biomarker elevated. No significant treatment group by biomarker category interactions were detected.

Conclusions:
and relevance
Intensive SBP control led to large absolute differences in death and HF among patients with abnormal hscTnT and NTproBNP levels. These findings demonstrate that risk associated with elevation of these biomarkers is modifiable with intensive BP control. A prospective, randomized clinical trial is needed to evaluate whether these biomarkers may help guide selection of patients for intensive SBP lowering.
Trial registration
ClinicalTrials.gov Identifier: NCT01206062.



JAMA Cardiol: 31 Aug 2021; epub ahead of print
Berry JD, Nambi V, Ambrosius WT, Chen H, ... Ballantyne CM, de Lemos JA
JAMA Cardiol: 31 Aug 2021; epub ahead of print | PMID: 34468696
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Impact:
Abstract

Effect of Goal-Setting Approaches Within a Gamification Intervention to Increase Physical Activity Among Economically Disadvantaged Adults at Elevated Risk for Major Adverse Cardiovascular Events: The ENGAGE Randomized Clinical Trial.

Patel MS, Bachireddy C, Small DS, Harrison JD, ... Snider CK, Volpp KG
Importance
Health promotion efforts commonly communicate goals for healthy behavior, but the best way to design goal setting among high-risk patients has not been well examined.
Objective
To test the effectiveness of different ways to set and implement goals within a behaviorally designed gamification intervention to increase physical activity.
Design, setting, and participants
Evaluation of the Novel Use of Gamification With Alternative Goal-setting Experiences was conducted from January 15, 2019, to June 1, 2020. The 24-week randomized clinical trial included a remotely monitored 8-week introductory intervention period, 8-week maintenance intervention period, and 8-week follow-up period. A total of 500 adults from lower-income neighborhoods in and around Philadelphia, Pennsylvania, who had either an atherosclerotic cardiovascular disease (ASCVD) condition or a 10-year ASCVD risk score greater than or equal to 7.5% were enrolled. Participants were paid for enrolling in and completing the trial.
Interventions
All participants used a wearable device to track daily steps, established a baseline level, and were then randomly assigned to an attention control or 1 of 4 gamification interventions that varied only on how daily step goals were set (self-chosen or assigned) and implemented (immediately or gradually).
Main outcome measures
The primary outcome was change in mean daily steps from baseline to the 8-week maintenance intervention period. Other outcomes included changes in minutes of moderate to vigorous physical activity. All randomly assigned participants were included in the intention-to-treat analysis.
Results
Of the 500 participants, 331 individuals (66.2%) were Black, 114 were White (22.8%), and 348 were women (69.6%). Mean (SD) age was 58.5 (10.8) years and body mass index was 33.2 (7.8). A total of 215 participants (43.0%) had an ASCVD condition. Compared with the control arm, participants with self-chosen and immediate goals had significant increases in the number of daily steps during the maintenance intervention period (1384; 95% CI, 805-1963; P < .001) that were sustained during the 8-week follow-up (1391; 95% CI, 785-1998; P < .001). This group also had significant increases in daily minutes of moderate to vigorous physical activity during the maintenance intervention (4.1; 95% CI, 1.8-6.4; P < .001) that were sustained during follow-up (3.5; 95% CI, 1.1-5.8; P = .004). No other gamification arms had consistent increases in physical activity compared with the control arm. No major adverse events were reported.

Conclusions:
and relevance
In this trial among economically disadvantaged adults at elevated risk for major adverse cardiovascular events, a gamification intervention led to increases in physical activity that were sustained during 8 weeks of follow-up when goals were self-chosen and implemented immediately.
Trial registration
ClinicalTrials.gov Identifier: NCT03749473.



JAMA Cardiol: 31 Aug 2021; epub ahead of print
Patel MS, Bachireddy C, Small DS, Harrison JD, ... Snider CK, Volpp KG
JAMA Cardiol: 31 Aug 2021; epub ahead of print | PMID: 34468691
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Impact:
Abstract

Interleukin 6 and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Chronic Coronary Syndrome.

Batra G, Ghukasyan Lakic T, Lindbäck J, Held C, ... Wallentin L, STABILITY Investigators
Importance
Inflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease.
Objective
To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function.
Design, setting, and participants
This multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020.
Exposures
Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (<2.0 ng/L vs ≥2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [≥90 mL/min/1.73 m2], mildly decreased eGFR level [60-90 mL/min/1.73 m2], and moderately to severely decreased eGFR level [<60 mL/min/1.73 m2]).
Main outcomes and measures
Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke.
Results
This substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata. Using predefined strata, elevated IL-6 level (≥2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99]).

Conclusions:
and relevance
In patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment.



JAMA Cardiol: 24 Aug 2021; epub ahead of print
Batra G, Ghukasyan Lakic T, Lindbäck J, Held C, ... Wallentin L, STABILITY Investigators
JAMA Cardiol: 24 Aug 2021; epub ahead of print | PMID: 34431970
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Impact:
Abstract

Prevalence of Transthyretin Amyloid Cardiomyopathy in Heart Failure With Preserved Ejection Fraction.

AbouEzzeddine OF, Davies DR, Scott CG, Fayyaz AU, ... Grogan M, Redfield MM
Importance
Heart failure (HF) with preserved ejection fraction (HFpEF) is common, is frequently associated with ventricular wall thickening, and has no effective therapy. Transthyretin amyloid cardiomyopathy (ATTR-CM) can cause the HFpEF clinical phenotype, has highly effective therapy, and is believed to be underrecognized.
Objective
To examine the prevalence of ATTR-CM without and with systematic screening in patients with HFpEF and ventricular wall thickening.
Design, setting, and participants
This population-based cohort study assessed ATTR-CM prevalence in 1235 consecutive patients in southeastern Minnesota with HFpEF both without (prospectively identified cohort study) and with (consenting subset of cohort study, n = 286) systematic screening. Key entry criteria included validated HF diagnosis, age of 60 years or older, ejection fraction of 40% or greater, and ventricular wall thickness of 12 mm or greater. In this community cohort of 1235 patients, 884 had no known ATTR-CM, contraindication to technetium Tc 99m pyrophosphate scanning, or other barriers to participation in the screening study. Of these 884 patients, 295 consented and 286 underwent scanning between October 5, 2017, and March 9, 2020 (community screening cohort).
Exposures
Medical record review or technetium Tc 99m pyrophosphate scintigraphy and reflex testing for ATTR-CM diagnosis.
Main outcomes and measures
The ATTR-CM prevalence by strategy (clinical diagnosis or systematic screening), age, and sex.
Results
A total of 1235 patients participated in the study, including a community cohort (median age, 80 years; interquartile range, 72-87 years; 630 [51%] male) and a community screening cohort (n = 286; median age, 78 years; interquartile range, 71-84 years; 150 [52%] male). In the 1235 patients in the community cohort without screening group, 16 patients (1.3%; 95% CI, 0.7%-2.1%) had clinically recognized ATTR-CM. The prevalence was 2.5% (95% CI, 1.4%-4.0%) in men and 0% (95% CI, 0.0%-0.6%) in women. In the 286 patients in the community screening cohort, 18 patients (6.3%; 95% CI, 3.8%-9.8%) had ATTR-CM. Prevalence increased with age from 0% in patients 60 to 69 years of age to 21% in patients 90 years and older (P < .001). Adjusting for age, ATTR-CM prevalence differed by sex, with 15 of 150 men (10.0%; 95% CI, 5.7%-16.1%) and 3 of 136 women (2.2%; 95% CI, 0.4%-6.3%) having ATTR-CM (P = .002).

Conclusions:
and relevance
In this cohort study based in a community-based setting, ATTR-CM was present in a substantial number of cases of HFpEF with ventricular wall thickening, particularly in older men. These results suggest that systematic evaluation can increase the diagnosis of ATTR-CM, thereby providing therapeutically relevant phenotyping of HFpEF.



JAMA Cardiol: 24 Aug 2021; epub ahead of print
AbouEzzeddine OF, Davies DR, Scott CG, Fayyaz AU, ... Grogan M, Redfield MM
JAMA Cardiol: 24 Aug 2021; epub ahead of print | PMID: 34431962
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Impact:
Abstract

Association of Atrial Fibrillation Burden With Health-Related Quality of Life After Atrial Fibrillation Ablation: Substudy of the Cryoballoon vs Contact-Force Atrial Fibrillation Ablation (CIRCA-DOSE) Randomized Clinical Trial.

Samuel M, Khairy P, Champagne J, Deyell MW, ... Tardif JC, Andrade JG
Importance
Patients with atrial fibrillation (AF) have impaired health-related quality of life primarily owing to symptoms related to AF episodes; however, quality of life can be influenced by AF therapies, AF complications, the frequency of follow-up visits and hospitalizations, illness perceptions, and patient factors, such as anxiety or depression.
Objective
To determine the association between change in AF burden and quality of life in the year following ablation.
Design, setting, and participants
The current study is a secondary analysis of a prospective, parallel-group, multicenter, single-masked randomized clinical trial (Cryoballoon vs Irrigated Radiofrequency Catheter Ablation: Double Short vs Standard Exposure Duration [CIRCA-DOSE] study), which took place at 8 Canadian centers. Between September 2014 and July 2017, 346 patients older than 18 years with symptomatic, primarily low-burden AF refractory to antiarrhythmic therapy referred for first catheter ablation were enrolled. All patients received an implantable cardiac monitor at least 30 days before ablation and were followed up with up to December 2018. Data were analyzed from April 2020 to June 2021.
Interventions
Patients were randomized 1:1:1 to contact force-guided radiofrequency ablation, 4-minute cryoballoon ablation, or 2-minute cryoballoon ablation. The exposure in the present analysis is the absolute difference in AF burden prior to ablation and 12 months following ablation, as evaluated by the Atrial Fibrillation Effect on Quality of Life (AFEQT) Score.
Main outcomes and measures
Absolute difference in quality of life from baseline to 12 months postablation.
Results
Of 346 included patients, 231 (66.7%) were male, and the median (interquartile range) age was 60 (52-66) years. A total of 328 patients (94.8%) had paroxysmal AF. The median (interquartile range) preablation AF burden was 2.0% (0.1-11.9), and the AF burden decreased to 0% at 12 months postablation. At 12 months, a 1-point improvement in AFEQT score was observed for every absolute reduction in daily AF burden of 15.8 minutes (95% CI, 7.2-24.4; P < .001), or every 0.63% (95% CI, 0.30-0.95; P < .001) reduction in relative AF burden from baseline.

Conclusions:
and relevance
In patients with primarily low-burden paroxysmal AF, the reduction in AF burden following ablation may be associated with a clinically meaningful improvement in quality of life.
Trial registration
ClinicalTrials.gov Identifier: NCT01913522.



JAMA Cardiol: 17 Aug 2021; epub ahead of print
Samuel M, Khairy P, Champagne J, Deyell MW, ... Tardif JC, Andrade JG
JAMA Cardiol: 17 Aug 2021; epub ahead of print | PMID: 34406350
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Impact:
Abstract

Association of Statin Treatment With Progression of Coronary Atherosclerotic Plaque Composition.

van Rosendael AR, van den Hoogen IJ, Gianni U, Ma X, ... Bax JJ, Chang HJ
Importance
The density of atherosclerotic plaque forms the basis for categorizing calcified and noncalcified morphology of plaques.
Objective
To assess whether alterations in plaque across a range of density measurements provide a more detailed understanding of atherosclerotic disease progression.
Design, setting, and participants
This cohort study enrolled 857 patients who underwent serial coronary computed tomography angiography 2 or more years apart and had quantitative measurements of coronary plaques throughout the entire coronary artery tree. The study was conducted from 2013 to 2016 at 13 sites in 7 countries.
Main outcomes and measures
The main outcome was progression of plaque composition of individual coronary plaques. Six plaque composition types were defined on a voxel-level basis according to the plaque attenuation (expressed in Hounsfield units [HU]): low attenuation (-30 to 75 HU), fibro-fatty (76-130 HU), fibrous (131-350 HU), low-density calcium (351-700 HU), high-density calcium (701-1000 HU), and 1K (>1000 HU). The progression rates of these 6 compositional plaque types were evaluated according to the interaction between statin use and baseline plaque volume, adjusted for risk factors and time interval between scans. Plaque progression was also examined based on baseline calcium density. Analysis was performed among lesions matched at baseline and follow-up. Data analyses were conducted from August 2019 through March 2020.
Results
In total, 2458 coronary lesions in 857 patients (mean [SD] age, 62.1 [8.7] years; 540 [63.0%] men; 548 [63.9%] received statin therapy) were included. Untreated coronary lesions increased in volume over time for all 6 compositional types. Statin therapy was associated with volume decreases in low-attenuation plaque (β, -0.02; 95% CI, -0.03 to -0.01; P = .001) and fibro-fatty plaque (β, -0.03; 95% CI, -0.04 to -0.02; P < .001) and greater progression of high-density calcium plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001) and 1K plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001). When analyses were restricted to lesions without low-attenuation plaque or fibro-fatty plaque at baseline, statin therapy was not associated with a change in overall calcified plaque volume (β, -0.03; 95% CI, -0.08 to 0.02; P = .24) but was associated with a transformation toward more dense calcium. Interaction analysis between baseline plaque volume and calcium density showed that more dense coronary calcium was associated with less plaque progression.

Conclusions:
and relevance
The results suggest an association of statin use with greater rates of transformation of coronary atherosclerosis toward high-density calcium. A pattern of slower overall plaque progression was observed with increasing density. All findings support the concept of reduced atherosclerotic risk with increased densification of calcium.



JAMA Cardiol: 17 Aug 2021; epub ahead of print
van Rosendael AR, van den Hoogen IJ, Gianni U, Ma X, ... Bax JJ, Chang HJ
JAMA Cardiol: 17 Aug 2021; epub ahead of print | PMID: 34406326
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Impact:
Abstract

Genomic Autopsy of Sudden Deaths in Young Individuals.

Webster G, Puckelwartz MJ, Pesce LL, Dellefave-Castillo LM, ... George AL, McNally EM
Importance
Postmortem genetic testing of young individuals with sudden death has previously identified pathogenic gene variants. However, prior studies primarily considered highly penetrant monogenic variants, often without detailed decedent and family clinical information.
Objective
To assess genotype and phenotype risk in a diverse cohort of young decedents with sudden death and their families.
Design, setting, and participants
Pathological and whole-genome sequence analysis was conducted in a cohort referred from a national network of medical examiners. Cases were accrued prospectively from May 2015 to March 2019 across 24 US states. Analysis began September 2016 and ended November 2020.
Exposures
Evaluation of autopsy and clinical data integrated with whole-genome sequence data and family member evaluation.
Results
A total of 103 decedents (mean [SD] age at death, 23.7 [11.9] years; age range, 1-44 years), their surviving family members, and 140 sex- and genetic ancestry-matched controls were analyzed. Among 103 decedents, autopsy and clinical data review categorized 36 decedents with postmortem diagnoses, 23 decedents with findings of uncertain significance, and 44 with sudden unexplained death. Pathogenic/likely pathogenic (P/LP) genetic variants in arrhythmia or cardiomyopathy genes were identified in 13 decedents (12.6%). A multivariable analysis including decedent phenotype, ancestry, and sex demonstrated that younger decedents had a higher burden of P/LP variants and select variants of uncertain significance (effect size, -1.64; P = .001). These select, curated variants of uncertain significance in cardiac genes were more common in decedents than controls (83 of 103 decedents [86%] vs 100 of 140 controls [71%]; P = .005), and decedents harbored more rare cardiac variants than controls (2.3 variants per individual vs 1.8 in controls; P = .006). Genetic testing of 31 parent-decedent trios and 14 parent-decedent dyads revealed 8 transmitted P/LP variants and 1 de novo P/LP variant. Incomplete penetrance was present in 6 of 8 parents who transmitted a P/LP variant.

Conclusions:
and relevance
Whole-genome sequencing effectively identified P/LP variants in cases of sudden death in young individuals, implicating both arrhythmia and cardiomyopathy genes. Genomic analyses and familial phenotype association suggest potentially additive, oligogenic risk mechanisms for sudden death in this cohort.



JAMA Cardiol: 10 Aug 2021; epub ahead of print
Webster G, Puckelwartz MJ, Pesce LL, Dellefave-Castillo LM, ... George AL, McNally EM
JAMA Cardiol: 10 Aug 2021; epub ahead of print | PMID: 34379075
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Impact:
Abstract

Sex Differences in Procedural Outcomes Among Patients Undergoing Left Atrial Appendage Occlusion: Insights From the NCDR LAAO Registry.

Darden D, Duong T, Du C, Munir MB, ... Freeman JV, Hsu JC
Importance
Left atrial appendage occlusion (LAAO) has emerged as an alternative to anticoagulation for select patients with atrial fibrillation; however, women have been underrepresented in clinical trials of LAAO, and sex-specific subanalyses are limited.
Objective
To evaluate the sex differences in the baseline characteristics of patients undergoing LAAO implant and in the in-hospital outcomes after LAAO implant.
Design, setting, and participants
A total of 49 357 patients in the National Cardiovascular Data Registry LAAO Registry undergoing LAAO with the Watchman device between January 1, 2016, and June 30, 2019, were included in this study.
Exposure
Female or male sex.
Main outcomes and measures
The primary outcomes were aborted or canceled procedure, major adverse event, any adverse event, prolonged hospital stay longer than 1 day, and death. Unadjusted and multivariable adjusted logistic regression analyses were performed to assess sex differences in in-hospital adverse events.
Results
In this cohort study of 49 357 patients (mean [SD] age, 76.1 [8.0] years), 20 388 women (41.3%) and 28 969 (58.7%) men underwent LAAO. Compared with men, women were older and had a higher prevalence of paroxysmal atrial fibrillation, prior stroke, and uncontrolled hypertension but a lower prevalence of congestive heart failure, diabetes, and coronary artery disease. After multivariable adjustment, there were no differences in aborted or canceled procedures between women and men (613 [3.0%] vs 851 [2.9%]; odds ratio [OR] 1.01, 95% CI, 0.90-1.13). Women were more likely than men to experience any adverse event (1284 [6.3%] vs 1144 [3.9%]; P < .001; OR, 1.63; 95% CI, 1.49-1.77; P < .001) or major adverse event (827 [4.1%] vs 567 [2.0%]; P < .001; OR, 2.06; 95% CI, 1.82-2.34; P < .001) owing to pericardial effusion requiring drainage (241 [1.2%] vs 144 [0.5%]) or major bleeding (349 [1.7%] vs 244 [0.8%]). Women were also more likely than men to experience a hospital stay longer than 1 day (3272 [16.0%] vs 3355 [11.6%]; P < .001; adjusted OR, 1.46; 95% CI, 1.38-1.54; P < .001) or death (adjusted OR, 2.01; 95% CI, 1.31-3.09; P = .001), although death was rare and absolute differences were minimal (58 [0.3%] vs 37 [0.1%]; P < .001).

Conclusions:
and relevance
This study suggests that, compared with men, women have a significantly higher risk of in-hospital adverse events after LAAO. Further research aimed at risk reduction, particularly strategies to reduce the risk of pericardial effusion and major bleeding, in women undergoing LAAO is warranted.



JAMA Cardiol: 10 Aug 2021; epub ahead of print
Darden D, Duong T, Du C, Munir MB, ... Freeman JV, Hsu JC
JAMA Cardiol: 10 Aug 2021; epub ahead of print | PMID: 34379072
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Impact:
Abstract

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

Dionne A, Sperotto F, Chamberlain S, Baker AL, ... Newburger JW, Friedman KG
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.



JAMA Cardiol: 09 Aug 2021; epub ahead of print
Dionne A, Sperotto F, Chamberlain S, Baker AL, ... Newburger JW, Friedman KG
JAMA Cardiol: 09 Aug 2021; epub ahead of print | PMID: 34374740
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Impact:
Abstract

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

Rizk JG, Gupta A, Sardar P, Henry BM, ... Lippi G, Lavie CJ
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.



JAMA Cardiol: 09 Aug 2021; epub ahead of print
Rizk JG, Gupta A, Sardar P, Henry BM, ... Lippi G, Lavie CJ
JAMA Cardiol: 09 Aug 2021; epub ahead of print | PMID: 34374713
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Impact:
Abstract

Blood DNA Methylation and Incident Coronary Heart Disease: Evidence From the Strong Heart Study.

Navas-Acien A, Domingo-Relloso A, Subedi P, Riffo-Campos AL, ... Zhao J, Cole SA
Importance
American Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions.
Objective
To investigate the association of blood DNA methylation (DNAm) with incident CHD using a large number of methylation sites (cytosine-phosphate-guanine [CpG]) in a single model.
Design, setting, and participants
This prospective study, including a discovery cohort (the Strong Heart Study [SHS]) and 4 additional cohorts (the Women\'s Health Initiative [WHI], the Framingham Heart Study [FHS], the Atherosclerosis Risk in Communities Study ([ARIC]-Black, and ARIC-White), evaluated 12 American Indian communities in 4 US states; African American women, Hispanic women, and White women throughout the US; White men and White women from Massachusetts; and Black men and women and White men and women from 4 US communities. A total of 2321 men and women (mean [SD] follow-up, 19.1 [9.2] years) were included in the SHS, 1874 women (mean [SD] follow-up, 15.8 [5.9] years) in the WHI, 2128 men and women (mean [SD] follow-up, 7.7 [1.8] years) in the FHS, 2114 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-Black, and 931 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-White. Data were collected from May 1989 to December 2018 and analyzed from February 2019 to May 2021.
Exposure
Blood DNA methylation.
Main outcome and measure
Using a high-dimensional time-to-event elastic-net model for the association of 407 224 CpG sites with incident CHD in the SHS (749 events), this study selected the differentially methylated CpG positions (DMPs) selected in the SHS and evaluated them in the WHI (531 events), FHS (143 events), ARIC-Black (350 events), and ARIC-White (121 events) cohorts.
Results
The median (IQR) age of participants in SHS was 55 (49-62) years, and 1359 participants (58.6%) were women. Elastic-net models selected 505 DMPs associated with incident CHD in the SHS beyond established risk factors, center, blood cell counts, and genetic principal components. Among those DMPs, 33 were commonly selected in 3 or 4 of the other cohorts and the pooled hazard ratios from the standard Cox models were significant at P < .05 for 10 of the DMPs. For example, the hazard ratio (95% CI) for CHD comparing the 90th and 10th percentiles of differentially methylated CpGs was 0.86 (0.78-0.95) for cg16604233 (tagged to COL11A2) and 1.23 (1.08-1.39) for cg09926486 (tagged to FRMD5). Some of the DMPs were consistent in the direction of the association; others showed associations in opposite directions across cohorts. Untargeted independent elastic-net models of CHD showed distinct DMPs, genes, and network of genes in the 5 cohorts.

Conclusions:
and relevance
In this multi-cohort study, blood-based DNAm findings supported an association between a complex blood epigenomic signature and CHD that was largely different across populations.



JAMA Cardiol: 03 Aug 2021; epub ahead of print
Navas-Acien A, Domingo-Relloso A, Subedi P, Riffo-Campos AL, ... Zhao J, Cole SA
JAMA Cardiol: 03 Aug 2021; epub ahead of print | PMID: 34347013
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Impact:
Abstract

Effect of Exercise Training on Ambulatory Blood Pressure Among Patients With Resistant Hypertension: A Randomized Clinical Trial.

Lopes S, Mesquita-Bastos J, Garcia C, Bertoquini S, ... Alves AJ, Ribeiro F
Importance
Limited evidence suggests exercise reduces blood pressure (BP) in individuals with resistant hypertension, a clinical population with low responsiveness to drug therapy.
Objective
To determine whether an aerobic exercise training intervention reduces ambulatory BP among patients with resistant hypertension.
Design, settings, and participants
The Exercise Training in the Treatment of Resistant Hypertension (EnRicH) trial is a prospective, 2-center, single-blinded randomized clinical trial performed at 2 hospital centers in Portugal from March 2017 to December 2019. A total of 60 patients with a diagnosis of resistant hypertension aged 40 to 75 years were prospectively enrolled and observed at the hospitals\' hypertension outpatient clinic.
Interventions
Patients were randomly assigned in a 1:1 ratio to a 12-week moderate-intensity aerobic exercise training program (exercise group) or a usual care control group. The exercise group performed three 40-minute supervised sessions per week in addition to usual care.
Main outcomes and measures
The powered primary efficacy measure was 24-hour ambulatory systolic BP change from baseline. Secondary outcomes included daytime and nighttime ambulatory BP, office BP, and cardiorespiratory fitness.
Results
A total of 53 patients completed the study, including 26 in the exercise group and 27 in the control group. Of these, 24 (45%) were women, and the mean (SD) age was 60.1 (8.7) years. Compared with the control group, among those in the exercise group, 24-hour ambulatory systolic BP was reduced by 7.1 mm Hg (95% CI, -12.8 to -1.4; P = .02). Additionally, 24-hour ambulatory diastolic BP (-5.1 mm Hg; 95% CI, -7.9 to -2.3; P = .001), daytime systolic BP (-8.4 mm Hg; 95% CI, -14.3 to -2.5; P = .006), and daytime diastolic BP (-5.7 mm Hg; 95% CI, -9.0 to -2.4; P = .001) were reduced in the exercise group compared with the control group. Office systolic BP (-10.0 mm Hg; 95% CI, -17.6 to -2.5; P = .01) and cardiorespiratory fitness (5.05 mL/kg per minute of oxygen consumption; 95% CI, 3.5 to 6.6; P < .001) also improved in the exercise group compared with the control group.

Conclusions:
and relevance
A 12-week aerobic exercise program reduced 24-hour and daytime ambulatory BP as well as office systolic BP in patients with resistant hypertension. These findings provide clinicians with evidence to embrace moderate-intensity aerobic exercise as a standard coadjutant therapy targeting this patient population.
Trial registration
ClinicalTrials.gov Identifier: NCT03090529.



JAMA Cardiol: 03 Aug 2021; epub ahead of print
Lopes S, Mesquita-Bastos J, Garcia C, Bertoquini S, ... Alves AJ, Ribeiro F
JAMA Cardiol: 03 Aug 2021; epub ahead of print | PMID: 34347008
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Impact:
Abstract

Performance of a Convolutional Neural Network and Explainability Technique for 12-Lead Electrocardiogram Interpretation.

Hughes JW, Olgin JE, Avram R, Abreau SA, ... Gonzalez JE, Tison GH
Importance
Millions of clinicians rely daily on automated preliminary electrocardiogram (ECG) interpretation. Critical comparisons of machine learning-based automated analysis against clinically accepted standards of care are lacking.
Objective
To use readily available 12-lead ECG data to train and apply an explainability technique to a convolutional neural network (CNN) that achieves high performance against clinical standards of care.
Design, setting, and participants
This cross-sectional study was conducted using data from January 1, 2003, to December 31, 2018. Data were obtained in a commonly available 12-lead ECG format from a single-center tertiary care institution. All patients aged 18 years or older who received ECGs at the University of California, San Francisco, were included, yielding a total of 365 009 patients. Data were analyzed from January 1, 2019, to March 2, 2021.
Exposures
A CNN was trained to predict the presence of 38 diagnostic classes in 5 categories from 12-lead ECG data. A CNN explainability technique called LIME (Linear Interpretable Model-Agnostic Explanations) was used to visualize ECG segments contributing to CNN diagnoses.
Main outcomes and measures
Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were calculated for the CNN in the holdout test data set against cardiologist clinical diagnoses. For a second validation, 3 electrophysiologists provided consensus committee diagnoses against which the CNN, cardiologist clinical diagnosis, and MUSE (GE Healthcare) automated analysis performance was compared using the F1 score; AUC, sensitivity, and specificity were also calculated for the CNN against the consensus committee.
Results
A total of 992 748 ECGs from 365 009 adult patients (mean [SD] age, 56.2 [17.6] years; 183 600 women [50.3%]; and 175 277 White patients [48.0%]) were included in the analysis. In 91 440 test data set ECGs, the CNN demonstrated an AUC of at least 0.960 for 32 of 38 classes (84.2%). Against the consensus committee diagnoses, the CNN had higher frequency-weighted mean F1 scores than both cardiologists and MUSE in all 5 categories (CNN frequency-weighted F1 score for rhythm, 0.812; conduction, 0.729; chamber diagnosis, 0.598; infarct, 0.674; and other diagnosis, 0.875). For 32 of 38 classes (84.2%), the CNN had AUCs of at least 0.910 and demonstrated comparable F1 scores and higher sensitivity than cardiologists, except for atrial fibrillation (CNN F1 score, 0.847 vs cardiologist F1 score, 0.881), junctional rhythm (0.526 vs 0.727), premature ventricular complex (0.786 vs 0.800), and Wolff-Parkinson-White (0.800 vs 0.842). Compared with MUSE, the CNN had higher F1 scores for all classes except supraventricular tachycardia (CNN F1 score, 0.696 vs MUSE F1 score, 0.714). The LIME technique highlighted physiologically relevant ECG segments.

Conclusions:
and relevance
The results of this cross-sectional study suggest that readily available ECG data can be used to train a CNN algorithm to achieve comparable performance to clinical cardiologists and exceed the performance of MUSE automated analysis for most diagnoses, with some exceptions. The LIME explainability technique applied to CNNs highlights physiologically relevant ECG segments that contribute to the CNN\'s diagnoses.



JAMA Cardiol: 03 Aug 2021; epub ahead of print
Hughes JW, Olgin JE, Avram R, Abreau SA, ... Gonzalez JE, Tison GH
JAMA Cardiol: 03 Aug 2021; epub ahead of print | PMID: 34347007
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Impact:
Abstract

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

Agarwal MA, Fonarow GC, Ziaeian B
Importance
Previous 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 lacking.
Objectives
To 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 2017.
Design, setting, and participants
This 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 2020.
Exposures
Admission for a primary diagnosis of HF at discharge.
Main outcomes and measures
Unique 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 year.
Results
There 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 72.1 (95% CI, 72.0-72.3) years, and 48.9% (95% CI, 48.7-49.0) were women. The primary HF hospitalization rates per 1000 US adults declined from 4.4 in 2010 to 4.1 in 2013 and then increased from 4.2 in 2014 to 4.9 in 2017. The rates per 1000 US adults for postdischarge HF readmissions (1.0 in 2010 to 0.9 in 2014 to 1.1 in 2017) and all-cause 30-day readmissions (0.8 in 2010 to 0.7 in 2014 to 0.9 in 2017) had similar trends.

Conclusions:
and relevance
In 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.



JAMA Cardiol: 31 Jul 2021; 6:952-956
Agarwal MA, Fonarow GC, Ziaeian B
JAMA Cardiol: 31 Jul 2021; 6:952-956 | PMID: 33566058
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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: 31 Jul 2021; 6:957-962
Wohlfahrt P, Nativi-Nicolau J, Zhang M, Selzman CH, ... Spertus JA, Stehlik J
JAMA Cardiol: 31 Jul 2021; 6:957-962 | PMID: 33950162
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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: 31 Jul 2021; 6:880-888
Berman AN, Biery DW, Ginder C, Singh A, ... Bhatt DL, Blankstein R
JAMA Cardiol: 31 Jul 2021; 6:880-888 | 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: 31 Jul 2021; 6:936-944
Landes U, Witberg G, Sathananthan J, Kim WK, ... Kornowski R, Webb JG
JAMA Cardiol: 31 Jul 2021; 6:936-944 | 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: 31 Jul 2021; 6:918-925
Abdel-Qadir H, Singh SM, Pang A, Austin PC, ... Dorian P, Ko DT
JAMA Cardiol: 31 Jul 2021; 6:918-925 | 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: 31 Jul 2021; 6:963-970
Diaz CL, Shah NS, Lloyd-Jones DM, Khan SS
JAMA Cardiol: 31 Jul 2021; 6:963-970 | PMID: 34009231
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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: 31 Jul 2021; 6:926-935
Parizo JT, Goldhaber-Fiebert JD, Salomon JA, Khush KK, ... Heidenreich PA, Sandhu AT
JAMA Cardiol: 31 Jul 2021; 6:926-935 | 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: 31 Jul 2021; 6:902-909
Sturm AC, Truty R, Callis TE, Aguilar S, ... Vatta M, Rader DJ
JAMA Cardiol: 31 Jul 2021; 6:902-909 | PMID: 34037665
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Impact:
Abstract

Extrapolating Long-term Event-Free and Overall Survival With Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis of a Phase 3 Randomized Clinical Trial.

Docherty KF, Jhund PS, Claggett B, Ferreira JP, ... McMurray JJV, DAPA-HF Investigators and Committees
Importance
Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients.
Objective
To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient\'s lifetime.
Design, setting, and participants
Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months.
Interventions
Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy.
Main outcomes and measures
The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient\'s lifetime for the primary outcome and the secondary outcome of death from any cause.
Results
A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival.

Conclusions:
and relevance
These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF.
Trial registration
ClinicalTrials.gov Identifier: NCT03036124.



JAMA Cardiol: 27 Jul 2021; epub ahead of print
Docherty KF, Jhund PS, Claggett B, Ferreira JP, ... McMurray JJV, DAPA-HF Investigators and Committees
JAMA Cardiol: 27 Jul 2021; epub ahead of print | PMID: 34319398
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Impact:

This program is still in alpha version.